Chapter 7 (Updated 10/26/12)
Type 1 Diabetes Mellitus of Man: Genetic
Susceptibility and Resistance
1.
Barbara Davis Center for Childhood Diabetes,
University of Colorado at Denver and Health Sciences Center
2.
Diabetes Research Institute, University of Miami
Though
there is heterogeneity for type 1A in age of diabetes onset1, age at which islet autoantibodies
first appear, rate of progression to diabetes2 and even completeness of beta cell
destruction3, overall the genetic determinants
are similar1.
Even latent Autoimmune Diabetes of adults appears to be a variant of
type 1A diabetes upon genetic analysis4.
This homogeneity is reflected in the islet autoantibodies expressed,
specific beta cell destruction within islets5,
6 and HLA associations. We believe that type 1A diabetes is driven
primarily by CD4 and CD8 T lymphocyte targeting of the molecule insulin (or
proinsulin) leading to the specific beta cell destruction7.
Thymic deletion of insulin reactive T cells for both man and animal
models8 is a critical determinant and
likely relates to diabetogenicity of the insulin gene VNTR and mutations of the
AIRE gene9,
10.
HLA alleles determine how and which islet peptides are recognized by
specific T cell receptors11 including the register in which
such peptides can be recognized by analogy with the NOD mouse12,
13.
Multiple additional genetic loci with smaller effects combine to
determine the probability of maintaining tolerance14 and thus patients with type 1A
diabetes are at risk for other autoimmune disorders related to both their
specific HLA alleles (e.g. DQ2 for type 1A and celiac disease) and less
characterized abnormalities of tolerance.
Already at onset of diabetes a third of the patients have multiple
autoimmune disorders15.
Insulin-dependent diabetes mellitus (IDDM), or type 1
diabetes, is a chronic disease usually characterized by the autoimmune
destruction (Type 1 A) of pancreatic ß-cells and severe insulin deficiency 16-18. Completion of multiple large scale genome wide association studies19-22 has provided a clearer understanding of the genetic architecture of
Type 1A diabetes14, 22, 23. In particular the overwhelming
genetic determinants of Type 1A diabetes are in the major histocompatibility20 complex 14, 24. This is followed by insulin
gene polymorphisms, the T cell receptors signaling molecule PTPN22, and the
multiple (>40) loci with very small effects. Of note, there appears to be
little or no overlap between loci for Type 2 and Type 1 diabetes25. Type 1B diabetes refers to
insulin dependent diabetes not of immune etiology, is not the subject of this
chapter and has been difficult to diagnose.
It has been suggested that fulminant diabetes, found almost exclusively
in Japan, represents type 1B diabetes, but even these patients that lack
anti-islet autoantibodies, have HLA alleles associated with type 1 diabetes 26. An increasing number of
“monogenic” forms of diabetes are now recognized, some of which result in
severe beta cell loss (e.g. neonatal diabetes with insulin gene mutations27 while others create forms of diabetes that require no therapy (e.g
glucokinase mutations) or are better treated with sulfonylureas rather than insulin
including mutations of the sulfonylurea receptor28 and HNF1alpha mutations27, 29. Monogenic forms of diabetes
occur in approximately 1.5% of children developing diabetes. Thus defining whether a patient has the more
common form of diabetes in children, namely immune mediated diabetes has
assumed greater importance as correct genetic diagnosis can alter therapy. Testing of new onset children with an
inclusive series of anti-islet autoantibody assays (assays for GAD65,
IA-2(ICA512), insulin and ZnT8 autoantibodies) can now identify more than 90%
of children with type 1A diabetes, and can aid in defining (negative
autoantibodies) a subgroup of children with new onset diabetes with both
monogenic (including insulin gene mutations30) and particularly for teenagers,
children with type 2 diabetes. It is estimated that 10% of autoantibody
negative children have monogenic forms of diabetes. Recent studies of the pancreas of the NPOD
program indicate that a significant proportion of African American and Hispanic
American individuals with childhood onset diabetes have islet pathology that is
very different from classical Type A diabetes pathology with pseudoatrophic
islets (islets lacking all insulin producing beta cells)31. The etiology of this form of
Type 1 diabetes is unknown but is not associated with islet autoantibodies or
HLA DR3 and DR4 alleles and may be related to poorly characterized ketosis
prone diabetes, “Flatbush” or “Type 1.5” diabetes 32-34.
Type 1A diabetes frequently develops in children,
adolescents and young adults, but approximately half of individuals developing
type 1A diabetes first present as adults35. The disease is quite heterogeneous in its clinical expression and it
can be confused with type 2 diabetes, especially in those patients who develop
diabetes at a later age 36, 37. Inherited genetic factors influence both susceptibility to and
resistance to the disease. Although a significant proportion of patients with
type 1A diabetes lack a first degree family history for the disease(>85%),
there is significant familial clustering with an average prevalence of
approximately 6% diabetic for siblings compared to 0.4% in the US Caucasian
population. The familial clustering (λs) can be calculated as the ratio of
the risk to siblings over the disease prevalence in the general population, and
thus λs = 6/0.4 = 15 38, 39.
One’s
genetic susceptibility depends on the degree of genetic identity with the
proband. The risk of diabetes in family members has a non-linear correlation
with the number of alleles shared with the proband. The highest risk is
observed in monozygotic twins (100% sharing) followed by first, second and
third degree relatives (50%, 25%, 12.5% sharing, respectively). Based on such
estimates of observed risk, it has been suggested that diabetes susceptibility
may be linked to a major locus and that several other minor loci may contribute
to diabetes risk in an epistatic way. This model generates the risk curve that
best parallels the risk curve obtained from observed risk estimates 40. The moderate disease
concordance observed even amongst identical twins (usually 30-50%, 70% in
studies with longest follow-up) implies that inherited genes provide increased
susceptibility 41-45 with dizygotic twins having a risk
not appreciably different from siblings46.
Much
technological progress has facilitated the study of the genome to map disease susceptibility
genes for multi-factorial diseases, including the increasing availability of
microsatellite markers, single nucleotide polymorphisms (SNPs), automated
typing technology 47, and recently whole genome
SNP analysis 48. In the
case of type 1 diabetes, genome scans for IDDM susceptibility loci have been
facilitated by the availability of large c
It is also
possible that a subset of the disease is genetically heterogeneous, with
different loci determining disease risk
in different families. Genetic heterogeneity has been demonstrated in most of
the genome wide scans performed to date. The genetic heterogeneity can also be
demonstrated with the study of groups of monozygotic twins. When the first twin of a twin-pair develops
type 1 diabetes after age 25, the risk of the second monozygotic twin
developing type 1 diabetes is less than 5% with long-term follow up 44, while
approximately 60% of initially discordant twins whose twin mate developed
diabetes prior to age 6 have progressed to diabetes (by life table analysis
with 40 years of follow-up). For
monozygotic twins of patients with type 1 diabetes, expression of anti-islet
autoantibodies directly correlates with progression to overt diabetes. Essentially all such twins who express
“biochemical” anti-islet autoantibodies (to GAD, IA-2/ICA512, insulin, measured
by radioimmunoassays) progress to diabetes, some after decades of follow-up 52. In contrast, dizygotic twins have a low risk
of expressing anti-islet autoantibodies, a risk that is essentially identical
to that of siblings. These risk
estimates have been validated through the exchange of sera 53 and confirmed by a large
study of the DPT-1 (Diabetes Prevention Trial – Type 1) cohort
of at-risk relatives 44. Similar
results were obtained studying a population-based twin cohort of 22,650 twin pairs
from Finland, the country with the highest disease incidence in the world 54.
Figure 7.1 Diabetes-free
survival analysis of the combined Great Britain and United States cohorts, by
age at diagnosis in the index twin: Ages 0-24 years (n=150) in solid line, 25
years and older (n=37) in dashed line.
Besides
inherited alleles, other mechanisms regulating gene expression including
epigenetic and parent-of-origin effects may influence susceptibility by
modifying the transmission and transcription of inherited genes. It is also an intriguing possibility that
additional epigenetic factors or their expression may be acquired after birth,
perhaps through environmental exposures.
Thus, a variety of genetic mechanisms may influence the autoimmune
responses leading to ß-cell destruction. This chapter will review the current
knowledge about the genetics of type 1 diabetes in humans.
Figure
7.2. Odds ratios for a series of
identified “genes/genetic loci” from recent genome screens and replication
studies. In most cases the association is with a locus and not proven for the
genes indicated (Concannon et al NEJM).
Both
association studies and linkage analysis using various analytical methods have
been used to identify IDDM susceptibility loci.
These are conventionally noted using the abbreviation IDDM and a number,
e.g. IDDM1, IDDM2, etc., with the number usually reflecting the order in which
such loci were reported (Table 7.1 and Figure 7.2). Many of the early IDDM loci
appear at present to have been “false positives” and are generally being
replaced by more recent GWAS studies and in a few instances identified genes
(figure 7.2). Using the candidate gene
approach, association studies provided evidence for the first two
susceptibility loci, the HLA region (IDDM1)
and the insulin gene (INS) locus (IDDM2). These two loci contribute the
great majority of known familial clustering (Figure 7.2). One estimate is that the MHC alone contributes 41% of the
familial clustering of type 1 diabetes of the 48% estimated to be accounted for
with all known genes 50. The next most potent locus for type 1
diabetes of man, after the insulin gene, was also discovered using a candidate
gene approach, namely the PTPN22 (LYP) gene with an odds ratio of approximately
1.7 for a “missense” mutation that creates susceptibility to multiple
autoimmune disorders 55-57. Figure 7.2 illustrates odds ratio for
multiple loci summarized for GWAS studies.
The ratio of differences in frequencies, except for PTPN22 are
relatively small (Figure 7.3), making it unlikely that the other indicated loci
will contribute to the genetic prediction of type 1A diabetes, except through
combinatorial analysis58, 59, in
contrast to the HLA and insulin region genes.
For instance the HLA DR3/4-DQ2/8 genotype is present in 2.3% of newborns
in Colorado, but more than 30% of children developing diabetes, providing
“extreme” risk, as will be discussed subsequently. Compared to a population prevalence of type 1
diabetes of approximately 1/300, DR3/4-DQ2/8 newborns from the general
population have a 1/20 genetic risk 60. As will be discussed subsequently additional
loci within or linked to the MHC (Major Histocompatibility Complex) can
increase this risk for first degree relatives of DR3/4-DQ2/8 newborns to as
high as 80% 51. Such extreme risk, suggests that for this
major subgroup of children, the bulk of familial aggregation is determined by
alleles of genes within or linked to the classic MHC, and the search for
additional (non-DR and DQ) genetic determinants in this region is underway 61-66.
Figure
7.3. Allele frequencies for case versus
control association studies with “significant” associations outside of the
major histocompatibility complex.
Prior to
the whole genome SNP analyses that have recently been reported, a number of
genome-wide studies of families and affected sibling-pairs have been performed
since the mid 1990’s in an attempt to identify susceptibility loci using
linkage analysis 67. Linkage analysis
confirmed linkage with IDDM1 (HLA)
and IDDM2 (insulin gene) and further
provided evidence for the existence of approximately 20 susceptibility loci.
Many of these loci show modest linkage and linkage is often not confirmed in
all genome scans. Sample size and composition, genetic heterogeneity and
analytical methods underlie much of the variability observed in these studies.
A coordinated effort to investigate the genetics of the disease, the Type 1
Diabetes Genetics Consortium (T1DGC) (www.t1dgc.org),
involves the study of patients and their families from around the world. In
2005 the consortium published its first report, with combined linkage analysis
of four datasets, three previously published genome scans, and a new
dataset of 254 families. This analysis included 1,435 families with 1,636
affected sibling pairs, representing one of the largest linkage
studies ever performed for any common disease and involving families from the
U.S., U.K. and Scandinavia 68. Given
the average map information content (67%, >400 polymorphic microsatellite
markers in each scan), this dataset had ~95% power to detect a locus with S
1.3
and p= 10-4. With this analytical power, more than 80% of
the genome was found not to harbor susceptibility genes of modest effect that
could be detected by linkage. The study confirmed linkage with IDDM1
(nominal P = 2.0 x 10–52). Moreover, nine non–HLA-linked
regions showed some evidence of linkage (nominal P <
0.01), including three at (or near) genome-wide significance (P <
0.05): 2q31-q33, 10p14-q11, and 16q22-q24. In addition, after taking
into account the linkage at the 6p21 (HLA) region, there was evidence of linkage
with the 6q21 region (IDDM15). The published literature on these loci is
discussed in detail in the following paragraphs. A comprehensive list of these
initial susceptibility loci is shown in Table 7.1 with LOD scores and S
from the 2005 T1DGC scan 68.
Locus |
Chromosome |
Candidate Genes |
Markers |
LOD
|
S
|
IDDM1 |
6p21.3 |
HLA DR/DQ
|
TNFA |
116.38 |
3.35 |
IDDM2 |
11p15.5 |
INSULIN VNTR
|
D11S922 |
1.87 |
1.16 |
PTPN22 |
1p13 |
PTPN22 (LYP)
|
SNP=R620W |
NR |
1.05 |
SUMO4 |
6q25
(IDDM5) |
SUMO4
|
SNP=M55VA
allele 163 [G] |
NR |
NR |
IDDM3 |
15q26 |
|
D15S107 |
NR |
NR |
IDDM4 |
11q13.3 |
MDU1, ZFM1, RT6, ICE, LRP5, FADD, CD3 |
FGF3,
D11S1917 |
NR |
NR |
IDDM5 |
6q25 |
SUMO4,MnSOD |
ESR,
a046Xa9 |
NR |
NR |
IDDM6 |
18q12-q21 |
JK (Kidd), ZNF236 |
D18S487,
D18S64 |
NR |
NR |
IDDM7 |
2q31-33 |
NEUROD
|
D2S152,
D251391 |
3.34* |
1.19* |
IDDM8 |
6q25-27 |
|
D6S281,
D6S264, D6S446 |
NR |
NR |
IDDM9 |
3q21-25 |
|
D3S1303,
D10S193 |
NR |
NR |
IDDM10 |
10p11-q11 |
|
D10S1426,
D10S565 |
3.21 |
1.12 |
IDDM11 |
14q24.3-q31 |
ENSA, SEL-1L |
D14S67 |
NR |
NR |
IDDM12 |
2q33 |
CTLA-4 |
(AT)n 3 |
3.34 |
1.19 |
IDDM13 |
2q34 |
IGFBP2, IGFBP5, NEUROD,
HOXD8 |
D2S137,
D2S164, D2S1471 |
NR |
NR |
IDDM15 |
6q21 |
|
D6S283,
D6S434, D6S1580 |
22.39 |
1.56 |
IDDM16 |
14q32.3 |
IGH |
|
NR |
NR |
IDDM17 |
10q25 |
|
D10S1750,
D10S1773 |
NR |
NR |
IDDM18 |
5q31.1-33.1 |
IL-12B |
IL12B |
NR |
NR |
|
1q42 |
|
D1S1617 |
NR |
NR |
|
16p12-q11.1 |
|
D16S3131 |
1.88 |
1.17 |
|
16q22-q24 |
|
D16S504 |
2.64 |
1.19 |
|
17q25 |
|
|
NR |
NR |
|
19q11 |
|
|
NR |
NR |
|
3p13-p14 |
|
D3S1261 |
1.52 |
1.15 |
|
9q33-q34 |
|
D9S260 |
2.20 |
1.13 |
|
12q14-q12 |
|
D12S375 |
1.66 |
1.10 |
|
19p13.3-p.13.2 |
|
INSR |
1.92 |
1.15 |
The recent
whole genome screens, with increasing power suggest as indicated above that
many of the prior loci are either false positives, have such small effects that
they were not detected in the genome screens, or are related to only specific
populations, as for instance is suggested for the SUMO4 gene for only Asian
patients 69. Table 7.2 summarizes “significant” regions
for the whole Wellcome Trust case control study using the combined “control”
reference population of 7,670 controls compared to 2,000 patients with type 1
diabetes (The locus for IFIH1 did not reach “significance” in this Wellcome
whole genome analysis with the SNPs analyzed, but is included in Table 7.2
related to a follow-up study50).
Locus |
Chromosome |
Candidate Genes |
Markers |
P
(-10)
|
Hetero
OR |
Homo
OR |
IDDM1 |
6p21.3 |
HLA DR/DQ
|
rs9272346 |
134 |
5.49 |
18.52 |
IDDM2 |
11p15.5 |
INSULIN VNTR
|
rs689;rs3741208 |
|
|
|
PTPN22 |
1p13 |
PTPN22 (LYP)
|
rs6679677Rs2476601=R620W |
41 |
1.82 |
5.19 |
IDDM12 |
2q33 |
CTLA-4 |
rs3087243 (AT)n 3 |
6 |
|
|
|
2q24 |
IFIH1 |
Rs1990760 |
3 |
|
|
|
10p15 |
IL2RA(CD25) |
rs2104286;rs52580101;rs11594656;
rs706778; D10S1426,
D10S565 |
8 |
1.30 |
1.57 |
|
12q13 12q14-q12 |
?ERBB3 |
rs11171739,
rs2292239 D12S375 |
11 |
1.34 |
1.75 |
|
3p21 |
|
|
7 |
|
|
|
12q24 |
?C12orf30,SH2B3,TRAFD1,PTPN11 |
rs17696736,
rs3184504 |
14 |
1.34 |
1.94 |
|
16p13 (16p12-q11.1) |
KIAA0350 |
rs12708716 D16S3131 |
10 |
1.19 |
1.55 |
|
17q21 17q25 |
|
|
6 |
|
|
|
18p11 |
PTPN2 |
rs2542151;rs1893217; rs478582 |
7 |
1.30 |
1.62 |
|
18q22 |
?CD226 |
rs763361 |
|
|
|
|
22q13 |
?IL2RB |
rs229541 |
6 |
|
|
|
12p13 |
?CD69,
CLEC |
rs11052552 |
8 |
1.57 |
1.48 |
The major
locus for type 1 diabetes susceptibility59 is
located within the HLA (Human Leukocyte Antigen) region 70 on the
short arm of chromosome 6 71 and is calculated to
provide up to 40-50% of the inheritable diabetes risk 72, though this calculation
is based upon certain assumptions, including negligible recombination between
susceptibility loci in the region. The
HLA complex was first linked to diabetes when associations with several HLA
class I antigens (HLA-B8, -B18, and -B15) were discovered by serological typing
and affected sib-pairs showed evidence of linkage 73-75. With the development of novel typing
reagents, HLA class II genes (DQ, DR, and DP in that order of risk)1, 20, 76-80 were
shown to be even more strongly associated with the disease 75, 81, 82. However, several loci within or near the HLA
complex appear to modulate diabetes risk, and add further complexity to the
analysis of IDDM1-encoded
susceptibility 51, 83. Alleles, modes of inheritance and putative
mechanisms of susceptibility encoded for at the IDDM1 locus are discussed below.
A schematic representation of the HLA region and its association with
IDDM is shown in Figure 7.4. A recent manuscript analyzes a large number of
families of the Type 1 Diabetes Genetics consortium and documents the influence
of multiple class II DR and DQ alleles and genotypes influencing risk of type
1A diabetes24.
Figure 7.4 The HLA Region and IDDM Susceptibility. Schematic representation of the HLA region showing
microsatellite markers, loci, and alleles associated with IDDM susceptibility.
Distances between loci are grossly approximated.
The HLA Class II Region. The great majority of Caucasian
patients have the HLA-DR3 or -DR4 class II alleles and approximately 30% to 50%
of patients are DR3/DR4 heterozygotes 84. The
DR3/DR4 genotype confers the highest diabetes risk24 with a
synergistic mode of action, followed by DR4 and DR3 homozygosity, respectively 85 [See attached teaching
slides by J. Noble summary of HLA nomenclature]. Following the development of
DNA-based sequencing and typing technology, the HLA-DQ locus was found to be
the most strongly associated with diabetes susceptibility. This locus encodes for multiple alleles of
the HLA-DQ molecule, a heterodimer consisting of two chains (a and ß) involved in immune recognition and antigen
presentation to CD4 T cells. In
Caucasians, the HLA-DQ heterodimers (the αchain genes are labeled DQA1
and the ß-chain genes DQB1) encoded by the DQA1*0301, DQB1*0302 and DQA1*0501,
DQB1*0201 alleles have the strongest association with diabetes. These alleles
are in linkage disequilibrium with the HLA-DR4 and -DR3 alleles (Table 7.3),
respectively 86. Linkage disequilibrium
often extends centromeric and telomeric of the class II region 87-89.
Table
HLA-DR |
DQA1 |
DQB1 |
DRB1 |
Susceptibility |
DR2 |
0102 |
0602 |
1501 |
Protective |
DR2 |
0102 |
0502 (AZH) |
1601 |
Predisposing |
DR2 |
0103 |
0601 |
1502 |
Neutral |
DR3 |
0501 |
0201 |
0301 |
High Risk |
DR4 |
0301 |
0302 |
0401 |
High Risk |
DR4 |
0301 |
0302 |
0402 |
Predisposing |
DR4 |
0301 |
0302 |
0403 |
Lower Risk |
DR4 |
0301 |
0302 |
0404 |
Predisposing |
DR4 |
0301 |
0302 |
0405 |
High Risk |
DR4 |
0301 |
0301 |
0401 |
Neutral |
DR4 |
0301 |
0303 |
0401 |
Neutral |
DR7 |
0201 |
0303 |
0701 |
Protective |
DR6 |
0101 |
0503 |
1401 |
Protective |
Allelic variation at the DQB1
locus differentiates diabetes susceptibility among the two most common HLA-DR4
haplotypes found in Caucasians based on the presence of the DQB1*0302 or
DQB1*0301 allele. Most patients with DR4
carry the DQB1*0302 allele, while the DQB1*0301 and *0302 alleles are more
evenly distributed in the general population.
An independent effect (DQB1*0302 versusDR3) has not been demonstrated
for DQB1*0201 because of the strong linkage disequilibrium between DQB1*0201
and DRB1*0301 on Caucasian DR3 haplotypes.
However, DQB1*0201 does not confer increased susceptibility in
association with DRB1*0701 on DR7 haplotypes.
The different risk conferred by DQB1*0201 when on a chromosome with DR3
or DR7 may be explained by the different DQA1 alleles associated with DQB1*0201
on such haplotypes (DQA1*0501 on DR3, DQA1*0201 on DR7) 90, 91. In addition, other susceptibility loci may be
in linkage disequilibrium with DQB1*0201 on DR3 haplotypes 72, although the class II
region may be the primary risk determinant on DR3 haplotypes 92. Trans-complementation of DQ α- and
ß-chains from opposite haplotypes has been demonstrated, and this significantly
increases the diversity of class II antigens participating in the immune
response and the potential for HLA-DQ contribution to IDDM susceptibility. A trans-complementing DQ molecule would be
unique to a heterozygous individual and usually it would not be expressed in
his parents. Thus, this phenomenon has
been proposed as an explanation for the increased diabetes risk observed in
DR4, DQA1*0301, DQB1*0302/DR3, DQA1*0501, DQB1*0201 heterozygotes 24, 91.
DQB1*0302
differs from DQB1*0301 at position 57, where it lacks an aspartic acid residue,
similar to the I-A molecule of the NOD mouse (reviewed in ref. 93). The DQB1*0201 allele
also lacks aspartic acid at position 57, and it has been proposed that this
residue may be involved in the molecular mechanism underlying IDDM1-encoded susceptibility 86, 89, 89. In fact,
the amino acid residue at position 57 of the DQ-ß chain appears to be critical
for peptide binding and recognition 94. Other residues of the DQ-ß chain may
influence peptide binding and diabetes susceptibility, and in particular the
combined variation of residues at positions 57 and 70 seem to more strongly
correlate with diabetes risk 95, 96, 96. An arginine residue at position 52 of the
DQ-α chain also correlates with diabetes susceptibility 90. The importance of the residue at position 57
has been disputed by trans-racial studies showing that DQB1 alleles found with
increased frequency in Japanese patients carry instead of lack an aspartic acid
residue at this position 97. Patients carrying similar
Asp57 high risk alleles are also found among Caucasians 98-107 (Figure
7.5). Moreover, certain low risk DQB1 genotypes also lack aspartic acid at
position 57, including DQB1*0302/DQB1*0201 (DR7), and DQB1*0201 (DR3)/DQB1*0201
(DR7).
It is
important to recognize that even the class II MHC genes with the greatest
impact on diabetes susceptibility have a complex inheritance and their effect
on risk cannot be explained by relatively simple rules (for instance, based on
the presence of certain amino acid residues in the DQ genes). As illustrated below (Figure 7.5), the rule
that lack of aspartic acid at position 57 of the DQB1 gene is strongly
associated with risk is not consistent with relatively potent diabetogenic DQ
alleles such as DQB1*0303 and DQB1*04 (usually 0401 in Caucasians and 0402 in
Korean and Japanese patients) 108.
Figure
7.5 High-risk genotypes in population
based
However,
there is clear evidence that certain residues have a functional role in determining
binding and presentation of certain peptides 109. By using X-ray crystallography, investigators
have determined the three-dimensional structure of the HLA-DQ8 molecule
(encoded by DQA1*0301/DQB1*0302) complexed with an immunodominant peptide of
the insulin molecule (insulin B:9-23) 110. The DQ8 structure suggests that the residue
at position 57 contributes to the shaping of the P9 pocket, which together with
the P1 and P4 pockets appear relevant to diabetes susceptibility. The P4 pocket is deeper in DQ8
compared to DR1, DR2, DR3, DR4 but predictably similar in HLA-DQ2 (DQA1*0501,
DQB1*0201) and the diabetes protective HLA-DQ6 (DQA1*0102, DQB1*0602), thus not
directly correlating with susceptibility. Moreover, the binding pockets of
HLA-DQ8 were similar to those of HLA-DQ2 and to those of the I-Ag7
molecule (corresponding to human DQ), the main genetic susceptibility locus in
NOD mice. This finding suggests that
diabetes may depend on antigen-presentation event(s) that may be similar in
humans and NOD mice. In further support of this hypothesis, it has been shown
that HLA-DQ8 and I-Ag7 select common peptides, use the same binding
register, which is not promiscuous and is rather selective and dominated by the
P9 pocket 111, 112. Though it was generally assumed that
autoantigenic peptides presented by high risk Asp 57 alleles (e.g. I-Ag7,
DQ8, DQ2) would bind to the class II allele with a negatively charged amino
acid binding to pocket 9, our recent studies of major insulin peptide B:9-23
and I-Ag7 of NOD mice indicates just the opposite. Namely the peptide, though it can bind in
multiple registers, is only recognized by diabetogenic T cell receptors when it
binds with B22 arg amino acid projecting into pocket 9. This is a low affinity unfavorable binding
register and we hypothesize that T cells reacting with the B:9-23 peptide escape
thymic deletion because so little of the peptide binds in an appropriate
register to delete the relevant anti B:9-23 T cells. In contrast to the thymus, islets produce a
huge amount of insulin and the B:9-23 peptide, presumably allowing targeting of
islets
IDDM1-encoded susceptibility is mostly
conferred by alleles of the HLA-DQ locus in the class II region. The above
conclusion is also supported by the fact that the DQA1*0102, DQB1*0602 alleles,
encoding for the HLA-DQ6 heterodimer found on HLA-DR2 haplotypes, confer
dominant protection from the development of type 1 diabetes (reviewed in ref. 113). Among four common DR2 haplotypes observed in
Caucasians, the DQA1*0102, DQB1*0602, DRB1*1501 haplotype is negatively
associated with type 1 diabetes and is reported in less than 1% of patients in
most populations studied, including those of Caucasian (both European and
North-American) 10, 103, 104, 110, 114-118, Asian 97, 119, 120,
African-American 102, 103, and
Mexican-American origin 121 compared
to approximately 20% of the general population.
The
DQB1*0602 allele in particular is the only class II allele exclusively found on
protective DR2 haplotypes while all the other alleles (DQA1*0102, DQA1*0103,
DQB1*0601, DQB1*0502, DRB1*1501, DRB1*1502, DRB1*1601) can be found on neutral
or moderately predisposing DR2 haplotypes.
Moreover, a few rare patients with type 1 diabetes have been described
carrying mutated DQB1*0602 alleles or unusual DQA1/DQB1 alleles in cis with the
usual DRB1*1501 allele. Thus, the
available evidence suggest that the diabetes-protective effect associated with
DR2 haplotypes may be mostly mapped within the DQ locus and in particular to
the DQB1*0602 allele. Although a number
of patients with DQB1*0602 have been identified 118, the overall number is
small (approximately 1% of children developing diabetes and perhaps 5% of
adults from the Swedish population) 122. Protection appears to be dominant since
DQB1*0602 protects from diabetes even in the presence of high-risk HLA alleles 101, 114.
However, a
subset of HLA-DR2, DQB1*0602 haplotypes marked by alleles at the D6S265 locus
has been identified as less protective (but still markedly protective) in a
Swedish cohort. HLA-DR2 (DRB1*15), DQB1*0602 haplotypes carrying D6S265*15 have
a ten-fold higher odds ratio (OR) than those carrying other alleles and thus
confer reduced protection (OR with D65265*15 0.186 (.074 to .472) versus .017
(.005 to .062)). Marker D6S265 maps 100 kb telomeric of the HLA-A locus, which has been
previously associated with diabetes susceptibility. Associations between D6S265
and other autoimmune diseases have been reported, including an association with
multiple sclerosis and D6S265 specifically on HLA-DRB1*15, DQB1*0602 haplotypes
123. Thus, genetic variation at D6S265 can influence or
is linked to a locus that can influence susceptibility to or protection from
the autoimmunity conferred by HLA-DRB1*15,
DQB1*0602 haplotypes. Known genes that may be marked by D6S265 include HLA-A,
HLA-B, MICA, TNF and BAT1. Polymorphisms at these loci may have important
effects on the function of cytotoxic T cells and cytokine secretion. Moreover,
possible effects on transcriptional regulation may perhaps influence the
expression of the HLA-DQ molecule encoded by DQA1*0102, DQB1*0602. Further
characterization of this region will be needed to identify the loci that
contribute to the genetic protection from type 1 diabetes conferred by DRB1*15,
DQB1*0602.
Studies in
transgenic mice have provided direct evidence that the DQ locus, and the
DQB1*0302 allele in particular, can engender an immune response leading to the
development of diabetes 102. However,
the mechanism by which the HLA-DQ locus influences diabetes susceptibility is
the subject of intense speculation. Since HLA-DQ molecules are known to play a
role in antigen presentation, allelic variation at this locus may affect the
binding and functional properties of DQ heterodimers and in turn the
presentation of islet cell antigen-derived peptides to immunocompetent cells. Protective HLA molecules may have higher
affinity for one or several peptides than predisposing molecules. Therefore, it
is suggested that predisposing HLA molecules may be ineffective at binding and
presenting peptides derived from islet cell antigens. Indeed, the HLA-DQ
molecules encoded by the protective DQA1*0102, DQB1*0602 and predisposing
DQA1*0301, DQB1*0302 alleles appear to differ in their affinity and specificity
for peptides derived from the insulin, glutamic acid decarboxylase (GAD), and
tyrosine phosphatase IA-2 autoantigens 104, 105, 105. Similar findings were reported for DR
molecules, with protective HLA-DR2 (DRB1*1501) molecules displaying stronger
affinity for (pro) insulin peptides than susceptible HLA-DR3 (DRB1*0301)
molecules 106. Our recent studies of I-Ag7
suggest that binding in a low affinity register may be key to autoreactivity to
NOD targeting the insulin peptide B:9-23.
It is
unclear whether genetically determined differences in peptide binding and
presentation affects the shaping of the T-cell repertoire in the thymus or
modulates immune responses in the extra-thymic periphery. A poor presentation
in the thymus could impair mechanisms of negative selection allowing
autoreactive T cells to escape deletion. In contrast, a protective HLA-DQ
molecule could promote tolerance to ß-cell molecules by eliciting more
efficient antigen presentation and negative selection in the thymus. Although
several studies involving the transgenic expression of MHC molecules in mice
did not support this hypothesis 107, 124, a study provided novel
evidence for thymic deletion as a mechanism of protection associated with MHC
genes in transgenic mice 125. Moreover, the demonstration that insulin and
other islet cell antigens are ectopically expressed in human thymus 10, 116
indirectly supports the hypothesis that thymic self-antigen presentation and
deletional mechanisms may be affected by the affinity and binding properties of
HLA-DQ and HLA-DR molecules.
An
alternative hypothesis is that DQB1*0602-associated protection may be mediated
outside the thymus through the stimulation of regulatory immune responses
associated with peripheral tolerance.
The predominance of Th2 responses is usually associated with lack of
progression to overt diabetes (reviewed in ref. 117) and
regulatory T-cells are essential for the prevention of autoimmunity. There is
indeed evidence that a non-diabetogenic immune response, mostly limited to the
production of autoantibodies against the GAD autoantigen, may occur in first
degree relatives with DQB1*0602 101, and in whom the presence
of DQB1*0602 and DQA1*0102 has been confirmed by direct sequencing of the
second exon 118. A similar response has
been reported in patients with type 1 autoimmune polyendocrine syndrome who do
not invariably progress to overt diabetes 126, 127. Moreover,
a similar protective effect has also been reported in first degree relatives
participating in the ongoing Diabetes Prevention Trial (DPT-1), although
different degrees of protection may occur in different ethnicities 128. The presence of GAD autoantibodies, often at
high titers, may reflect the predominance of Th2 responses in relatives with
DQB1*0602. Finally, the two hypotheses
are not mutually exclusive and DQB1*0602-associated protection could be
mediated both in the thymus and the periphery.
Two
additional strongly protective haplotypes are DRB1*1401, DQA1*0101, DQB1*0503
and DRB1*0701, DQA1*0201, DQB1*0303. The DRB1*1401 haplotype is particularly
interesting in that it is a HLA-DR allele with an apparent lack of transmission
to affected children as dramatic as for DQB1*0602 (Both DRB1*1401 and
DQA1*0201/DQB1*0303 are relatively infrequent but strongly protective) 129. (Fig. 7.6).
Figure
7.6: Transmission of DR/DQ haplotypes to
patients with type 1 diabetes. Note that
DQ6 (DQB1*0602) containing haplotypes and DRB1*1401 containing haplotypes are
not/rarely transmitted to diabetics, while the usual DR or DQ alleles
associated are transmitted when DQB1*0602 (e.g. DRB1*1501) or DRB*1401
(DQB1*0503) are not present in the haplotype.
Other loci in the class II
region have been associated with diabetes susceptibility besides HLA-DQ.
Several studies indicate that DRB1 alleles (Figure 7.7) significantly
contribute and modulate diabetes susceptibility 88, 130-137. The DRB1*0405 and *0401 alleles have been reported as predisposing,
*0402 and *0404 as mostly neutral, while *0403, *0406, and *0407 are
protective.
Figure 7.7
Modified risk of diabetes relative DRB1*04 alleles, with DRB1*0403/0403 even
when combined with high risk DQB1*0302, decreasing risk to background
population (approximately 1/300).
There is
evidence for contribution to risk from the DPB1 locus, confirmed in an
extensive analysis by Valdes et al. 138-140. An independent association has been observed
in Mexican American 141 and Caucasians with DPB1*0301
142. The frequency of DPB1*0101 is increased in
patients (almost exclusively found on DR3 haplotypes). The maternal transmissions of
DRB1*0301-DPB1*0101 haplotypes to affected children occurred twice as frequently
as do paternal transmissions 72. Transmissions of DR3 haplotypes carrying
other DPB1 alleles occurred at approximately equal maternal and paternal
frequencies. A recent analysis indicates that the DPB1*0402 allele, previously associated
with decreased diabetes risk, is associated with dominant protection from
development of anti-islet autoantibodies and diabetes in young children 61 amongst
children having the highest risk DR3/4-DQ2/DQ8 genotype.
It is
controversial whether loci (TAP1, TAP2) encoding for peptide transporter genes
associated with antigen processing and localized centromeric to the DQ loci may
also affect IDDM susceptibility 65, 143. Homozygosity for the TAP2*0101 allele was
associated with increased IDDM risk independent of HLA-DQ susceptibility in a
French study 144, but other studies have
failed to show such independent effect and suggested linkage disequilibrium
between the HLA-DQ and TAP2 loci 145, 146. Of note, a mutation at the same locus has
been implicated as the cause of the class I deficiency associated with IDDM in
studies in humans and NOD mice 147-151.
The HLA Class I Region. A number
of observations indicate that class II genes cannot explain all of the HLA
association with IDDM. A role for HLA
complex genes other than the DR-DQ or other class II genes was first
demonstrated by Robinson et al. 152. They
examined affected sib pairs with parents homozygous for the DR3 haplotype and
used the HLA class I B locus to distinguish between the two DR3 haplotypes of
the homozygous parent. Under the null
hypothesis that no HLA region variation additional to that defined by the DR3
haplotype is involved in IDDM, the affected sib pairs should share the two
parental DR3 haplotypes at the same frequency.
Significant deviation from 50% sharing was observed. Since the DR3 haplotypes examined in this
study could be assumed to be homogeneous for their DR-DQ alleles at the
molecular level (DRB1*0301 DQA1*0501 DQB1*0201), this test implicated other HLA
loci in IDDM susceptibility. Several
other reports suggest that HLA class I genes, and in particular the HLA-A24 allele,
may also influence susceptibility and particular clinical aspects of the
disease such as age of onset 153, 154 and the
rate of ß-cell destruction 125, 155-159. Besides
HLA-A24 (*2401), other class I alleles are independently associated with
susceptibility (HLA-A*0101 and *3002) and though uncommon B*3906 is associated
with diabetes risk. 160. There
is also evidence that several alleles at the class I HLA-B and C loci modulate
susceptibility and influence age of onset 161. A
risk-modifying locus may lie between HLA-B and marker D6S2702, which is located
970 kb telomeric of HLA-B 162.
Another
diabetes-associated locus has been found in the class I region, telomeric to
HLA-F 65. By considering the
transmission ratios of microsatellite variation from parents homozygous for the
HLA class II DR-DQ genes (using the Homozygous Parent Transmission
Disequilibrium Test), the possible confounding effect of linkage disequilibrium
was removed. Evidence for a second IDDM
locus in this region was demonstrated, near the HFE (hemochromatosis) gene and
8.5 Mb distal to the HLA class II loci. Analyses from three independent family data
sets from Norway (100 families), Denmark (51 families), and UK (74 families)
suggested the presence of additional type 1 diabetes gene(s). Allele 3 of
marker D6S2223, 5.5 Mb telomeric of the class II region, was associated with
type 1 diabetes when the haplotype was fixed for HLA-DRB1*03, DQA1*0501,
DQB1*0201. In a case-control study allele 3 at D6S2223 was found to be reduced
among DRB1*03, DQA1*0501, DQB1*0201 homozygous patients with type 1 diabetes
compared to DR-DQ matched controls, thus corroborating the results of the
family analysis 66. The
protective effects seem to be inherited as a recessive trait. An association
with D6S2223 has been reported in a Dutch family dataset 163. Analyzing the large TZDGC
cohost with SNP typing we have found an additional locus at .
The HLA Class III Region. Moghaddam
et al. 145 analyzed 11 markers in the
HLA region in IDDM patients and controls fully matched for the highest risk
DQA1*0501, DQB1*0201/HLA-DQA1*0301, DQB1*0302 (DR3/DR4) genotype. Their study provided strong evidence that
another critical region for IDDM susceptibility, approximately 200 kb in size,
lies around the microsatellite locus D6S273 which is located between the TNF
and HSP70 genes. Another study has
independently confirmed linkage with marker D6S273 showing evidence for
non-random transmission from DRB1*03-DQA1*0501-DQB1*0201 homozygous parents 65. Further studies in
multiplex families from the US indicate that allele D6S273*2 marks an extended
DR3-B18 haplotype associated with increased susceptibility. On DR3 haplotypes,
other D6S273 alleles were significantly associated with both increased
transmission (D6S273*5; P < 0.02) and decreased transmission (D6S273*7; P
< 0.05) to affected individuals. The differential transmission was most
evident among DR3-B8 haplotypes. Thus, these data indicate that D6S273 marks a
susceptibility locus that increases diabetes risk associated with DR3
haplotypes 164. Linkage disequilibrium analysis suggested
that "diabetogenic haplotypes" might have resulted from a
recombination telomeric of D6S1014 in the region of D6S273 and TNF. The TNF
gene is a strong candidate since polymorphisms of this gene may affect the
production of TNFa (Tumor Necrosis Factor), a potent cytokine, and in turn the
magnitude of immune responses. It has
also been reported that TNFa polymorphisms are associated with age-of onset and
may influence the inflammatory process leading to the destruction of pancreatic
ß-cell and the development of IDDM 146.
In
addition, the class I chain-related MIC-A and MIC-B genes, located between the
HLA-B and the TNFa genes, may also affect IDDM susceptibility. MIC-A polymorphisms are associated with
disease susceptibility in several populations 165-172. In a
case-control study of Italian patients, the frequency of the MIC-A5 allele was
increased in patients while none of the TNFa alleles were statistically
significantly associated with the disease.
In this study, the MIC-A5 allele was associated with IDDM independently
of class II alleles, suggesting an independent contribution of this locus to
diabetes risk 165. MIC-A
alleles have a strong effect on development of Addison’s disease and a weaker
apparent influence on the development of type 1 diabetes. However, homozygosity for the MIC-A 5.1
allele (with a premature stop codon) was associated with increased diabetes
risk and faster progression to diabetes in young children followed from infancy
in the DAISY study, especially in those with the HLA-DR3-DQ2/DR4-DQ8 genotype 173. Finally,
HSP70-2 and HSP70-Hom genes are also located in the class III region although
there is no evidence for an independent association with IDDM from studies that
could not circumvent linkage disequilibrium 153, 174-178.
Clinical Heterogeneity of Type 1 diabetes in Relation to the IDDM1 Locus.
Age
dependent HLA heterogeneity has been observed in Caucasian IDDM patients,
indicating that high risk HLA genotypes occur at a higher frequency among the
younger age onset groups 103, 179-181, whereas
older age at diagnosis is associated with an increased heterogeneity of DRB1
and a decreased heterogeneity of DPB1 133. Caillat-Zucman and coworkers have found a
decreased frequency of DR3 and DR4 haplotypes and of DR3/DR4 heterozygosity
amongst patients who had developed diabetes after age 15 155. Similar findings were
reported by Tait et al. 139. Earliest development of
diabetes is strongly associated with the DR3/DR4-DQ8 genotype and such a
genotype is preferentially followed in the population based DAISY (Diabetes
Study of the Young) study 182. The
immunogenetic analysis of islet cell antibody (ICA) positive first-degree
relatives from our family study has confirmed that DR3 (in the absence of
DR4/DQB1*0302) is associated with a slower rate of progression to
diabetes. This slower rate may be in
part explained by a recessive lack of humoral response to insulin during the
prediabetic period that was noted in a subset of first degree relatives at
increased IDDM risk. This lack of humoral anti-insulin autoimmunity is mostly
associated with DR3 homozygosity, but it was observed also in relatives with
DR5 or DR8 haplotypes. All these haplotypes carry DQA1 alleles from the
evolutionary lineage 4 157, 158 sharing glutamic acid and
phenylalanine amino acid residues at position 40 and 51 of the second exon.
Thus, lack of or reduced humoral responsiveness to insulin during the
prediabetic period may be associated with this particular subset of DQA1
alleles rather than with DR3 itself 183. The percentage of new onset patients with
DR3/4-DQ8/DQ2 hetero zygosity, (genotype strongly associated with Type 1
diabetes risk and younger age of diabetes onset) has decreased dramatically
over the past 50 years 184-187. This suggests that lower risk genotypes have
become more “diabetogenic” as at the same time the incidence of type 1 diabetes
is increasing dramatically (doubling every 20 years)188.
Extended (Ancestral) MHC Haplotypes
Early
studies by Alper and co-workers and Dawkins and co-workers documented the
existence of haplotypes in the MHC region that were very large and relatively
common where all polymorphic markers were essentially all conserved 189, 190. With high throughput SNP analysis or
extensive sequencing the remarkable size and conservation of these haplotypes
has been confirmed 191, 192. In particular, the HLA-A1, B8, DR3 haplotype
is often conserved for more than 2.7 megabases, within which greater than 99.9%
of SNPs or sequences are identical.
Another remarkable haplotype is the A30, B18, DR3 “Basque” haplotype 193. Overall the 8.1 haplotype does not show
enhanced transmission to diabetics compared to non 8.1 DR3 haplotypes 92 while the
HLA-A30, B18, DR3 haplotype does show enhanced transmissions. It is likely that careful analysis of these
haplotypes will aid in localization of additional genes contributing to type 1
diabetes susceptibility.
We have
evidence from analysis in the DAISY study that there is a major gene(s) linked
to DR-DQ such that for siblings with DR3-DQ2, DR4-DQ8 sharing both MHC
haplotypes with their proband the risk of islet autoimmunity exceeds 60% 51 with type
1 diabetes following the appearance of islet autoantibodies by several years in
this high risk young population. In
contrast siblings with the same HLA DR and DQ alleles, but sharing only one or
no HLA haplotypes (despite being DR3/4-DQ2/DQ8) have a risk of activating anti-islet
autoimmunity of “only” 20% (figure 7.8).
This strongly implicates non-DR/DQ loci, linked to or within the major
histocompatibility complex contributing to diabetes risk. It also suggests that for this DR-DQ genotype,
environmental factors essential to activate anti-islet autoimmunity are
unlikely to be rare, given the extremely high penetrance of disease.
Figure 7.8
Extreme risk of type 1A diabetes for siblings of patients with type 1
diabetes who share both HLA haplotype identical by descent with their sibling
proband 51.
The Insulin Gene Locus, IDDM2
Insulin was the only autoantigen in humans for which
expression within the pancreatic islet is specifically restricted to
ß-cells. Recently
The
insulin gene (INS) is therefore an obvious candidate susceptibility
locus. Its role in disease susceptibility was easily demonstrated by
association studies and was replicated by linkage analysis 68, 216. Indeed,
the 4.1 Kb region containing INS
and its flanking regions contain several polymorphisms in linkage disequilibrium
that have been associated with diabetes risk 217. Extensive studies involving
polymorphisms in the neighboring HUMTHO1
(tyrosine hydroxylase) and IGF2 genes
provided strong evidence that INS is the main susceptibility determinant
in this region 194, 195, 218-221. All of the polymorphisms lie outside
coding sequences, confirming that diabetes susceptibility must derive from
modulation of INS transcription. Susceptibility in the INS
region, or the IDDM2 locus, has been
primarily mapped to a variable number of tandem repeats (VNTR) located ~0.5 kb
upstream of INS 222-224 (Figure
7.8). The VNTR may not explain all of the susceptibility in this region 209, 225 and at
least two other polymorphisms (-23HphI and +1140A/C) may contribute to the
etiological effect 226 (Figure
7.8).
The VNTR. This
polymorphic repeat, also known as the insulin gene minisatellite or ILPR
(insulin-linked polymorphic region), consists of a 14-15 bp unit consensus
sequence (ACAGGGGTCTGGGG) with slight variations of the repeat sequence. Any number from 30 to several hundred repeats
has been observed, but allele frequencies tend to cluster in the 30-60 repeats
range (class I alleles) or at 120-170 repeats (class III alleles). The
intermediate class II alleles are rare in Caucasians, and less rare in individuals
of African descent 227, 228. The
sequence of the VNTR is particularly G-rich, and it tends to form unusual DNA
structures in vitro and in vivo, presumably through the
formation of G-quartets 162, 229. Shortly
after its discovery 222, the insulin VNTR was
found to be associated with type 1 diabetes 208. Homozygosity for the short class VNTR I
alleles is found in ~75-85% of the patients compared to a frequency of 50-60%
in the general population, suggesting that it predisposes to type 1 diabetes.
In contrast, homozygosity for the longer class III VNTR alleles is rarely seen
in patients and the class III VNTR is believed to confer a dominant protective
effect 208, 230, 231. The
relative risk ratio of the I/I genotype vs. I/III or III/III has been reported
to be moderate (in the 3-5 range) and it accounts for about 10% of the familial
clustering of type 1 diabetes 232.
Moreover, by measuring the HphI
polymorphism (in tight linkage disequilibrium with the VNTR) 217, Metcalfe
et al. 233 showed
that homozygosity for the predisposing INS
genotype increases the likelihood that identical twins will be concordant for
the development of autoimmunity and diabetes in the BabyDiab study, in which
offspring of affected parents are followed prospectively from birth (Fig. 7.9) 234. Halminen
et al. 235 reported
that IDDM2-encoded susceptibility is
associated with reduced insulin secretory capacity found in
autoantibody-positive first-degree relatives (siblings) from the Childhood
Diabetes Study in Finland. This finding
may be explained with more aggressive autoimmunity against insulin in subjects
with the high-risk genotype and is consistent with the hypothesis that IDDM2 may modulate immune responsiveness
to insulin. There is evidence that the
insulin VNTR interacts with the AIRE transcription factor to influence thymic
epithelial cell expression of insulin236 though
such regulation varies237 and
cytokines also influence thymic insulin expression237.
Figure 7.9 Insulin gene VNTR (Variable Nucleotide Tandem Repeats)
polymorphisms increase risk of developing anti-islet autoimmunity in the
BabyDiab study.
VNTR
heterogeneity. Although VNTR alleles cluster in two main classes
with divergent associations with type 1 diabetes, there is evidence that VNTR
alleles are quite heterogeneous and may differ in their ability to modulate
disease susceptibility. Further
classification of VNTR alleles is indeed possible according to size differences,
and at least 21 class I and 15 class III VNTR alleles were described by
fluorescence-based DNA fragment sizing technology 238 (Fig. 7.7). Bennett et al. grouped the 15 class III VNTR
alleles identified according to two main modes of transmission based on the
linkage disequilibrium pattern with alleles at the HUMTHO1 locus on chromosome 11p15.
Thus, by taking both size and flanking haplotypes into account class III
VNTR alleles linked to the HUMTH01
Z-8 allele were found more protective (very protective haplotype or VPH) than
those linked to the HUMTH01 Z allele
(protective haplotype or PH) (Fig. 7.7) 238, 239. However, certain VNTR alleles can be found in
linkage disequilibrium with either the Z or Z-8 alleles. The variable degree of protection observed
for these alleles may also be influenced by sequence heterogeneity and its
effects on the VNTR physical state and transcriptional activity 162, 229, 232, 238, 240. Sequencing studies have indeed identified
several variants of the commonest VNTR repeat sequence that characterize yet
another level of heterogeneity 222, 227, 228, 232, 241.
Studies
have also analyzed the variant repeat distribution within the VNTR using
minisatellite variant repeat mapping by PCR (MVR-PCR) 242. Some of the variation
within the repetitive sequence most probably arises from mitotic replication
slippage at an estimated frequency of 10-3 per gamete. However, sperm DNA analysis revealed a second
class of mutation occurring at a frequency of approximately 2 x 10-5
that involved highly complex intra- and inter-allelic rearrangements which are
probably meiotic in origin 243. These
events may help explain the heterogeneity of the VNTR locus. The combined
analysis of the variant repeat distribution and of the haplotypes flanking the
VNTR has allowed defining five new ancestral allele lineages 220. By this
approach, class III VNTR alleles can be divided into two diverging lineages,
IIIA and IIIB (Fig. 7.10). These two
lineages correspond to the PH and VPH haplotypes previously defined by Bennett
et al. 238. Class I alleles can also
be divided into three newly defined lineages, IC+, ID+ and ID-. The lineage denomination reflect the class of
alleles, noted by the letter “I”, while the letters “C” or “D” identify two different
lineages defined by the very different distribution of variant repeats noted by
multi-dimensional scaling 220. The
notation “+” or “-“ refers to the presence (+) or absence (-) of a MspI restriction site at position
+3,850, so that depending on this haplotypic analysis lineages could either be
IC+, ID+ or ID- 220. IC+ and
ID+ alleles are predisposing to type 1 diabetes.
In
contrast, ID- alleles are protective when transmitted from ID-/III heterozygous
fathers. Similar findings had been previously reported for the class I allele
termed 814 (42 repeats), which is included in the ID- lineage (see next
paragraph). The analysis of class ID-
alleles into those of 42 repeats and those of other sizes suggested that the
protective effect was a feature of all ID- alleles, irrespective of size. However, ID- alleles are clearly
distinguished from all other alleles by a MspI
variant within the IGF2 gene. This suggests that at least for class I ID-
alleles the susceptibility conferred by the VNTR may be modified by nearby
sequences, and that in this case IDDM2
susceptibility may have a multi-locus origin (145). All together, the above
studies suggest that the VNTR locus is extremely polymorphic, and that not only
size of the VNTR but also sequence variation may play a significant role in
modulating INS transcription and
diabetes susceptibility.
Figure 7.10 The IDDM2
Susceptibility Locus. Top to bottom, the figure shows the HUMTH01, INS
and IGF2 loci, as well as a schematic structure of the insulin gene with
the approximate location of some of the most characterized polymorphic loci
(VNTR, HphI, DraIII, PstI). Also shown are a schematic representation of
the two main VNTR classes, their association with diabetes, as well as the VNTR
alleles and allele lineages that have been defined with the variety of
approaches described in the figure and in the main text.
VNTR effects
on transcription. Several studies have investigated the effects of the
VNTR on INS transcription236. Transfection of rodent ß-cell lines with
reporter constructs representing the INS
promoter flanked by class I or class III alleles resulted in three-fold
differences going in opposite directions in reports from different laboratories
223, 224. These
discrepant results may be due to species-specificity, differences among
specific alleles within each class, or the absence of the genomic context
necessary for the VNTR to have its physiologic effects. Studies on the transcriptional effects of the
VNTR in vivo produced more meaningful
results. In fetal pancreas RNA, the INS transcript in cis with the class III VNTR was expressed at lower levels (15-20%)
than the class I transcript, a small but statistically significant difference 219. Bennett et al. 238 found a somewhat larger
difference in adult pancreas. Moreover,
single nucleotide differences in the VNTR sequence can affect INS transcription and correlate with the
ability to form unusual DNA structures, both at the inter- and intra-molecular
levels 240. These
findings led to the hypothesis that VNTR variants may differ in their ability
to stimulate transcription as a function of the binding of inter- and
intra-molecular quartets with the transcription factor Pur1. However, the transcriptional activity of
these variants observed in vitro may
not always correspond to that in vivo,
where overall transcription may depend on the interaction with other proteins
involved in the transcriptional machinery and on differences among the various
cell types that actively transcribe the insulin gene. The studies described
above report only marginal differences in pancreatic INS transcription, and the lower transcription associated with
diabetes-protective class III VNTR alleles does not fit well with their
dominant protective effect. It seems
unlikely that such minor differences in pancreatic INS transcription may
influence susceptibility to a form of diabetes resulting from the autoimmune
destruction of pancreatic ß-cells.
It was
later discovered that INS is actively
transcribed in the thymus in mouse 225, rat 244, and humans 10, 116. The
human thymus was found to express low levels of INS message throughout fetal development and childhood but also
during adulthood 230. Overall, genes encoding
for several self-molecules have been found to be expressed in the thymus,
including pancreatic and thyroid hormones, neuroendocrine molecules and other
peripheral proteins 245. Functional studies in transgenic mice and
fetal organ thymic cultures have provided both in vivo and in vitro data
showing that thymic expression of self-antigens and their levels of expression
can dramatically affect the development of self-tolerance (reviewed in 246). The fact that negative selection of
autoreactive thymocytes is dose-dependent suggested the hypothesis that
different VNTR alleles may modulate tolerance to insulin by affecting insulin
expression levels in the thymus.
Consistent with this hypothesis, INS
mRNA levels in the thymus were found to correlate with VNTR alleles in opposite
fashion to that observed in the pancreas 238. INS transcripts in cis
with class III VNTR alleles are transcribed at much higher levels (on average
2-3 fold) than those in cis with
class I VNTR alleles 10. The increased
transcription levels detected in thymus fit well with the dominant protective
effect associated with class III VNTR alleles, as higher insulin levels in the
thymus may more efficiently induce negative selection of insulin-specific
T-lymphocytes (or improved selection of regulatory T cells). In contrast, homozygosity for diabetes-associated
class I VNTR alleles determines lower insulin levels that may be associated
with a less efficient deletion of insulin-specific autoreactive T-cells (or
impaired selection of regulatory T cells).
Proinsulin appears to be the main product of the insulin gene in the
thymus 116, 230. This is
not surprising since thymus cells expressing proinsulin are not likely to
possess the refined machinery necessary to process proinsulin to mature
insulin. Proinsulin expression may be
sufficient to obtain tolerance to insulin since most of the known immunodominant epitopes identified as targets of the
insulin autoimmune responses in type 1 diabetes are shared by both insulin and
proinsulin. Primarily thymic epithelial cells and to a lesser extent bone
marrow derived dendritic cells have been shown to transcribe INS and
other genes coding for self-molecules 230, 246-250. Similar
cells and INS transcription have also
been demonstrated in peripheral lymphoid organs, suggesting that insulin
expression in lymphoid organs may also play a role in maintaining peripheral
self-tolerance throughout life 230, 251. Direct
support for the hypothesis that levels of INS
expression in thymus and lymphoid organs can influence type 1 diabetes
susceptibility is provided by studies in insulin gene knockout mice and
transgenic mice 210, 212, 252-254, 246.
Other
effects at the IDDM2 locus. It is also possible that other
loci in the 11p15 region may also contribute to IDDM2-encoded susceptibility, as suggested for certain class I VNTR
allele lineages (ID-) 220. The four
promoters of the IGF2 gene are
situated only 5-20 kb downstream of the INS
VNTR, a distance that would allow
enhancer effects. IGF-II is a growth
factor with ubiquitous expression and has been implicated in biological
functions that could be relevant to autoimmune diabetes. These include inhibition of apoptosis 255 and the stimulation of
ß-cells proliferation 256,
functions that are of potential importance in resistance to immune injury and
regeneration, respectively. IGF-II is
also produced by T-lymphocytes 257 and can
influence an activation-induced autocrine loop that would amplify clonal
expansion of autoreactive T cells.
However, the demonstration that the INS-VNTR
does not influence IGF2 transcription
in the human thymus, pancreas, and leukocytes argues against a role for IGF2 as a major contributor to IDDM2-encoded susceptibility 258. It has
also been suggested that IGF-II expression in the thymus may be important for
the development of self-tolerance to IGF-II and other proteins of the
IGF/insulin family, including insulin 259. There
also appears to be a thymus defect in IGF-II expression in the thymus of
diabetes-prone BB rats, and this has led to the hypothesis that defective
IGF-II expression in the thymus of BB rats may impair tolerance to insulin and
favor diabetes development in BB rats 260-262. However,
it is controversial whether insulin is an autoantigen in the autoimmune
diabetes of BB rats 263. An
alternative hypothesis is that the thymic IGF-II deficiency reported in this
model may perhaps determine some more generic defects of the immune system and
not necessarily affect tolerance to insulin.
Overall,
the studies reviewed here suggest that the IDDM2
is a quantitative trait resulting from allelic variation and, as discussed in a
later paragraph, from complex parental and epigenetic effects at the VNTR
locus. IDDM2-associated
susceptibility and resistance may derive from quantitative differences in INS transcription in the specialized
antigen presenting cells found in thymus and peripheral lymphoid tissues, where
production of self-antigens such as proinsulin may be crucial for the shaping
and maintaining of a self-tolerant T cell repertoire 230, 264, 265. Such
mechanisms may influence the probability of developing autoimmune responses to
insulin, a key autoantigen in type 1 diabetes and thus risk of type 1 diabetes58, 266, 267.
PTPN22 (Lyp)
This gene
was also identified through the candidate gene approach. Bottini and coworkers
evaluated a functional polymorphism in the lyp gene (no relation to the
lymphopenia gene of the BB rat) in two series of patients with type 1 diabetes,
one from Denver and one from Sardinia 55. The odds ratio was approximately 1.7 (Figure
7.11), making this polymorphism the most potent after IDDM1(HLA) and IDDM2(insulin gene).The Lyp molecule,
coded for by PTPN22, is a
lymphoid tyrosine phosphatase located on chromosome 1p13. The relevant diabetes associated polymorphism
appears to be a missense mutation that changes an arginine at position 620 to a
tryptophan and thereby abrogates the ability of the molecule to bind to the
signaling molecule Csk 55, 56, 268. The lyp-Csk complex downregulates T cell
receptor signaling and thus loss of this interaction was thought to enhance T
cell receptor signaling, though a study by Bottini and c
Figure
7.11 PTPN22 (Lyp) genotypes. The minor T
allele is associated with type 1 diabetes.
CTLA-4
(IDDM12)
Linkage
with markers on chromosome 2q33 was initially reported in a group of Italian
families 272. This chromosomal region contains the CTLA-4
(cytotoxic T lymphocyte associated-4) and CD28 genes, which encode for two
molecules that are intimately involved in the regulation of T-cell activation
and proliferation. Differential
regulation of these molecules could easily affect T-cell function and hence the
regulation of immune responses. The
CTLA-4 gene is a strong candidate gene for autoimmune diseases since it encodes
for a molecule that functions as a key negative regulator of T-cell activation,
and the linked markers encompass a region containing an (AT)n microsatellite
located in the 3
Further
confirmation of association with the IDDM12-CTLA-4
locus came through linkage disequilibrium (association) analysis using a
multi-ethnic c
A
multiethnic (U.S. Caucasian, Mexican-American, French, Spanish, Korean, and
Chinese) c
In a very
large combined analysis of more than 3,600 families, Ueda and coworkers
reported that a CTLA-4 polymorphism was transmitted to 53.3% (versus the
expected transmission of 50%) to affected individuals, with a relative risk
1.14 (figure 7.10) 283. Susceptibility was mapped to a polymorphism
in the non-coding 6.1 kb 3’ end associated with lower messenger RNA levels of a
soluble form of CTLA-4, which results from alternative splicing. The 49 exon 1
G/G variant is associated with decreased expression of a soluble variant of
CTLA-4 that may have an influence on immune function, especially in light of
CTLA-4 polymorphism associated with diabetes of the NOD mouse 284, Graves’
disease 285, and
Addison’s disease 286. Evidence for linkage was also obtained in
2005 scan of the T1DGC, albeit the region is likely to contain also IDDM7 68. Because
the effect of the reported CTLA-4 polymorphism in human diabetes is so small,
lack of confirmation in smaller studies or discordant results among studies is
to be expected 285. However,
the biological contribution of this polymorphism remains to be assessed by
functional studies. Overall, CTLA-4 appears to be a stronger determinant for
Graves’ disease than for type 1 diabetes (figure 7.12). Concordant with its relatively weak effect in
the Wellcome Trust Case Control Consortium genome-wide association study of
2,000 patients and 3,000 controls, no SNPs at 2q33 were significant at either
the 5X10(-7) cutoff48. Of note, CTLA4 G allele of rs3087243 was more
strongly associated with patients with type 1 diabetes plus thyroid peroxidase
autoantibodies (OR=1.49) compared to those without the thyroid autoantibodies
(OR 1.16)287.
There is
controversy as to the specific polymorphisms associated with diabetes risk with
effects on CTLA-4 glycosylation (CTLA-4 17 Ala – T) as genetic influence more
associated with 3' region283, 288 and there
are contradictory reports of effects of secreted CTLA4 isoform283, 289.
Figure 7.12 Summary of CTLA-4 association with type 1 diabetes (man and
mouse) and Grave’s disease.
IL2RA(IL-2Rd
= CD25)
In the Wellcome Trust Case Control Consortium Study
SNP rs2104286 was analyzed with rs706778 referenced as the prior reported SNP
(HApMAp r2=.25) with finding of an association trend value of
8.0X10(-6), and p value of approximately 10(-8) with expanded control
series. The odds ratio was 1.30 for
heterozygotes and 1.57 for homozygotes 48. There
was evidence of two different SNPs associated with type 1A diabetes for the
IL2RA region (ss52580109 (P=7.8X10(-11)) and rs11597367(P=8.19X10(-7)). The odds ratio for the minor A allele of
rs11597367 was 0.78 (1.0/0.78=1.28). The
odds ratio for the ss52580109 minor A allele was 0.68 (1/0.68=1.47)290.
A large replication study failed to confirm the one
SNP291 while fine mapping implicated protection associated with a low
frequency SNP290. A
recent report evaluating healthy individuals correlated the K2 RA diabetes
associated haplotype with diminished K2 response and decreased Foxp3 expression292. The associated SNPs are located in region of
intron 1 of IL2RA and 5’ intergenic sequence between IL2Ra and RBM17 (RNA
binding motif protein 17). There is an
interesting observation (Figure 7.13) that soluble IL2 receptor correlates with
the genotype of the SNPs, though with very extensive overlap, leading to the hypothesis
that influence on diabetes might relate to lower immune responsiveness
contributing to type 1 diabetes 290.
Figure
7.13 Soluble IL2 receptor levels (serum)
relative to IL2RA SNP genotypes. Lowe et
al, Nature Genetics 39:1074, 2007.
IFIH1
The minor allele of rs1990760 of
the Interferon Induced Helicase region (IFIH1) was reported to be associated
with type 1 diabetes with a risk ratio of 0.86 in a large study of 4,253 cases,
5,842 controls, and with an additional 2,134 parent-child trio analysis. The
Wellcome Trust analysis utilizing a different SNP (rs3788964) found a genotypic
P-value of 7.6X10(-3) and Trend p-value of 1.9X10(-3), suggesting a very modest
association in this study 293. The gene is of particular interest in that it
may relate the innate immune system to the development of a disease presumably
mediated by the adaptive immune system, and animal models are available where
activation of innate immunity, and interferon alpha, is associated with
induction of autoimmune diabetes 294, 295. Polymorphisms of IFIH1 were not associated
with Addison’s disease, though study population for this rarer disorder relatively
small296.
KIAA0350
(16p13)
The association of KIAA0350 with type 1 diabetes
was discovered with the Wellcome Trust Case Control Consortium study with a
Trend P Value of 9.2X10(-8) and a heterozygous odds ratio of 1.19 and
homozygous of 1.55 (SNP rs12708716) 48. The
association was confirmed with analysis of 4,000 patients and 5,000 controls
(10(-8)) and in a family analysis (trios, 10(-6)). There are only two genes in the region, the
lectin KIAA0350 and dexamethasone-induced transcript. KIAA0350 is a putative C-type lectin, and
also has an immunoreceptor tyrosine-based activation motif (ITAM) 50.
PTPN2
(18p11)
In
the Wellcome Trust the region associated with PTPN2 (protein tyrosine
phosphatase, non-receptor type 2) was associated with all of the autoimmune
disorders studied, namely Crohn’s disease, rheumatoid arthritis and type 1
diabetes (for type 1 diabetes P=1.9X10(-6) with a heterozygote odds ratio of
1.30 and homozygote odds ratio of 1.62 48.
Follow up study gave a P value of 3.36X10(-10) with an odds ratio of
1.29 48. The
molecule is a member of the same family as PTPN22, an allele of which is
strongly associated with type 1 diabetes (R620W)48, 55.
The Wellcome Trust Case Control
Consortium (WTCCC) primary genome-wide association (GWA) scan 48 on seven diseases, including the
multifactorial autoimmune disease type 1 diabetes (T1D), has recently shown
associations at P < 5 10-7
between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and
4q27. Four of those regions have been replicated by another big study including
4,000 individuals with T1D, 5,000 controls and 2,997 family trios 50, 51: there was strong evidence for
disease association for chromosomes 12q24, 12q13, 16p13 and 18p11 in
independent cases and controls (P 1.82 10-6),
in families (P = 5.23 10-3
to 1.07 10-6)
and overall (P = 1.15 10-14
to 1.52 10-20).
12q13
In the WTCCC, SNP rs11171739 showed
strong evidence of association with T1D with heterozygote odds ratio (OR) of
1.34 and a homozygote OR of 1.75 and a genotypic P value of 9.71 x 10-11. This
SNP rs11171739 is close to the ERRB3 gene (v-erb-b2 erythroblastic leukemia
viral oncogene homolog 3) and another SNP rs2292239, in the ERRB3 gene, has
also shown association with T1D in the study by Todd et al 50, 51. The ERRB3 gene encodes a member of
the epidermal growth factor receptor (EGFR) family of receptor tyrosine
kinases. Amplification of this gene and/or overexpression of its protein have
been reported in numerous cancers, including prostate, bladder 297 and breast tumors 298. In diabetic rats, expression of
both ERRB2 and ERRB3 is enhanced during oral oncogenesis, possibly resulting in
promotion of cell proliferation and inhibition of apoptosis 299.
The VDR gene is located on chromosome 12q12-q14. Four common
single nucleotide polymorphisms (SNPs) in the VDR gene have been
studied: FokI T>C (rs10735810), BsmI A>G (rs1544410), ApaI
G>T (rs7975232), and TaqI C>T (rs731236). FokI
polymorphism in exon 2 results in an alternative transcription initiation site,
leading to a protein variant with 3 additional amino acids 300. SNPs BsmI and ApaI
are located in intron 8, and TaqI is a silent SNP in exon 9.
Several studies reported association of type 1 diabetes with one of
these four SNPs. Pani et al. genotyped 152 Caucasian families for these
four polymorphisms and suggested an association with T1D susceptibility in
Germans 301. Guja et al studied 204 Romanian
diabetic families and found that VDR FoqI F allele seemed to be predisposing
while TaqI T allele seemed to be protective 302. However, these associations have
not been confirmed in more recent and bigger studies: one study in the Finish
population (1000 cases and 2000 controls) 303, another report by Todd et al. with
up to 3,763 T1D families from the UK, Finland, Norway, Romania and US and 3414
case-control subjects from the UK 304, and finally a recently conducted
meta-analysis also found no evidence of association 305.
Recently, several studies have reported associations of type
1 diabetes and other autoimmune diseases with polymorphisms in the CYP27B1 gene
on chromosome 12q13.1-q13.3, which encodes 1[alpha]-hydroxylase, the enzyme
that converts 25-hydroxyvitamin D (25OHD3) into 1,25-dihydroxyvitamin D
(1,25diOHD3). Lopez et al. 306 report
a significant association between allelic variation of the promoter (-1260) C/A
polymorphism and Addison
Lower serum concentrations of 1,25-dihydroxyvitamin D
(1,25diOHD3), the hormonally active form of vitamin D, and of its precursor
25-hydroxyvitamin D (25OHD3) have been reported at the diagnosis of type 1
diabetes compared with normal control subjects 308,
309. Epidemiological studies have
suggested that vitamin D supplementation in early childhood is associated with
a decreased risk of developing type 1 diabetes 310,
311. In the immune system, vitamin D
and its analogs have been shown to function by stimulating Th-2
T-helper cells to produce transforming growth factor-1
and IL-4 that might serve to suppress the TNF-
and interferon-
production by Th-1 cells 312. In the animal models, 1,25diOHD31
and its analogs have been effective in prevention diabetes in NOD mice 313,
314.
12q24
The SNP (from the WTCCC study)
rs17696736 in C12orf30 (Chr. 12 open reading frame 30) maps to regions of
extensive linkage disequilibrium covering more than ten genes. Several of these
represent functional candidates genes because of their presumed roles in immune
signaling, considered to be a major feature of T1D-susceptibility. These include
SH2B3/LNK (SH2B adaptor protein 3), TRAFD1 (TRAF-type zinc finger
domain containing 1) and PTPN11 (protein tyrosine phosphatase,
non-receptor type 11). In the study by Todd et al. 50, 51, rs3184504, a nsSNP in exon 3 of SH2B3
encoding a pleckstrin homology domain (R262W), had the highest association (P
= 1.73 10-21;
OR = 1.33, 95% CI = 1.26–1.42). SH2B3 is an adaptor protein that regulates
growth factor and cytokine receptor-mediated pathways implicated in lymphoid,
myeloid and platelet homeostasis. It has been shown to negatively regulates
TNF-alpha expression in endothelial cells 315. TRAFD1, also known as FLN29, is a
novel interferon- and LPS-inducible gene that acts as a negative regulator of
toll-like receptor signaling 316.
PTPN11 is probably the most attractive candidate gene in the
region given a major role in insulin and immune signaling 317. It is also a member of the same
family of regulatory phosphatases as PTPN22, already established as an
important susceptibility gene for T1D and other autoimmune diseases.
12p13
In the multilocus analysis of the
WTCCC, there was increased support for a region on chromosome 12p13 containing
several candidate genes, including CD69 (CD69 antigen (p60, early T-cell
activation antigen)) and multiple CLEC (C-type lectin domain family)
genes. The SNP rs3764021 is located in the CLEC2D (C-type lectin domain
family, member D) gene, also known as LLT1 (lectin-like transcript). The LLT1
receptor induces IFN-gamma production by human NK cells 318. CD69 is involved in lymphocyte
proliferation and functions as a signal-transmitting receptor in lymphocytes,
NK cells and platelets. CD69 appears to be the earliest inducible cell surface
glycoprotein acquired during lymphoid activation. Locus 12p13 has not been
replicated so far.
22q13
SNP rs229541 close to the IL2RB gene
shows evidence of T1D association in the WTCCC study (P = 2.18 10-6), but has not been replicated so far. The
IL-2 receptor, which is involved in T cell-mediated immune responses, is a
trimeric molecule of alpha (IL2RA), beta (IL2RB, also known as CD122) and gamma
(IL2RG) chains. IL2RB is an interesting candidate as IL2Ra on chr. 10p15 is
already a known susceptibility gene for T1D. IL-2 plays a major role in the
proliferation of cell populations during an immune reaction 319.
18q22
In the study by Todd et al. 50, 51, another locus showed association
with T1D: rs763361 in the T lymphocyte costimulation gene CD226 on
chromosome 18q22 (Poverall = 1.38 10-8).
CD226 is a glycoprotein expressed on the surface of NK cells, platelets,
monocytes and differentiated Th1 cells. Anti-CD226 treatment has been shown to
delay the onset and reduce the severity of experimental autoimmune
encephalomyelitis, a Th1-mediated autoimmune disease 320.
The
initial evidence for linkage with marker D15S107 on chromosome 15q26 was
initially reported in 250 Caucasian families from the U.K., USA, and Canada 321. Families
lacking the typical HLA predisposition provided most of the evidence for
linkage, with sibling pair disease concordance or discordance being strongly
affected by allele sharing at the D15S107 locus 322. Linkage was confirmed in additional studies
of 104 U.S.A. Caucasian families 323 and 81 Danish families 324. In the Danish data set,
the D15S107*130 allele provided increased susceptibility with a relative risk
of 3.55 and the D15S107 locus was found to contribute up to 16% of the familial
clustering of type 1 diabetes 324. However, linkage was not
confirmed in another data set of 265 Caucasian families 325. Studies of Han chinese
nationality found allele A5 at D15S657 increased in frequency in patients 326. At present there is no known candidate gene
in the 15q26 region, and evidence for IDDM3 has not been replicated in
the 2005 T1DGC scan 68.
Several
studies reported evidence for the existence of the IDDM4 susceptibility locus. This locus is tightly linked to the
FGF3 marker on chromosome 11q13 323, 325, 327-330. Evidence
was found for a decreased transmission (46.4%) to the affected offspring of a
15 Kb stretch of DNA containing two tightly linked alleles (D11S1917*03 and
H0570polyA*02) 331. In
contrast, the D11S1917*03-H0570polyA*02 haplotype showed increased transmission
(56.6%) to unaffected siblings. These
results suggest that IDDM4
susceptibility may derive from a gene very close to the D11S1917 marker.
Moreover, similar to that discussed for IDDM1
and IDDM2, these findings show that
analysis of both predisposing and non-predisposing alleles may be of value when
mapping genes for common polygenic diseases 331. A subsequent study provided further evidence
for linkage with a peak LOD score of 3.4 at the D11S913 marker 332. Moreover, the extended transmission
disequilibrium test (ETDT) revealed significant association/linkage with the
marker D11S987 (P= 0.0004) within an interval of approximately 6 cM between
D11S4205 and GALN. Several candidate
genes can be found in this chromosomal region.
MDU1, encoding a cell-surface cell protein regulating intracellular
calcium, and ZFM1, a nuclear protein, are both expressed in the pancreas. The RT6 gene lies also in this region, coding
for a T-cell protein that is deficiently expressed in the BB rat animal model
of diabetes 328. The interleukin-converting enzyme (ICE) and
CD3 genes were also proposed as candidates to explain IDDM4 susceptibility. However, the CD3 gene has been excluded by
both association and linkage analysis 333. A previous report of an association of the
CD3 gene with T1D could have been due to population stratification 334. The gene coding for the low-density
lipoprotein receptor related protein 5 (LRP5) has been mapped within the
boundaries of the IDDM4 locus and
proposed as yet another candidate.
However, its functional role in the pathogenesis of T1D remains unclear 335. A large
study of markers in the LRP5 region involving 1,106 T1D families provided no
further evidence for disease association at LRP5 or at D11S987. In the same
study, the analysis of 1,569 families from Finland failed to replicate linkage
at LRP5 283. Three additional genes have been identified
in the LRP5 region: the CGI-85 gene and two novel genes, C11orf24 and C11orf23.
The C11orf24 gene has no known similarity to other genes, and its function is
unknown. C11orf23 has similarity which genes involved in regulation of the cell
cycle 336. Finally, the gene coding for the
Fas-associated death domain protein FADD/MORT1 has been mapped to chromosome
11q13.3 337. Both its
chromosomal localization and function in apoptosis, a mechanism of cell death
implicated in the autoimmune destruction of ß-cells 338, 339, 339, make it
another plausible candidate for a susceptibility gene at the IDDM4 locus. However, polymorphisms in the FADD and GALN
genes were not found to be associated or in linkage with diabetes 332. Supporting evidence for IDDM4 has not
been replicated in the 2005 T1DGC scan 68.
Linkage
with the 18q12-q21 region, and in particular with the Kidd Blood group locus
(JK), was suggested almost 20 years ago 349 and linkage
to the JK-D18S64 marker was initially confirmed by the very first genome-wide
scan performed in 1994 327. The Transmission
Disequilibrium Test (TDT) provided evidence for increased transmission of
allele 4 of marker D18S487 to affected children in a total of 1,067 families
from four different countries. Analysis using the TDT also provided evidence
for genetic heterogeneity, which can often play as a confounding factor when
mapping susceptibility genes in complex diseases 350. Additional evidence for
the existence of the IDDM6
susceptibility locus near D18S487 was provided by another large study of 1,708
families from seven different countries 351. There is evidence that this region may
predispose to several autoimmune diseases 342. Later studies in the Finnish population and
the 2005 T1DGC genome wide scan did not confirm evidence for linkage at this locus
68. A
candidate gene has been reported in this region, ZNF236, a gene coding for a
Kruppel-like zinc-finger protein. ZNF236 is ubiquitously expressed in all human
tissues tested. Its expression levels are highest in skeletal muscle and brain,
intermediate in heart, pancreas, and placenta, and lowest in kidney, liver, and
lung. Two alternative spliced forms of the ZNF236 transcript have been found to
be up-regulated in human mesangial cells in response to elevated levels of
glucose, suggesting that ZNF236 may be a candidate gene for diabetic
nephropathy 352.
Linkage on
chromosome 2q near the marker D2S326 was initially reported in U.K. families 327 and was later observed for
the D2S152 marker (2q31-q33) in 348 affected sibling pairs and 107 simplex
families from three different populations 353. Further
analysis and expansion of the above data sets did not reproduce evidence for a
susceptibility gene in this region 278, similar
to studies of families from the U.S.A. and China 325, 354. However,
linkage has been replicated in 241 Danish families 355. Analysis
of a combined 831 affected sib pairs by Cox and coworkers gave suggestive
evidence for 2q31 (IDDM7) 216, and this
has been confirmed in the 2005 T1DGC genome scan 68, in a
region that also comprises IDDM12. IDDM7
lies within two centiMorgans of D2S152, a chromosomal region that is synthenic
with the nonobese diabetic (NOD) mouse chromosome 1 region containing the Idd5
susceptibility gene 330, 353. The HOXD8 gene has been proposed as a
possible susceptibility gene at the IDDM7
locus 356. Another potential candidate gene in this chromosomal
region is NEUROD, another transcription factor regulating the expression of the
insulin gene and playing an important role in the development of pancreatic
ß-cells. The NEUROD gene has been mapped
to the long arm of human chromosome 2 (2q32).
A polymorphism consisting of a nucleotide G-to-A transition results in
the substitution of alanine to threonine at codon 45 (Ala45Thr). The analysis
of this polymorphism in Japanese and Danish patients suggested an association
with type 1 but not type 2 diabetes 357, 358, but a
case-control study in France did not find a similar association 359. The frequency of the Ala45 allele was 70.3%
in Polish patients and 62.9% in controls (p= 0.04) but a TDT analysis with 209
trio families did not show significant distortion of transmission 360. Another candidate gene in this region is
GALNT3, which encodes a polypeptide N-acetyl-galactosaminyltransferase-T3
(GalNAc-T3) and was mapped to a region
5-25 cM from D2S152 361. GalNAc transferases may influence
autoimmunity by glycosylating autoantigens. However, both a marker
corresponding to GALNT3 (D2S2363) and the T284A polymorphism in the GALNT3 3
Several
groups reported evidence for linkage with markers D6S264, D6S446 323, 327, and
D6S281 325, 340, 341 on
chromosome 6q25-q27 . At present there is no known candidate gene in the
6q25-q27 region. Owerbach has defined a
linkage disequilibrium map of nearly 1 Mb in the 6q27 region and identified
multiple haplotypes associated with IDDM8, suggesting localization of
this putative susceptibility locus to the terminal 200 kb of chromosome 6 362. The IDDM8 locus may also be subject to
parental effects 363 and may
confer susceptibility to rheumatoid arthritis as well 364. Analysis of 831 affected sib pairs in the
study of Cox and coworkers implicated IDDM8 only after stratification by
HLA genotype 216. Owerbach
et al. examined five potential candidate genes in the IDDM8 region using 36
genetic markers in 478 families and detected evidence for an association of a
CAG/CAA polymorphism in exon 3 of the TATA box-binding protein gene 365. There is also evidence
that the IDDM8 region contains polymorphisms in the insulin-growth factor II
receptor gene that are associated with increased susceptibility when maternally
transmitted 366.
Initial
evidence suggested a susceptibility locus on chromosome 3q21-q25 in linkage
with marker D3S1303 327. IDDM9 appears to be distinct from a susceptibility locus for
Rheumatoid Arthritis reported on chromosome 3q 367. Laine et al. 368 analyzed 22
microsatellite markers in 121 Finnish type 1 diabetes multiplex families in the
IDDM9 region and detected LOD scores of 3.4 and 2.5 with markers D3S1589
and D3S3606, respectively. Two additional markers showed association using the
TDT in 384 Finnish type 1 diabetes simplex families. Marker AFM203wd10 showed
association with type 1 diabetes. Interestingly, there was evidence of
interaction with IDDM2. There was no strong evidence of linkage in the
2005 T1DGC genome scan 68.
Another
susceptibility locus may exist on chromosome 10p11-q11 (marker D10S193), and
has been termed IDDM10 327.
Additional support for the existence of IDDM10
was provided by the TDT analysis of 1, 159 families with at least one affected
child from the U.K., the U.S.A., Norway, Sardinia, and Italy 369. A study in Russian
patients gave a multipoint LOD score (MLS) of 2.2 between markers D110S1733 and
D10S1780, while Todd and coworkers analyzed 418 United Kingdom sib pairs and
did not confirm linkage 370, 371. Evidence
for linkage was confirmed by the 2005 scan of the T1DGC with D10S1426 68. The IDDM10 locus may be subject to parental
effects 363 and may
play a stronger role in younger patients 372. A
possible candidate gene may be Stromal-cell derived factor-1 (SDF-1) 373. Nejentsev and c
IDDM11 appears to lie on chromosome
14q24.3-q31 and was linked to the microsatellite D14S67 using both maximum likelihood
methods and affected sib pair methods. This represents the strongest evidence
for linkage to any locus outside the HLA region. Similar to IDDM3, the strongest linkage (with the
D14S67 marker) was obtained in a subset of families lacking increased HLA
sharing among the affected offspring, suggesting that IDDM11 may be an important susceptibility locus in families lacking
strong HLA region predisposition 375. Supporting evidence for IDDM11 has not
been replicated in the 2005 T1DGC scan 68. Two
candidate genes have been mapped to this chromosomal region. The ENSA gene
encodes alpha-endosulfine, an endogenous regulator of ß-cell K(ATP) channels 376. The recombinant alpha-endosulfine has been
shown to inhibit sulfanylurea binding to ß-cell membranes, to reduce cloned
K(ATP) channel currents, and to stimulate insulin secretion from ß-cells. The
SEL-1L gene encodes for a negative regulator of the NOTCH, LIN-12, and GLP-1
receptors, which are required for differentiation and maturation of cells as
well as cell-to-cell interactions during development 336. SEL-1L
is abundantly expressed only in the pancreas, and appears to be involved in the
down-regulation of mammalian Notch signaling, shown to be critical for the
development of the pancreas and ß-cells 337. However, a study of families from Denmark and
Sardinia found no evidence that SEL-1L is directly linked to diabetes 377.
The IDDM13 susceptibility locus lies in the
2q34 region and is linked to the D2S164 marker in Caucasian families from Australia
and the U.K. (BDA Repository) 378. Similarly to IDDM3 and IDDM11, IDDM13 may be of
particular interest since it was detected in non-HLA identical siblings,
suggesting that yet another locus may be an important susceptibility factor in
subjects lacking the typical HLA predisposition. It has also been suggested
that IDDM13 may be active early
during the evolution of diabetes since linkage was found also in prediabetic
subjects. Moreover, it appears that IDDM13 may favor diabetes development
predominantly in males 379. Several biological explanations are possible
for these findings, including X and Y linkage, effects of sex hormones on gene
expression, and quasi-linkage between sex chromosomes and autosomes. Another study in Japanese families has
confirmed linkage to the D2S137 microsatellite in siblings lacking HLA
predisposition 380. In contrast, little
evidence for IDDM13 was found in a
data set including 352 U.K. families and 94 U.S.A. families 278. Some
evidence for linkage and association of the IDDM13/D2S137-D2S1471
region (approximately 3.5 cM) was found in Danish families 279. It is of interest that IDDM13, IDDM7, and IDDM12, are
all located on chromosome 2q31-35. This region may correspond to the mouse
Idd5, possibly a multigenic susceptibility locus in the NOD mouse. Candidate
genes in the region include the insulin growth factor-2 and 5 binding proteins
(IGFBP2, IGFBP5), which are expressed at decreased levels in patients with type
1 diabetes 381. A number
of polymorphisms of IGFBP2, IGFBP5 and other genes in the region (including
NEUROD, HOXD8, and CTLA4) were not associated with diabetes in a case-control
study 382.
IDDM14
This denomination has not been
assigned to any locus.
Linkage
with the microsatellite D6S283 on chromosome 6q21 has been reported in families
from France, Denmark, and the U.S. An
Analysis of 408 multiplex families from Scandinavia confirmed HLA, INS, and IDDM15
383. This
locus is linked to HLA in males but not in females 341. IDDM15 is the third locus localized on 6q together with IDDM5 and IDDM8, but there is no evidence that these loci interact or are
linked to IDDM1 on chromosome 6p.
Multilocus analysis shows that linkage decreases with increasing distance from IDDM1 (Lod Score IDDM15>IDDM5>IDDM8) 341. As discussed later in
this chapter, parental effects may influence susceptibility at the IDDM15 locus, and it has been suggested
that the susceptibility gene at this locus may correspond to an imprinted gene
associated with transient neonatal diabetes mellitus 341, 384, 385. Evidence
for IDDM15 has been replicated in the latest genome scan performed by
T1DGC, and this study provided evidence that this locus confers susceptibility
independently of IDDM1 68.
Field and
coworkers analyzed immunoglobulin heavy chain (IGH) region microsatellites in
351 North American and British families and 241 families from Denmark with
affected sibling pairs. Linkage was obtained for three markers close to the IGH
gene cluster using affected sib-pair analysis but not using family-based
methods. There was no linkage in the Danish data set but significant evidence
for association, suggesting the IGH region may influence susceptibility to type
1 diabetes 386. The study raises the possibility that an
immunoglobulin heavy chain gene may contribute to an autoimmune disorder with
anti-islet autoantibodies. There was no evidence for IDDM16 in the 2005
T1DGC scan 68.
Unlike all
of the preceding susceptibility loci, which have been mostly pinpointed by
studying large c
Morahan
and coworkers 389 reported linkage
dysequilibrium between a single base pair change in the 3’ UTR of the IL12B
gene (5q31.1-q33.1) and type 1 diabetes in two Australian cohorts . This gene encodes for the p40 subunit of
interleukin-12 (IL-12). IL-12 is a disulphide-linked heterodimer composed of a
heavy chain (p40, 40 kDa) and a light chain (p35, 35 kDa). The IL12A gene located
on chromosome 3 encodes the light chain.
The resulting heterodimer (p70 or p75) is the biologically active form
of IL-12. IL-12p40 has been shown to stimulate Th-1 differentiation and IL-12
accelerates diabetes development in NOD mice. Thus, the IL-12B gene appears to
be an important candidate gene in terms of immune function. Unfortunately, multiple studies of family
datasets from the U.K., U.S. and Scandinavian countries did not reproduce
evidence for linkage 68. A
possible functional influence of the 3’ UTR on the mRNA expression levels of
Il-12p40 remains unconfirmed, but it mostly relied on mRNA analysis in EBV cell
lines without stimulation. While later
studies used peripheral blood lymphocytes, a clear functional significance was
not found 390. Further
validation of the original findings reported by Morahan and whether the IL12B
locus is a bona fide susceptibility seems critical, while there was no further
evidence in the 2005 T1DGC scan 68.
Linkage
has been reported with a few other loci that have not received an official
denomination. The glucokinase gene (GCK) on chromosome 7 was linked to IDDM in
339 affected sib-pair families, but this finding has not been reproduced in other
studies 391. Linkage
was also reported for the D1S1617 marker on chromosome 1q (D1S1617) 392, and yet
another locus may lie on chromosome X linked to markers DX6678 and DXS1068.
This locus may influence the male-female bias in HLA-DR3-positive patients 393. The combined analysis of multiple data sets showed
the most dramatic linkage (LOD=3.83) after IDDM1
and IDDM2 with a region on chromosome
16q22-q24 in association with D16S3098.
This was the only “significant” LOD score (outside of IDDM1 and IDDM2) in this study of 767 multiplex families of Cox et al. 216. Evidence for linkage at this locus has been
confirmed in the 2005 T1DGC genome scan.
In this study, additional chromosomal regions with linkage to diabetes
were 3p13-p14 (D3S1261), 9q33-q34 (D9S260), 12q14-q12 (D12S375), 16p12-q11.1
(D16S3131, 16q22-q24 (D16S504) and 19p13.3-p13.2 (INSR) 68.
The genetics of type 1 diabetes is further
complicated by the possible existence of parental effects acting on the
transmission and expression of inherited genes. Several studies have shown that
diabetes risk differs in the offspring of diabetic mothers and fathers,
although the results of different studies have been discrepant 394, 395. It is also controversial whether parent of origin effects influence
the transmission of IDDM1 alleles to
the diabetic offspring 396-398. Moreover, there is evidence that parental origin effects may be
operative at the IDDM8, IDDM10, and IDDM15 loci 341, 363.
Parental effects also influence the transmission of
the VNTR alleles at the IDDM2 locus,
and probably this is the most studied locus in this regard. The first report of
linkage at the IDDM2 locus found
evidence, in a small subset of families that were informative for parental
origin, that the excess allele sharing was exclusively paternal 399. Most of the subsequent studies of intra-familial
association demonstrated a statistically significant difference only for
paternally transmitted alleles 180, 400 401. These observations may be explained by imprinting,
a mechanism that regulates gene expression by silencing either the maternal or
the paternal allele. The silencing
effect results from the epigenetic modification (probably mediated by
methylation) of the DNA during the passage from the male or the female
germline. This modification of the DNA
marks the genetic material as maternal or paternal (parental imprint). Of note, the insulin gene is located in a
region of the human genome that is known to be subject to parental imprinting 401. The IGF2
gene, which is adjacent to the insulin gene on chromosome 11p15, was the first human gene found to be
imprinted and it is expressed exclusively from the paternal chromosome 402. Several other genes in the region are expressed
from the paternal or maternal chromosomes only, at least in some tissues or
developmental stages 403. INS is
expressed from both copies in the pancreas of mice 404, human fetuses of 7-20 weeks gestation 219 and adult humans 239, 405. However, monoallelic INS
expression was observed in the pancreas of a 40-week old female fetus 405. INS is also expressed monoallelically,
and specifically from the paternal chromosome in the mouse yolk sack 238. In addition, evidence has been presented for the
imprinted paternal expression of INS
in the human yolk sac 406. Thus, imprinted expression can depend on the tissue and possibly the
developmental stage 407. The effects of imprinting on insulin expression may influence insulin
expression during development and susceptibility to insulin/growth-related
diseases in later life, such as insulin resistance and type 2 diabetes 406. More importantly, it has been shown that INS can be expressed monoallelically in the thymus 10, 116. In all instances identified, the silenced allele was the one in cis with a class III VNTR. Such monoallelic expression resulting from
the silencing of class III VNTR transcripts in the thymus may prevent the
protective effect associated with the class III VNTR and explain the
parent-of-origin effects discussed above.
Vafiadis et al. studied in more detail the class III alleles that were
silenced in the thymus 408. They developed a DNA
fingerprinting method for identifying the type of alleles corresponding to the
class III VNTR alleles that were found silenced in two thymus samples (S1, S2),
and then analyzed the parental transmission of these type of class III alleles
in a set of 287 diabetic children.
Twelve of 18 possible transmissions of alleles matching the fingerprint
of the S1 or S2 alleles were transmitted to the diabetic offspring, at a
frequency of 0.67, which is significantly higher than the frequency of 0.38
seen in the remaining 142 class III alleles. These findings suggest that certain class III
alleles may be predisposing instead of protective, and presumably these alleles
are silenced in the thymus with obvious effects on the development of tolerance
to insulin. Moreover, monoallelic INS expression was reported in the
spleen of an 18 year-old Caucasian male, again preventing the expression of the
INS transcript in cis with the class III VNTR allele 405. Assuming that monoallelic expression in this
subject was mediated by imprinting (parents were unavailable to determine the
parental origin of the silenced allele), this finding suggests that the imprint
status may be maintained beyond development and perhaps throughout life.
There is
also evidence for even more complex mechanisms regulating INS transcription. Bennett
et al. 409 studied more than 1,300
triads (two parents and affected child) and showed that the most common class I
VNTR allele among Caucasians, termed 814 in arbitrary electrophoresis’ mobility
units, has a protective effect similar to that of class III VNTR alleles. A protective effect of the 814 allele was
independently confirmed in Basque families 272. This protective effect was apparent only when
the 814 allele was inherited from fathers with an 814/class III VNTR genotype. In contrast, fathers with an 814/class I VNTR
genotype transmitted both the 814 and other class I VNTR alleles to their
diabetic children at similar frequency.
This unusual transmission pattern suggests that this allele may behave
differently in the offspring depending on the father
Besides
parent of origin effects and other epigenetic phenomena, there is also evidence
that alternative splicing can affect gene expression in a tissue specific
manner and predispose to certain conditions 412. These include type 1
diabetes, multiple sclerosis, and other neurological diseases 413. In the case of type 1 diabetes, alternative
splicing may affect the probability that one would mount autoimmune responses
to the autoantigen IA-2. IA-2 is a
tyrosine-phosphatase-like protein enriched in the secretory granules of islet
and neuroendocrine cells and consists of a single transmembrane (TM) region
(residues 577-600) and extra- and intra-cellular domains 414, 415. An alternatively spliced variant of the IA-2
transcript has been discovered through the sequencing of a clone (ICA512.bdc)
derived from a human pancreas library that is routinely used as a source of antigen
in a specific assay for the detection IA-2 autoantibodies 416. This alternatively
spliced transcript lacks exon 13 (Dexon 13), which codes for
73 amino acids (aa 557-629) encompassing the TM and juxta-membrane
domains. The evaluation of the IA-2
expression in islets, thymus and spleen from non-diabetic human tissue donors
revealed that thymus and spleen specimens exclusively express the Dexon 13 transcript and lack expression of the full-length
transcript. Both transcripts are expressed in the pancreas. Another alternatively
spliced IA-2 transcript in which 129 bp of exon 14 are spliced out, resulting
in the deletion of 43 amino acids (aa 653-695) in the intracellular domain, was
detected in about 50% of the pancreatic samples studied but essentially in none
of the thymus and spleen specimens. Thus, alternative splicing causes
differential IA-2 mRNA and protein expression in pancreas compared to lymphoid
organs. Such differences may affect
immune responsiveness to specific epitopes and help explain why IA-2 and not
many other islet proteins become targets of autoimmunity in IDDM. Tolerance to
linear or conformational epitopes typical of the full-length protein or of the Dexon
13 variant may not be achieved if these epitopes are expressed in islets
but not in lymphoid organs. The specific
lack of expression of the TM/Juxta-membrane domains (exon 13) in lymphoid
organs helps in explaining why epitopes from these domains are often targeted
by autoimmune responses in IDDM 413. Autoantibodies against IA-2 epitopes encoded
by exons 13 and 14 have been reported in patients and can precede the
appearance of autoantibodies against other intra-cellular epitopes (epitope
spreading) 417-420. There is evidence that the HLA-DR4
restricted, naturally processed 654-674 epitope (exon 14) is recognized by
autoreactive T-cells 421. Similar
to the parent-of-origin effects affecting insulin gene expression in thymus 10 and peripheral lymphoid
organs 116, 405,
differential IA-2 splicing appears to function as mechanism regulating gene
expression independent of inherited alleles at the insulin and IA-2 loci. Although investigations had excluded linkage
with IA-2 polymorphisms 278, these findings suggest that expression
studies for selected candidate genes in tissues relevant to the disease process
can help dissect the complex genetics of a multi-factorial disease such as type
1 diabetes.
Factors
other than inherited genes must play a role in determining progression to overt
disease in those individuals carrying predisposing genes. Environmental factors
(viruses, diet) are suspected to be such determinants (reviewed in ref. 422). The ability to identify
genetic risk is aiding the search for environmental factors. It has been
suggested that early introduction of cereals into infant diets dramatically
increases development of anti-islet autoimmunity of high-risk (HLA/family
history) individuals 423, 424. Viruses
could trigger specific autoimmune responses through mechanisms of molecular
mimicry or by mediating a direct insult to ß-cells. It is also an intriguing
and yet unproven possibility that novel genes may be acquired through, or their
expression stimulated by, environmental factors (viruses or diet) after birth.
Unlike more common viruses, retroviruses can integrate in the human genome.
Retroviral genes can be either inherited or acquired after birth, and common
viral infections and/or sex hormone changes associated with puberty may
activate quiescent retroviruses. Such acquired expression may trigger the
development of diabetes in genetically predisposed individuals either via
cross-reactivity or immunity against novel viral antigens previously unknown to
the immune system. This could drive immunity against the tissue that is
expressing the novel gene, or to any tissue expressing molecules with
significant cross-reactivity. Thus, environmental factors may provide or
activate genes that could act as "disease genes". This hypothesis was
supported by the finding that a human endogenous retrovirus, termed IDDMK1,
222, is apparently expressed and released from leukocytes in patients with type
1 diabetes but not in control individuals 425. Yet it is unclear whether
this or similar retroviruses could be expressed in the endocrine pancreas. It was also suggested that IDDMK1, 222 could
drive the same T-cell receptor restriction observed in T-lymphocytes
infiltrating the endocrine pancreas of two children who died at the onset of
diabetes 426, and act as a
superantigen. However, the role of IDDMK1, 222 has been questioned by later
studies. In fact, IDDMK1, 222 was found expressed at similar frequencies in
patients and controls in several studies and no evidence for autoreactivity
against this virus has been reported 427, 428. The
analysis of polymorphisms in the region of the endogenous retrovirus HERV-K18
or the DNA flanking it, including the CD48 gene, provided evidence for
association of three variants belonging to a single haplotype. Genotype
analysis suggested a dominantly protective effect of this haplotype. Further
genetic and functional analyses are required to confirm these findings 429.
With
current knowledge, high-risk individuals can be identified by genetic analysis
in the general population 60. Extremely
high-risk individuals can be identified in families. In particular a number of large population
based studies have been carried out stratifying individuals at birth by HLA
genotype and insulin gene polymorphisms.
Children born in Denver with the highest risk genotype DR3/4-DQ8
(further increase in risk can be provided by DRB1*04 and DP sub-typing) comprise 2.4% of newborns
and almost 50% of children developing anti-islet autoimmunity by age five
(DAISY study) 182, 430. The BabyDiab study of offspring of patients
with type 1 diabetes in Germany and the DIPP study from Finland provide similar
information concerning the risk associated with specific HLA genotypes and
insulin gene polymorphisms 234, 431-434. Of note, a recent report from the Baby Diab
study indicates that simply adding together the number of risk alleles from 12
non-HLA loci (ERBB3, PTPN2, IFIH1, PTPN22, KIAA03550, CD25, CTLAF, SH2B3, IL2,
ILI8RAP, IL10 and COBL) high and low risk(e.g. <12 risk alleles) children followed from birth could be
identified58.
In the
DAISY study, siblings of patients with type 1 diabetes who have the highest
risk HLA genotype (DR3/4-DQ8) have a risk of activating anti-islet autoimmunity
of approximately 50% versus a risk of approximately 5% for the general
population and intermediate risk for offspring with the same class II HLA
alleles. This dramatic difference in
risk is at present unexplained and we have termed it the “relative
paradox”. A risk exceeding 50% for
children who at birth are characterized only by high-risk class II HLA alleles
(and if both the highest risk DR-DQ alleles and identical by descent for HLA
haplotypes51) and
relation to a proband with type 1 diabetes suggests that if environmental
factors are of importance they are ubiquitous or “family” based. There may be ubiquitous environmental factors
but being ubiquitous they play a minor role in determining familial aggregation
of type 1 diabetes. The difference
between relatives and the general population with the same class II HLA alleles
could also be explained by additional genetic polymorphisms outside the HLA
complex. Combined analysis of
polymorphisms of the insulin and PTPN22 genes may further refine prediction 435. Among
first-degree relatives with the high-risk HLA genotype that were followed for 3
years, 9 of 43 (28.1%) with the high-risk -23HphI polymorphism developed
anti-islet autoantibodies versus two of 36 (5.6%) relatives with the lower-risk
-23HphI genotypes. However, PTPN22 polymorphisms did not show a significant
difference in risk by genotype in a study of 85 relatives. Overall, these
results highlight the multiplicative risk of combined high-risk genotypes at
different loci in terms of time to autoantibody and autoimmune disease
development.
In
addition, it is plausible that polymorphisms linked to the HLA complex or
modulating the effects of the primary HLA determinants may have a greater
impact on familial aggregation. This
hypothesis stems from the observation that DR3/4-DQ8 siblings of patients with
type 1 diabetes in the Denver DAISY study are almost always HLA identical to
their sibling with diabetes. Namely,
they share the complete HLA region by descent with their affected sibling, and
thus all polymorphisms in this region are inherited together. There is growing evidence that polymorphisms
of genes such as DP436, class I HLA, and other
genes within this region can modulate and contribute to risk and these would in
families be shared with patients. In contrast, DR3 and DR4 haplotypes in the
general population may not always carry the full complement of susceptibility
alleles. A major effort to further
dissect risk associated with the HLA region remains therefore crucial.
At present
we can predict greatly increased risk of type 1 diabetes and a series of other
autoimmune disorders by genetic typing at birth, using primarily information
provided by HLA DNA based typing. The
importance of this information will primarily be driven by our ability to use
that information to prevent morbidity and mortality. For some disorders such as celiac disease,
strongly associated with HLA-DR3-DQ2 haplotypes, altering the intake of gliadin
is an effective therapy, and timing of gliadin introduction may be an important
risk factor given genetic susceptibility.
For type 1 diabetes we do not at present have a preventive therapy, but
participation in studies such as DAISY decrease morbidity at the time of
diagnosis 182.
Whereas only 1 child of 30 in the DAISY study (HLA typing at birth
followed by anti-islet autoantibody determination and metabolic follow up)
required hospitalization at the onset of diabetes, approximately 40% of
children presenting with diabetes of the general population (without screening)
presented with ketoacidosis and required hospitalization 182. As
illustrated in Fig. 7.14, many of the children from the general population had
glucose greater than 1,000 mg% at diagnosis, and there is an important risk of
death from cerebral edema when diagnosis of diabetes is delayed. Of note, even children from the general
population (“control”) with a relative with type 1 diabetes presented with
severe metabolic abnormalities. This
prevention of onset morbidity will need to be balanced against increased
anxiety in families where a child is identified with increased disease
risk. We believe it is likely that as
the major efforts for prevention and rational treatment of a series of
autoimmune diseases are developed, the balance will weigh toward
identification, similar to newborn screening for a series of diseases in
developed countries.
“MONOGENIC” FORMS OF IMMUNE
MEDIATED DIABETES
Dramatic
progress in the understanding of the immunogenetics and pathogenesis of
immune-mediated diabetes has come with the definition of a series of genes in
animal models and man that underlie Mendelian forms of the disease. In particular, two very rare syndromes are
now genetically characterized with plausible mechanistic hypotheses, namely
APS-1 (Autoimmune Polyendocrine Syndrome Type 1 (also termed APECED: Autoimmune
Polyendocrinopathy-candidiasis-ectodermal dystrophy; OMIM 240300) 437, 438 and IPEX
(immune dysregulation, polyendocrinopathy, enteropathy, X-linked), also termed
the XPID syndrome (X-linked Polyendocrinopathy, Immune Dysfunction and
Diarrhea). The APECED or APS-I syndrome
results from mutations of the AIRE (Autoimmune Regulator) gene. AIRE is a
transcription factor acting as a major (but probably not the only one)
determinant of the development of central thymic tolerance to “peripheral
antigens” 439-441, which is
mediated by the transcription of genes coding for peripheral proteins, for
example, insulin, in medullary thymic epithelial cells and dendritic cells 251, 442. The IPEX
syndrome results from mutations in the Foxp3 gene. The Foxp3 gene is
essential for the development of regulatory T lymphocytes 443. Both the APECED and IPEX syndromes are
characterized by the development of immune mediated diabetes. Neonatal diabetes develops in patients with
the IPEX syndrome while 18% of patients with APS-I develop diabetes as young
children or even adults. Both syndromes are covered in detail in
chapter 8 of this web book. There is much to learn from these diseases
about the pathophysiology of autoimmunity including thymic expression of
self-molecules (AIRE) and the generation of regulatory cells (Foxp3) 440. At present there is no or
little indication that polymorphisms at these two loci contribute to common
forms of T1D susceptibility. While one
small case-control study has reported an association of the Foxp3 gene with T1D
in Japanese patients, another study in Sardinian families and a case-control
cohort have not found evidence for linkage or an association with Foxp3 444, 445. Further
genetic manipulation of diabetes prone nonobese diabetic (NOD) mice suggest
that Foxp3 does not play a major role in the spontaneous development of
diabetes in a model that closely resembles human type 1 diabetes 446. However,
the administration of Foxp3+CD4+CD25+ regulatory T cells or the administration
of T cells transduced with Foxp3 are reported to antagonize diabetes
development in experimental rodent models, suggesting therapeutic potential
even though Foxp3 may be a less specific marker of regulatory T cells in man 447, 448.
A large
body of evidence indicates that genetic factors influence both susceptibility
to and resistance to type 1 diabetes.
Multiple chromosomal regions have been associated with the disease,
suggesting that this is a polygenic disorder in most families. Coordinated
efforts with large datasets combined with whole genome analyses, are now
providing further insight into the genetic factors associated with type 1
diabetes. Mendelian mutations affecting certain genes result in rare monogenic
syndromes, the study of which has led to better understanding of the molecular
basis of autoimmunity and autoimmune diabetes. These are candidate genes for
type 1 diabetes, as polymorphisms may affect their expression and function
(albeit less dramatically than in the syndromes) and predispose to type 1
diabetes. Predictably, some of the susceptibility genes for type 1 diabetes are
shared with other autoimmune diseases (e.g. PTPN22, CTLA4), while others appear
to be disease specific. Based on the information generated so far, almost all
of the loci appear to control immune function.
It is still possible that some loci may have an effect on selected
functions in pancreatic ß-cells, though genetic loci such as TCF7L2 that
influences insulin secretion and development of type 2 diabetes is not
associated with type 1 diabetes 449. It is likely no other loci with a major
effect exist, similar in risk determination to that of HLA, though loci may
exist but be rare variants . In addition
we believe it is likely that additional loci with effects potentially larger
than those found in the recent Wellcome Trust Whole Genome analysis are present
within or linked to the Major Histocompatibility Complex. Defining such loci is complicated by the
extensive linkage dysequilibrium in this region that can extend for millions of
base pairs. A number of groups are actively pursuing genetic candidates in this
region. The ability to predict diabetes
with the greatest accuracy based on genetic testing is a critical pre-requisite
for the success of primary prevention strategies and, given the dramatic
ability to predict risk of type 1A diabetes amongst relatives with the highest
risk DR/DQ genotypes. Trials for primary
prevention with for instance oral insulin (to induce mucosal tolerance:
PrePoint) have begun based on algorithms identifying extreme genetic risk
(determined by having multiple first degree relatives and HLA DR3/4-DQ2/8 or
sibling HLA identity by descent of HLA DR3/4-DQ2/8). A major goal is to define such extreme
genetic risk in the general population, and this will almost certainly be
dependent upon a fuller understanding of additional polymorphisms contributing
to disease that are within or linked to the major histocompatibility complex51.
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