Genetics of type 1 diabetes mellitus

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Genes and Immunity (2002) 3, 235–249  2002 Nature Publishing Group All rights reserved 1466-4879/02 $25.00 www.nature.com/gene

REVIEW

Genetics of type 1 diabetes mellitus F Pociot1 and MF McDermott2 1

Steno Diabetes Center, DK-2820 Gentofte, Denmark; 2Department of Diabetes and Metabolic Medicine, Barts and the London, Queen Mary School of Medicine and Dentistry, University of London, UK

At least 20 different chromosomal regions have been linked to type 1 diabetes (T1D) susceptibility in humans, using genome screening, candidate gene testing, and studies of human homologues of mouse susceptibility genes. The largest contribution from a single locus (IDDM1) comes from several genes located in the MHC complex on chromosome 6p21.3, accounting for at least 40% of the familial aggregation of this disease. Approximately 30% of T1D patients are heterozygous for HLA-DQA1*0501–DQB1*0201/DQA1*0301–DQB1*0302 alleles (formerly referred to as HLA-DR3/4 and for simplification usually shortened to HLA-DQ2/DQ8), and a particular HLA-DQ6 molecule (HLA-DQA1*0102–DQB1*0602) is associated with dominant protection from the disease. There is evidence that certain residues important for structure and function of both HLA-DQ and DR peptide-binding pockets determine disease susceptibility and resistance. Independent confirmation of the IDDM2 locus on chromosome 11p15.5 has been achieved in both case-control and family-based studies, whereas associations with the other potential IDDM loci have not always been replicated. Several possibilities to explain these variable results from different studies are discussed, and a key factor affecting both linkage and association studies is that the genetic basis of T1D susceptibility may differ between ethnic groups. Some future strategies to address these problems are proposed. These include increasing the sample size in homogenous ethnic groups, high throughput genotyping and genomewide linkage disequilibrium (LD) mapping to establish disease associated ancestral haplotypes. Elucidation of the function of particular genes (‘functional genomics’) in the pathogenesis of T1D will be a most important element in future studies in this field, in addition to more sophisticated methods of statistical analyses. Genes and Immunity (2002) 3, 235–249. doi:10.1038/sj.gene.6363875 Keywords: type 1 diabetes mellitus; T1DM; genetic susceptibility; human leukocyte antigen; genome scan

Introduction Diabetes mellitus represents a heterogeneous group of disorders. Some distinct diabetic phenotypes can be identified in terms of specific aetiology and/or pathogenesis, but in many cases overlapping phenotypes make etiological and pathogenic classification difficult. Type 1 (insulin-dependent) diabetes mellitus (T1D) [MIM 222100] develops as a result of pancreatic beta-cell destruction and is characterised by absolute insulin deficiency, an abrupt onset of symptoms, proneness to ketosis and dependency on exogenous insulin to sustain life. It is the most common form of diabetes among children and young adults in populations of Caucasoid origin, where the prevalence is approximately 0.4%. The overall age-adjusted incidence of T1D varies from 0.1/100.000 per year in China and Venezuela to 36/100.000 per year in Sardinia and Finland.1 T1D is a leading cause of end-stage renal disease, blindness and

Correspondence: Dr F Pociot, Steno Diabetes Center, Niels Steensensvej 2, DK-2820 Gentofte, Denmark. E-mail: fpoc얀novo.dk This work was in part supported by the EU BioMed 2 Programme (grant no. BMH4–CT97–2311), Novo Nordisk A/S, The Danish Diabetes Association, and the DANDY Foundation. Support from the Juvenile Diabetes Foundation International is also acknowledged. Received 28 November 2001; revised and accepted 21 February 2002

amputation and is also a major cause of cardiovascular disease and premature death in the general population.2,3

Genetics of T1D Rare monogenic and oligogenic forms of T1D have been described, and genetic studies in families affected by these disorders, have allowed mapping of the corresponding genes.4–9 However, in general, T1D is considered as a complex genetic trait, ie, not only do multiple genetic loci contribute to susceptibility, but environmental factors also play a major role in determining risk. A large body of evidence indicates that inherited genetic factors influence both susceptibility and resistance to the disease. There is significant familial clustering of T1D with an average prevalence risk in siblings of 6% compared to 0.4% in the general population.1,10 The familial clustering (␭s),11 which can be calculated from the increased T1D risk in siblings over population prevalence (6.0/0.4), results in an ␭s value of 15. Genetic susceptibility in family members is clearly dependent on the degree of genetic identity with the proband, and in fact the risk of T1D in families 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 and second degree relatives (50% and 25% sharing respectively). The genetics of T1D has a long history of studies evalu-

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ating candidate genes for association with disease status in either case-control or family-based studies. Two chromosomal regions have emerged with consistent and significant evidence of association with T1D across multiple studies. These are the human leukocyte antigen (HLA) region, at chromosome 6p21.3, and the insulin gene region at chromosome 11p15. In the 1970s, association and affected-sib pair linkage studies established the role of HLA genes in T1D predisposition (the HLA locus contribution to disease is referred to as IDDM1).12–14 HLA studies also demonstrated that T1D and type 2 (non insulin-dependent) diabetes mellitus (T2D) were distinct disease entities, since T2D generally does not show an association with HLA, although certain subsets may demonstrate some association.15 The variability in rates of T1D disease concordance in siblings who share two, one or zero parental HLA haplotypes in addition to the different concordance rates in monozygotic vs dizygotic twins, the risk in relatives, and the population prevalence implicates the existence of additional non-HLA genetic factors. More recently genome-wide linkage analysis has been used to try to identify the genetic determinants for T1D. Five complete genome scans,16–20 including a combined analysis of the UK and US genome scan data,21 and several specific linkage studies of certain regions or chromosomes have now been reported.22–30 Together these studies suggest that close to 20 genomic intervals, with variable degrees of linkage evidence, might be influencing T1D risk. The most up-to-date reports are probably from the two recent studies by Cox et al21 and by the European Consortium for IDDM Genetic Studies (ECIGS).20 The first study is a combined analysis of US and UK families from previously published genome scans,16,18,19 including a new collection of 225 US multiplex families. In total, the combined sample comprised 831 affected sib-pairs (ASPs).21 The ECIGS study included 464 Scandinavian ASPs, which have never before been included in previous genome scans. It is significant that both studies provide evidence of interaction between the different T1D susceptibility loci.20,21 For all these loci the etiological mutation(s) in sensu strictu has not been identified. Even in the HLA region several genes seem to be involved (see below). Most of the other putative T1D loci comprise regions of 1–40 centimorgans (cM) in size, corresponding roughly to 1– 40 Mb, which may contain several genes. Mapping these genes will be a major challenge of the genome era. Currently, little is known about the nature of genetic variation underlying T1D, which makes it difficult to be confident about strategies used to address this problem. One hypothesis proposes that the genetic basis of T1D will involve alleles that are themselves common in the population at large.31,32 Assumptions about genetic factors contributing to T1D are relevant to the approach undertaken. Under the ‘common disease, common variant’ hypothesis, it may be possible to generate a catalogue of common SNPs and use association mapping to identify disease-susceptibility polymorphisms.33–35 In this regard strategies to identify SNPs that delineate the different haplotypes of a gene or a region of linkage disequilibrium (LD)36–39 seem most promising. Interestingly, very recent studies suggest that much of the difficulty in mapping T1D susceptibility genes results from inadequate sample sizes and the study of mixed ethnic groups.21,40

Genes and Immunity

The genes HLA-encoded susceptibility to T1D The best evidence for a genetic component in the susceptibility to T1D comes from studies of the HLA genes in both populations and families as well as from animal models. It has been estimated that HLA (IDDM1) provides up to 40–50% of the familial clustering of T1D.11,41 The HLA region is a cluster of genes located within the major histocompatibility complex (MHC) on chromosome 6p21. Identification of the genes involved has proved to be extremely elusive, despite tremendous efforts, involving several complementary approaches eg functional studies and animal models. This is due to several complicating factors, amongst which is the strong LD between neighbouring genes in the HLA complex, and the fact that several HLA-linked genes, acting in concert, may determine disease susceptibility. The contribution of the IDDM1 region is easily detectable in genome-wide linkage analyses, as indicated by a LOD score of 65.8, recently reported in a consensus analysis of 767 multiplex T1D families.21 The genes of the MHC region are classified into four families, classes I, II, III and IV.42–44 The statistically strongest genetic association with T1D is conferred by HLA class II gene alleles. From both human genetics and animal model studies there is good evidence that particular alleles of the HLADQA1, DQB1 and DRB1 loci all are primarily involved in the genetic predisposition to T1D.45–50 However, due to the strong LD between these loci it has been very difficult to study the effect of individual HLA-DQ or -DR genes separately. It is clear that some combinations of HLA-DQ genes, eg those encoding DQ8 (ie. DQA1*03– DQB1*0302) and DQ2 (ie DQA1*05–DQB1*02), and particularly those present in HLA-DQ2/DQ8 heterozygotes are associated with susceptibility to T1D (Table 1). Approximately 30% of T1D patients are HLA-DQ2/DQ8 heterozygotes.51 By contrast, a particular DQ6 molecule, encoded by HLA-DQA1*0102–DQB1*0602, is associated Table 1 Type 1 diabetes-associated HLA class II alleles and haplotypes HLA-DQ alleles

HLA-DR-alleles

RR

Positive associations (Susceptibility haplotypes) A1*0301-B1*0302 A1*0501-B1*0201 A1*0501-B1*0302 A1*0301-B1*0201 A1*0301-B1*0402 A1*0301-B1*0201 A1*0301-B1*0201 A1*0301-B1*0401 A1*0301-B1*0303

DRB1*04 DRB1*301 DRB1*301/DRB1*04 DRB1*301/DRB1*04 DRB1*04/DRB1*801 DRB1*701 DRB1*901 DRB1*04 DRB1*901

2.5–9.5 2.5–5.0 12.0–32.0

Negative associations (Protective haplotypes) A1*0102-B1*0602 A1*0103-B1*0603 A1*0301-B1*0301 A1*0501-B1*0301

DRB1*1501 DRB1*1301 DRB1*04 DRB1*1101

0.03–0.2 0.05–0.25 0.2–0.5 0.05–0.5

4.0–15.0 8.0–13.0 5.5 3.5–4.5 2.0–4.5

Relative risk (RR) is for the combined DQ-DR haplotype and refers to high-risk populations. There is significant variation between different ethnic populations.

Genetics of type 1 diabetes mellitus F Pociot and MF McDermott

types.73 Additional susceptibility loci in the class II region include the antigen-processing genes (TAP1, TAP2, LMP2, and LMP7), although current evidence suggests that these are not directly involved in T1D.74–76 A number of observations indicate that class II genes cannot explain all of the MHC associations with T1D. A role for MHC complex genes other than class II genes was first suggested by Thomsen et al77 and Pociot et al78 by studying HLA-DR3/4 heterozygous individuals, and by Robinson et al79 using a family study design, which to some degree eliminated the LD effects involving HLADQ/DR loci; however, in all these studies the number of subjects/families was small. Subsequently, several studies have supported a role for both MHC HLA class IV and class I genes in T1D predisposition. The most studied class IV genes are tumour necrosis factor and lymphotoxin (TNFA and TNFB).78,80–82 The strongest evidence for susceptibility genes in the class I region comes from recent systematic assessment of microsatellite markers spanning this region.83–89

with strong protection from the disease, even in the presence of T1D-associated autoantibodies and/or of highrisk HLA alleles,52 and has been reported in less than 1% of patients in most populations studied (Table 1). Thus, this HLA-DQB allele appears to confer dominant protection.53,54 It has been more difficult to ascertain the roles of separate HLA-DR genes.45,55 Analysis of the linkage between HLA-DQ and DR alleles on DQ8-haplotypes, demonstrated that the frequencies of only certain HLADR4-associated DRB1 alleles are increased among T1D patients.55 This has since been confirmed in larger studies by other groups.56–58 The varying risk conferred by different HLA-DR4 haplotypes is illustrated in Table 2. There is evidence that the different risk categories are determined by the predicted structure and action of the peptidebinding pockets, P1 and P4, of the DRB1 molecule.59 The fact that several different class II HLA alleles and combinations of alleles may be associated with T1D can be reconciled by a hypothesis implicating a factor common to all these alleles that is central to disease susceptibility, eg presence of specific amino acid residues. Indeed, certain amino acids of the HLA-DQB1 and DRB1 chains correlate well with disease susceptibility and resistance. These residues are known to be critical for the peptide-binding function of the class II molecule.59–63 In particular, aspartic acid (Asp) at residue 57, which is in pocket 9 of the HLA-DQB1 molecule, is encoded by a HLA-DQB protective allele, whilst an alanine, valine or serine residue at the same position characterises predisposing alleles. In the absence of aspartic acid the charge at the ‘right hand’ end of the peptide-binding pocket becomes more positive.64 Nevertheless, and despite the fact that residue 57 has indeed a pronounced role in the function of class II molecules with respect to peptide binding,65,66 it cannot completely account for all the complexity of HLA and T1D associations, eg Asp 57 is not associated with T1D in Japanese.67,68 Interestingly, the major DQB1 allele associated with T1D in Japan, 0401, has a different residue 56 than other Asp57 bearing allotypes, and it was recently suggested that residue 56, which is also in pocket 9, may influence the structure and function of this pocket in peptide binding and T1D susceptibility.59,63 Other loci in the class II region have been associated with T1D besides HLA-DQ and DR. Most interestingly, an independent association with HLA-DPB1*0301 has been observed,69–71 although this may not be the case on DR4-positive haplotypes.72 Also, HLA-DPB1*0402 may be associated with protection on HLA-DR4 negative haplo-

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Non-HLA encoded susceptibility to T1D HLA-encoded T1D susceptibility may account for less than 50% of the inherited disease risk and thus, there is a substantial role for non-HLA encoded susceptibility. Genome-wide linkage analysis has been used in an attempt to identify the T1D genetic determinants. This approach has the advantage of being a comprehensive search for genetic factors that does not require a priori knowledge of the underlying biology or risk alleles. However, linkage analysis thus far has had only limited success.40 Specifically, most studies have failed to generate strong evidence of linkage (except for IDDM1), and those few regions with significant results have proven difficult to replicate (Table 3). Nevertheless, several loci have now been linked to T1D, providing evidence that this disease is a polygenic disorder in most patients studied. T1D susceptibility loci mapped by different genome screenings are listed in Table 3. The symbols of these putative loci, approved by the Human Gene Nomenclature Committee, are IDDM1–IDDM18 (www.gene.ucl.ac.uk/ nomenclature). The symbols IDDM9 and IDDM14 have not yet been approved, even though these symbols have been reserved by particular researchers, based upon preliminary data suggesting evidence of linkage of new chromosomal regions to T1D. Based upon current analyses of completed genome screens, these non-HLA region genes may contribute

Table 2 Critical polymorphic residues of the HLA-DRB1*04 beta chain associated with predisposition to type 1 diabetes DRB1*04 allele

0401 0402 0403 0404 0405 0406 0407

Polymorphic residues

Disease predisposition

37

57

67

70

71

74

86

Tyr Tyr Tyr Tyr Tyr Ser Tyr

Asp Asp Asp Asp Ser Asp Asp

Leu lle Leu Leu Leu Leu Leu

Gln Asp Gln Gln Gln Gln Gln

Lys Glu Arg Arg Arg Arg Arg

Ala Ala Glu Ala Ala Glu Glu

Gly Val Val Val Gly Val Gly

+++ +/− −−− +/− +++ −−− −−−

‘+’ and ‘−’ indicate degree of predisposition, ie ‘+ + +’ confer the strongest susceptibility, whereas ‘−−−’ corresponds to strong protection. Genes and Immunity

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Table 3 Summary of previous linkage results Locus

Chromosome

Markers

Significance level (reference)

Independent or overlapping replication (reference) – *18,19,21,24,245 *18 –

IDDM7-IDDM12 IDDM13 IDDM9 IDDM18 IDDM15

1 2 2 3 5 6

D1S1644–AGT HOXD8–D2S72–CTLA4 D2S137–D2S301 D3S1279 IL12B D6S283

**18 ***150 **27 *19

IDDM5

6

D6S476–D6S473

***26

IDDM8 IDDM10

6 10

D6S446–D6S281 D10S191–D10S220

***24 ***19

IDDM17 IDDM2 IDDM4

10 11 11 14 14 14 15 16

D10S1750–D10S1773 INS D11S1296–FGF3 D14S70–D14S276 D14S67 D14S292–D14S293 D15S107 D16S515–D16S520

***6 **19 ***26 **19 ***25

IDDM11 IDDM16 IDDM3

29

***28

**20 ** (not corrected for MHC)18,21 *16,19 *18,21,125 **24,125; *18,19,28 **17 **21 *21 **16,17 – –

30

**22 **19

– –

Significance levels: *LOD ⭓ 1.0, **LOD ⭓ 2.0, ***⭓ 3.6.

relatively smaller (but significant) increments in genetic risk on an individual basis. For example, the IDDM2 locus (see below), which is the only other generally accepted genetic contributor to T1D risk has an odds ratio (OR) 苲3, but an estimated sibling genetic risk ratio (␭s) of only 1.12. Other locus-specific effects, excluding HLA, range from 1.05–1.3. Power analyses suggest that 苲4.300 affected sib-pair families will be required to achieve 80% power to detect a linkage at the suggested significance level with P ⬍ 2.2 × 10−5 90 at these levels of risk. IDDM2—the insulin gene (INS) region The immune-mediated process leading to development of T1D is highly specific to pancreatic beta cells. The insulin gene, therefore, is a plausible candidate susceptibility locus since insulin or insulin precursors may act as autoantigens. Alternatively, insulin levels could modulate the interaction between the immune system and the beta cells. A unique minisatellite (VNTR), which arises from tandem repetition of a 14–15 bp oligonucleotide sequence, is located in the 5⬘ regulatory region of the human insulin gene (INS) on chromosome 11p15.5. The number of tandem repeats varies from about 26 to over 200, and VNTR alleles occur in three discrete size classes: class I (26–63 repeats), class II (mean of 80 repeats), and class III (141– 209 repeats).91–93 Class II alleles are virtually absent in Caucasoid populations, in whom the frequencies of class I and class III alleles are 0.71 and 0.29 respectively. The class I/I homozygous genotype is associated with a twoto five-fold increase in risk of developing T1D, whereas class III alleles seem to provide dominant protection.93–102 This susceptibility locus, IDDM2 [MIM 125852], has been mapped to chromosome 11p15.5, and most likely corresponds to the INS VNTR locus,93 although it has been pointed out that the T1D association extends beyond the 4.1 kb region originally identified97 towards the tyrosine hydroxylase gene.103 This is important because subsequent studies including those cited above, Genes and Immunity

which followed this original mapping, presumed that the 4.1 kb was the minimal region—in other words haplotypes were analysed within the 4.1 kb region and not outside it, and eventually provided substantial evidence for the insulin VNTR being the primary locus. However, without actually searching more thoroughly for associations in the TH gene and beyond, the question remains whether there may be a second susceptibility locus or in fact that the major determinant may lie outside the 4.1 kb region, and that the insulin VNTR is in LD with the true etiological variant. This seems unlikely, but until the mapping study is done it remains a possibility. The existing evidence for IDDM2 as a true locus comes from multiple replications of the disease association studies in both case-control and family-based cohorts. High-resolution genotyping has revealed that variable degrees of susceptibility are associated with each VNTR allele and probably reflect sequence heterogeneity within the VNTR that may affect its function and physical state.104–108 There are also data to suggest that the VNTR may modulate INS transcription in pancreas and thymus93,101,109–113 and that INS class III alleles, as compared with class I alleles, correlate with low INS mRNA levels in the pancreas but with higher levels in the thymus (on average 2–3 fold). Greater thymic expression of INS may explain the dominant protective effect of class III VNTR alleles, reported in T1D, by enhancing tolerance to the preproinsulin protein.114,115 IDDM3–IDDM18 IDDM1 and IDDM2 (the HLA and INS components) were both originally identified by a candidate gene approach, based on case-control studies. The remaining IDDM loci, ie IDDM3–IDDM18, with the exception of IDDM17, have all been discovered by linkage studies using affected sib-pair families, either in whole or partial genome scans. For most of these regions positional candidate genes have been further analyzed. IDDM3 [MIM 600318] was originally reported to be located near the

Genetics of type 1 diabetes mellitus F Pociot and MF McDermott

D15S107 marker on chromosome 15q26, in a collection of 250 Caucasoid families from the US, UK and Canada.22 Interestingly, those families possessing HLA genes that provided less predisposition to T1D produced most of the evidence for linkage to the D15S107 marker. Although some support for linkage and association to the IDDM3 locus has been published,24,116 most other studies have failed to replicate this original observation,18–21,26 and so far no positionally identified candidate genes have been investigated in this region. Evidence for IDDM4 [MIM 600319], which is located near the fibroblast growth factor 3 (FGF3) locus on chromosome 11q13, was reported simultaneously by two different groups.16,17 A major effort has been expended to fine-map IDDM4 by LD analysis. In a two-stage approach 2042 families were genotyped for markers from this region, and a specific haplotype comprising alleles of the two polymorphic markers, D11S1917 and H0570polyA, showed decreased transmission (46.4%) to affected offspring and increased transmission (56.6%) to unaffected siblings.117 Several potential candidate genes map to the region near FGF3 in humans, including ZFM1 (zinc finger protein 162), which encodes a putative nuclear protein demonstrable in the pancreas.118 The gene encoding the Fas-associated death domain protein (FADD) has also been mapped to this region.119 Transduction of an apoptotic signal depends on association and interaction between the intracellular ‘death domain’ of Fas with FADD. Recent experimental findings indicate that binding of the Fas ligand (FasL) on cytotoxic T cells to Fas expressed on beta cells may trigger apoptosis in the insulin-producing beta cells.120,121 Analyses of FADD polymorphisms by transmission disequilibrium testing (TDT) failed to provide any evidence for association with this candidate gene; however, ETDT analysis did reveal significant association/linkage with the D11S987 marker (P = 0.0004), which is 4.4 cM upstream the FADD gene.122 A gene encoding a novel transmembrane protein has been identified by sequence analysis of the IDDM4 locus.123 This gene, termed low-density lipoprotein receptor related protein (LRP5), encodes a protein that contains conserved sequences, characteristic of the low-density lipoprotein receptor family. LRP5 is in close proximity to the two markers, D11S1917 and H0570PolyA, and the exon encoding the signal peptide of LPR-5 is only 3 kb downstream the H0570polyA marker. In addition, two novel genes were recently identified in this region, C11orf23 and C11orf24.124 The C11orf24 gene has no known sequence similarity to other genes, and its function is unknown. C11orf23 has sequence similarity to the SIT4 (sporulation-induced transcript 4)-associated protein (SAP) family of yeast proteins, which are involved in regulation of the cell cycle. The full-length C11orf23 cDNA is the first mammalian orthologue of the yeast SAP family to be identified.124 Three regions on chromosome 6q, with varying degree of linkage, have been identified through genome screenings. These are IDDM5 [MIM 600320] on 6q25, IDDM8 [MIM 600883] on 6q27, and IDDM15 [MIM 601666] on 6q21. Initial evidence of linkage for IDDM5 was found for the ESR1, oestrogen receptor 1, marker.16 IDDM5 is one of the few susceptibility regions that have been replicated in multiple studies, although partly overlapping family collections were used.16,26,28,125 In the recent joint analysis IDDM5 featured with a LOD score of 1.96.21

IDDM5 maps to a region approximately 40 cM centromeric to IDDM8, and fine mapping analysis has placed the IDDM5 locus within a 5 cM region between the D6S476 and D6S473 markers.26 The gene encoding manganese superoxide dismutase (SOD2) maps close to this region.126 There is evidence to support a role for free oxygen radicals (FOR) in the immune-mediated beta-cell destruction,31,127 and protection of beta cells from cytokine exposure is correlated with superoxide dismutase (MnSOD) expression/activity.128,129 Furthermore, polymorphisms of the SOD2 gene have been associated with T1D susceptibility.130 Structural variants of the MnSOD protein with reduced activity have been reported,131 and such variants might be hypothesised to increase predisposition to T1D. Because of previous evidence of linkage of the 18q12– q21 region containing the Kidd blood group132 and the D18S64 marker16 to T1D, fine mapping of this region, now designated IDDM6 [MIM 601941], has been performed.133,134 In 1708 families from seven different countries, a haplotype designated ‘10–2–4’ composed of the markers 129, II-IO43 and 56-D18S487 showed some positive evidence of association with T1D.134 However, in an independent set of 627 families no association was detected, although there was evidence for linkage.135 Whether the differences in TDT results between data sets is due, in part, to the presence of more than one common diseaseassociated haplotype (allelic heterogeneity), which confounded the analysis of individual alleles by TDT133–135 or simply indicates that the original observation of association was false is at present not clear. A candidate gene, deleted in colorectal carcinoma (DCC), was tested for association with autoimmunity in one of these studies,135 and evidence for an association with autoimmunity was reported (P = 5 × 10−6). Another candidate gene, ZNF236, which encodes a Kruppel-like zinc-finger protein, has recently been identified in this region; this gene may be a candidate for diabetic nephropathy136 in particular. Also, the anti-apoptotic molecule, bcl-2, maps to the IDDM6 region. One Japanese study137 has reported an association of T1D with an Ala43Thr polymorphism of BCL2; however, this association has not been confirmed in a recent study of different Caucasoid populations.138 Several loci on chromosome 2q have been linked to T1D. IDDM7 [MIM 600321] on chromosome 2q31 was identified by linkage of D2S326 in one of the first genome scans.16 Subsequent linkage and TDT studies have located IDDM7 to D2S152 in several populations, although some controversy exists.139–141 It is important in this regard that a single peak near the D2S1391 marker, with a LOD score of 2.62, was reported in the study by Cox et al.21 Part of this region is homologous to the region of mouse chromosome 1 containing the murine T1D susceptibility locus, idd5, in the non-obese diabetic (NOD) mouse.142,143 A number of genes have been proposed and investigated as candidate genes for the IDDM7 region. These include genes of the interleukin-1 gene cluster (ie IL1R1,144–146 IL1B,130,147,148 and IL1RN130,149) HOXD8,150 GAD1,151 GALNT3,141 and NEUROD.152–154 However, linkage or association has not been convincingly demonstrated for any of these candidate genes. IDDM8 was initially mapped to chromosome 6q2716,24 and significant evidence of linkage was subsequently obtained through multipoint analyses in additional data sets.26 Supporting evidence for this locus was reported in

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other studies, using partially overlapping sets of families.19,28,155 Combined evidence from these studies (nonoverlapping families), as well as results from the consensus analysis by Cox et al,21 suggest that IDDM8 meets the criteria for confirmed linkage for complex diseases.90,156 Although the IDDM9 symbol has not been approved, IDDM9 has been proposed for a region on chromosome 3q21–q25, demonstrating some evidence of linkage of the D3S1303 marker in the UK genome scans,16,19 where strongest evidence was found in HLA-DR3/4 heterozygous diabetic offspring.19 However, further studies are needed for confirmation of this locus. Linkage of T1D to chromosome 10p11–q11 (marker D10S193) has provided evidence for a susceptibility locus in this region,16,19,157 which has been designated IDDM10 [MIM 601942]. In the recent consensus analysis of US and UK T1D multiplex families, evidence of linkage was also observed at chromosome 10p11, near the D10S565 marker, with a LOD score of 2.8.21 The chromosomal location of this marker corresponds approximately to that of IDDM10,19,157 and GAD2, encoding GAD65, is also closely linked to this region. However, several studies have failed to demonstrate evidence of linkage of GAD2 to T1D.151,157 IDDM11 [MIM 601208] is the symbol for a possible susceptibility locus on 14q24.3–q31, which was identified by the finding of significant linkage to D14S67.25 Most support for linkage of this marker came from the subset of families in which affected children did not show increased sharing of HLA genes. Significant linkage heterogeneity between HLA-defined subsets of families suggests that IDDM11 may be an important susceptibility locus in families lacking strong HLA region predisposition. However, no further studies have been able to replicate this original observation. Two candidate genes have been identified in the region. The ENSA gene encodes ␣-endosulfine, an endogenous regulator of beta-cell K (ATP) channels,158 and the recombinant ␣-endosulfine has been shown to inhibit sulfonylurea binding to betacell membranes, to reduce K(ATP) channel currents, and to stimulate insulin secretion.158 Furthermore the SEL1L gene,159,160 which is an important negative regulator of the Notch signalling pathway161 and involved in proper development of pancreatic endocrine cells,162–164 maps to this region. SEL1L exhibits high mRNA levels only in adult pancreata160 and in islets of Langerhans,165 but not in the other tissues that were tested. However, a recent study, analysing two intragenic microsatellite markers,166 was unable to find evidence for SEL1L as a plausible candidate gene for IDDM11-conferred susceptibility. Furthermore, mutation scanning of the SEL1L promoter and cDNA sequences did not reveal any disease-associated polymorphisms.167 The IDDM12 [MIM 601388] locus maps to chromosome 2q33 and strongest evidence for linkage to IDDM12 has been obtained for the D2S72–CTLA4–D2S116 region.168 Candidate genes at this locus include those that encode the T-cell costimulatory receptors, CD28 and CTLA-4 (cytotoxic T lymphocyte antigen 4, also called CD152). Although the evidence linking both of these molecules is inconclusive, CTLA-4 is the leading candidate gene in this region for T1D susceptibility. This is partly due to the fact that markers used in linkage and association studies map within CTLA-4. In addition, knowledge of the functional properties of CTLA-4 supports this possibility169

Genes and Immunity

and a single study did not find support for CD28 as the candidate gene of this region.170 There is a microsatellite marker in the 3⬘UTR of the CTLA4 sequence, and several polymorphisms have been detected at CTLA4.39 These polymorphisms, in particular the exon 1 (49 G⬎A) SNP, have been investigated by TDT analysis in several populations,41,140,171–186 and combined data sets from these large studies support linkage of the CTLA4 locus to T1D.168,171,187 Interestingly, some evidence has also been produced to suggest that CTLA4 polymorphisms may influence gene expression.174,188,189 The role of this gene has been examined in various autoimmune diseases and there is evidence for a general role of CTLA-4 in autoimmunity,190,191 as the gene is expressed only on activated T lymphocytes and functions by downregulating T-cell function.192,193 Chronic blockade of this pathway will lead to maintenance of T cells in an activated state and results in an autoimmune syndrome in wild-type mice.194 Interestingly, recent data arising from the completion of the human genome sequence and from a series of functional studies, using genetic knockouts, suggest that an additional costimulatory receptor, the inducible costimulator (ICOS),195,196 which is structurally and functionally related to CD28 and CTLA-4, may be an additional candidate gene for this region on chromosome 2q33. Sequence data closely link ICOS to both CD28 and CTLA-4, and the gene encoding ICOS is separated by only approximately 100,000 bases from that encoding CTLA-4 (www.genome.ucsc.edu), indicating that both genes are completely within the limits of resolution of current genetic studies. Studies using ICOS knockouts197–199 have demonstrated that ICOS is essential for development of normal T cell help and plays a protective role during induction of experimental autoimmune disease.197 These data suggest that there may be more autoimmune disease genes at chromosome 2q33 and that the immune response is a dynamic process, wherein there is obviously a large potential for multiple costimulatory signals. The IDDM13 [MIM 610318] locus maps to 2q34, and the strongest evidence for linkage has been obtained for the D2S137–D2S164 region.27 Thus, IDDM12 and IDDM13 are separated by only 17–18 cM, and IDDM7, IDDM12 and IDDM13 cover a region of approximately 27 cM. Additional evidence for IDDM13 has been obtained in two other studies.140,187 A recent study found evidence for association to T1D of the D2S1327–D2S1471 region, which spans 3.5 cM.187 Several IDDM13 candidate genes have been investigated, including IA-2,140 IGFBP2,172 IGFBP5,172 and NRAMP1140 but no diseaseassociated mutations have been identified in these genes. IDDM15 is a putative susceptibility locus that has been mapped to 6q21, in the region of D6S283–D6S1580,28 which is linked to HLA, with an estimated recombination rate (␪) of 0.32 in male meiosis, and 0.47 in female meiosis.28 Therefore, statistical evaluation of cosegregation of IDDM15 with disease should take these gender related recombination rates into account. In a recent genome scan of Scandinavian T1D families20 suggestive evidence of linkage was found at marker D6S283, with a P value of 0.002. These data were then combined with results from French and US multiplex families, since no locus heterogeneity was observed between these populations.20 Taking into account the 95% confidence interval for the estimate of the distance between HLA and

Genetics of type 1 diabetes mellitus F Pociot and MF McDermott

D6S283,28 it was estimated that the P value in the combined family set would be 3 × 10−5 to 5 × 10−8 (7 × 10−7 for the recombination rates given above).20 Additional support for this locus was also reported in combined studies of US and UK families.18,21 Thus, the combined evidence in favour of IDDM15 is the most compelling that has been reported thus far for any of the putative T1D-susceptibility loci, apart from IDDM1 and IDDM2. Interestingly, it has also been suggested that this region on chromosome 6 contains a gene responsible for transient neonatal diabetes mellitus, which could also be a candidate gene for IDDM15 in this region.200,201 A very recent report provides evidence for a locus in the immunoglobin heavy chain region on chromosome 14q32.3 producing susceptibility to T1D,30 this locus has been designated IDDM16. Support for linkage was obtained in 351 North American and UK families (P = 0.002).30 Replication in 241 Danish T1D families did not confirm linkage, but there was significant evidence for association (P = 0.019).30 Between 1984 and 1991, more than 20 studies examined serologically-detected Gm allotypes in T1D (reviewed in Dugoujon and CambonThomsen202). Although none of these studies found direct evidence of linkage or association with T1D, many reported evidence of immunoglobin heavy chain (IGH) region involvement through interaction with HLA genes. Over the last decade, there have been very few new studies of IGH markers in T1D. A Finnish study found no evidence for linkage to IGH variable region markers, but there was significant association for two of the four markers.203 This evidence for association but not for linkage is similar to the observation in the Danish dataset in the study by Field et al.30 Immunoglobulin molecules have a central role in immune response to foreign and selfantigens, and it is therefore conceivable that genetically controlled differences in immunoglobulin structure and function could alter a person’s immune response to such antigens and affect T1D risk. Also, this locus needs replication in other populations to be confirmed. IDDM17 [MIM 603266] was identified on the basis of a genomic search for linkage to T1D in a large Bedouin Arab family.6 A locus contributing to T1D susceptibility was located on chromosome 10q25. The family contained 19 affected relatives, all of whom carried one or two highrisk HLA-DR3 haplotypes that were rarely found in other family members. This susceptibility locus was mapped to an 8 cM interval between D10S1750 and D10S1773, and two adjacent markers, D10S592 and D10S554, showed evidence of linkage disequilibrium with the disease locus. The FAS gene maps to this region (10q24.1), but has been excluded as the disease-contributing locus. Also, the FAS gene has been excluded in population-based family studies,204 and this particular region has not been identified in other genome scans.16–20 However, increased LOD scores were observed near the putative IDDM17 locus in the consensus analysis of UK and US ASPs.21 These increased LOD scores occurred in the subset of families in which all affected individuals were HLA-DR3/non-HLA-DR4, which is consistent with the original report.6 Thus, this study suggests that T1D may also be an oligogenic disease rather than a polygenic disease in some circumstances, and that perhaps just two or three genes may suffice to explain all the inherited susceptibility in a given family. Recently, a new susceptibility locus, IDDM18 [MIM

605598], was identified and mapped to chromosome 5q31.1–q33.1, close to the gene for the p40 subunit of the interleukin 12 gene, IL 12B.29,205 IL-12p40 production influences T-cell responses, and may therefore be important in T1D susceptibility.206 IL-12 drives the differentiation of T-lymphocytes into the Th1 subset, characterised by production of cytokines leading to cell-mediated immunity.207,208 Furthermore, in the NOD mouse, IL-12 has been shown to play a primary role in T1D induction,206,209,210 and in addition, plays a key role in immune reactivity against infections. However, it has been shown that in the absence of infection, IL-12-induced autoreactive T cell responses might predispose to self-destructive immunity.211,212 Several polymorphisms have been identified in the IL 12B locus.205,213 A 3⬘UTR (untranslated region) single base change showed strong linkage disequilibrium with the T1D susceptibility locus in Australian and British diabetes families,29 but this observation needs to be replicated in other populations.214

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Other susceptibility loci A number of additional chromosomal regions demonstrating some evidence of linkage to T1D have been identified. Regions with multipoint LOD scores ⬎1.5 identified in the two recent genome scans20,21 are listed in Table 4. Due to the size of these studies, and the fact that there is no overlap between the families analysed, these regions are probably more likely to harbour genes predisposing to T1D than some of the previously designated IDDM loci (Table 3) with the exception of IDDM1 and IDDM2. Interestingly, the ECIGS study20 identified a region on chromosome 2p12, marker D2S113, near the gene for eukaryotic translation-initiation factor-2 ␣ kinase-3 (EIF2AK3), in which disease-causing mutations have been identified in patients with Wolcott-Rallison syndrome (neonatal insulin-dependent diabetes and epiphyseal dysplasia).7 On that basis additional markers were selected to cover the EIF2AK3 region, and evidence of linkage at this locus increased to a LOD score of 2.6 in HLADR3/4 positive ASPs.20 Also, a region on chromosome 4p was identified,20 which demonstrated linkage to T1D in conditional analysis of the UK multiplex families.215 The region incorporates the Wolfram syndrome (phenotype includes insulin-dependent diabetes and optic atrophy) locus, WFS1.216,217 Several mutations have been identified in WFS1,216–218 and it has been suggested that variations Table 4 ‘New’ non-HLA regions with multipoint LOD scores ⬎1.5 in unconditional analyses from references a21 and b20 Chromosome 1 2 4 5 12 16 16 16 17 19

Marker/position

LOD score

P-values

1q42 D2S113 D4S403 D5S407 D12S99 D16S405–D16S287 16p11–p13 D16S3098 17q25 19q11

2.20a 1.82b 1.84b* 2.16b* 1.97b* 2.80b 1.74a* 3.93a 1.81a* 1.80a*

7.4 × 10−4 0.002

2 × 10−4 ⬍2.2 × 10−5

*Corresponding P-values not reported. Genes and Immunity

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in the WFS1 locus could play a minor role in the more common forms of diabetes mellitus.216 Thus, these examples suggest that genes identified in oligogenic forms of diabetes may contribute to T1D susceptibility in the general population. The effects of gender and HLA genotype complicate studies of the contribution of genes on the X chromosome to T1D susceptibility but there is some evidence for linkage to Xp13-p11 in HLA-DR3/X affected sibpairs.20,219 There is also increasing evidence of the key role of vitamin D levels in T1D susceptibility.220–222 Vitamin D has important immunomodulatory properties223 and depletion or relative resistance may play a part in the aetiology of both T1DM and T2DM, possibly through effects on insulin secretion.224 It has been shown that allelic variations in the vitamin D receptor (VDR) gene is a significant determinant of the amount of VDR mRNA and VDR protein expressed,225 and may also affect plasma concentrations of 1,25(OH)2D3, and the response to oral vitamin D.226 An association between VDR polymorphisms and T1DM has been reported in South Indian, German and Taiwanese populations,227–229 although not necessarily with the same VDR polymorphisms. As illustrated above, a complex disease like T1D most often involves multiple interacting genetic determinants. However, statistical methods in current use for localizing such genes essentially work under single gene models, either implicitly or explicitly, thus not allowing identification of such complex traits. Therefore new methods have been developed. These include variance components methods for quantitative trait loci (QTL);230,231 conditional tests for QTL by multiple regression analysis;232,233 conditional and simultaneous search methods from high-resolution maps of identity-by-descent,234 methods for searching for an additional locus given an established susceptibility locus,235,236 interaction analysis,237 and multi-locus nonparametric linkage analysis with neural networks.238 Most of these newer methods focus on two-loci traits and their statistical properties (applications) for genome-wide searches of susceptibility genes are not well known. In current practice, the majority of whole genome scans for complex trait loci are conducted by multipoint methods16–21,239,240 that work under the implicit assumption of a single trait locus or multiple trait loci, unrelated to each other. Therefore there is an urgent need for the exploration of new strategies for detecting sets of marker loci, which are linked to multiple interacting disease genes. At present, evidence of statistical interactions between unlinked loci is either calculated by evaluation of correlations between family-specific LOD scores for pairs of loci237 or by conditioning on other loci eg on specific HLA genotypes or age-at-onset.19–21 Although the data, at this point in time, should be considered preliminary, interesting results have emerged from recent studies and should be explored further.20,21

Conclusion and future strategies In addition to candidate-gene driven and genome-wide linkage studies other approaches may be useful in identifying new T1D susceptibility/resistance regions. Identification of syntenic regions, ie regions demonstrating correspondence in gene-order between the chromosomes of Genes and Immunity

different species, and conferring susceptibility/resistance to diabetes in the spontaneous animal models (the NOD mouse241 and the BB rat242), will be useful for identification of similar genes in man. Characterisation of overlapping regions identified through genome scans in other autoimmune or inflammatory diseases is another approach.191,243,244 The occurrence of common features of autoimmune diseases and the co-association of multiple autoimmune diseases in the same individual or family support the notion of common genetic factors that predispose to autoimmunity. Indeed, by correlating data from existing genome scans in other human autoimmune disease, overlaps with already identified T1D susceptibility loci are revealed (Table 5). This clustering of autoimmune susceptibility loci suggests that there may be related genetic backgrounds contributing to susceptibility of clinically distinct disease, and that the genes identified in these clusters are most likely to be involved in primary or secondary regulation of the immune system. Several analytical approaches to identification and/or clarification of the contributions of loci to T1D susceptibility have been used over the last decade. Obviously, the most effective strategy seems also to be one of the most simple ie increasing sample size.21,40 This can be accomplished by performing new larger genome scans and/or by merging data from previous studies. Given the number of families already investigated in linkage studies worldwide, the obvious approach to further progress in the identification of genes predisposing to T1D would be through the efforts of a consortium to merge and jointly analyse all existent datasets for linkage, although power calculations (see above) suggest that even more families are needed. Furthermore, genome-wide LD mapping may be more powerful than linkage analysis. By determining the extended haplotypes at any given locus in a population, it is possible to identify which SNPs will be redundant and which will be essential in association studies. This will make genome-wide SNP typing much more feasible. It was recently suggested that for an initial catalogue of ‘haplotype tag SNPs’, including all the coding region and 3 kb of up- and downstream sequence, each gene should be re-sequenced in a minimum of 30 individuals.39 This will result in ⬎95% power to detect all variants with frequencies higher than 5%. Table 5 IDDM loci for which susceptibility loci for other autoimmune diseases have been mapped to the same region Locus IDDM1 IDDM2 IDDM3 IDDM5 IDDM6 IDDM8 IDDM9 IDDM12 (CTLA4) IDDM13 16q22–q24 DXS998

Other autoimmune diseases All autoimmune diseases MS246 CD247 RA248 RA249, AITD250, SLE135 RA248 RA249 RA, MS, AITD, AD191 RA249 Psoriasis251, asthma252, CD253 MS, RA249

MS = multiple sclerosis; CD = celiac disease; RA = rheumatoid arthritis; AITD = autoimmune thyroid disease; AD = Addisons’ disease.

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An enormous amount of genomics and genetics still have to be carried out using adequately sized datasets. Several regions have been implicated but not yet confirmed. These studies are still difficult to perform due to the fact that the human genome sequence is not completed, and the gene content is very uncertain. Finally, when all the genes have been identified there is likely to be a great increase in demand for functional genomics. The number of identified susceptibility genes may continue to grow, but the elucidation of their function in the pathogenesis of T1D will be the most important factor towards understanding the molecular pathogenesis. The approaches used will vary according to the function of these genes, but will include expression studies and generation of transgenic and knockout animal models.

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