Genes and Immunity (2002) 3, 235249

2002 Nature Publishing Group All rights reserved 1466-4879/02 $25.00

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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*0501DQB1*0201/DQA1*0301DQB1*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*0102DQB1*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, 235249. doi:10.1038/sj.gene.6363875

Keywords: type 1 diabetes mellitus; T1DM; genetic susceptibility; human leukocyte antigen; genome scan

Introduction amputation and is also a major cause of cardiovascular

Diabetes mellitus represents a heterogeneous group of
disorders. Some distinct diabetic phenotypes can be
identified in terms of specific aetiology and/or patho-
genesis, 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 chil-
dren and young adults in populations of Caucasoid ori-
gin, 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: fpocnovo.dk
This work was in part supported by the EU BioMed 2 Programme
(grant no. BMH4CT972311), Novo Nordisk A/S, The Danish Dia-
betes 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
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 corre-
sponding genes.49 However, in general, T1D is con-
sidered as a complex genetic trait, ie, not only do multiple
genetic loci contribute to susceptibility, but environmen-
tal 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% com-
pared 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 suscepti-
bility 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-
 Genetics of type 1 diabetes mellitus
F Pociot and MF McDermott

236
ating candidate genes for association with disease status The genes
in either case-control or family-based studies. Two
chromosomal regions have emerged with consistent and HLA-encoded susceptibility to T1D
significant evidence of association with T1D across mul- The best evidence for a genetic component in the suscep-
tiple studies. These are the human leukocyte antigen tibility to T1D comes from studies of the HLA genes in
(HLA) region, at chromosome 6p21.3, and the insulin both populations and families as well as from animal
gene region at chromosome 11p15. models. It has been estimated that HLA (IDDM1) pro-
In the 1970s, association and affected-sib pair linkage vides up to 4050% of the familial clustering of T1D.11,41
studies established the role of HLA genes in T1D predis- The HLA region is a cluster of genes located within the
position (the HLA locus contribution to disease is major histocompatibility complex (MHC) on chromo-
referred to as IDDM1).1214 HLA studies also demon- some 6p21. Identification of the genes involved has
strated that T1D and type 2 (non insulin-dependent) dia- proved to be extremely elusive, despite tremendous
betes mellitus (T2D) were distinct disease entities, since efforts, involving several complementary approaches eg
T2D generally does not show an association with HLA, functional studies and animal models. This is due to sev-
although certain subsets may demonstrate some associ- eral complicating factors, amongst which is the strong LD
ation.15 The variability in rates of T1D disease concord- between neighbouring genes in the HLA complex, and
ance in siblings who share two, one or zero parental HLA the fact that several HLA-linked genes, acting in concert,
haplotypes in addition to the different concordance rates may determine disease susceptibility.
in monozygotic vs dizygotic twins, the risk in relatives, The contribution of the IDDM1 region is easily detect-
and the population prevalence implicates the existence of able in genome-wide linkage analyses, as indicated by a
additional non-HLA genetic factors. LOD score of 65.8, recently reported in a consensus
More recently genome-wide linkage analysis has been analysis of 767 multiplex T1D families.21 The genes of the
used to try to identify the genetic determinants for T1D. MHC region are classified into four families, classes I, II,
Five complete genome scans,1620 including a combined III and IV.4244 The statistically strongest genetic associ-
analysis of the UK and US genome scan data,21 and ation with T1D is conferred by HLA class II gene alleles.
several specific linkage studies of certain regions or From both human genetics and animal model studies
chromosomes have now been reported.2230 Together there is good evidence that particular alleles of the HLA-
these studies suggest that close to 20 genomic intervals, DQA1, DQB1 and DRB1 loci all are primarily involved
with variable degrees of linkage evidence, might be in the genetic predisposition to T1D.4550 However, due
influencing T1D risk. The most up-to-date reports are to the strong LD between these loci it has been very dif-
probably from the two recent studies by Cox et al21 and ficult to study the effect of individual HLA-DQ or -DR
by the European Consortium for IDDM Genetic Studies genes separately. It is clear that some combinations of
(ECIGS).20 The first study is a combined analysis of US HLA-DQ genes, eg those encoding DQ8 (ie. DQA1*03
and UK families from previously published genome DQB1*0302) and DQ2 (ie DQA1*05DQB1*02), and parti-
scans,16,18,19 including a new collection of 225 US mul- cularly those present in HLA-DQ2/DQ8 heterozygotes
tiplex families. In total, the combined sample comprised are associated with susceptibility to T1D (Table 1).
831 affected sib-pairs (ASPs).21 The ECIGS study included Approximately 30% of T1D patients are HLA-DQ2/DQ8
464 Scandinavian ASPs, which have never before been heterozygotes.51 By contrast, a particular DQ6 molecule,
included in previous genome scans. It is significant that encoded by HLA-DQA1*0102DQB1*0602, is associated
both studies provide evidence of interaction between the
different T1D susceptibility loci.20,21
For all these loci the etiological mutation(s) in sensu Table 1 Type 1 diabetes-associated HLA class II alleles and haplo-
strictu has not been identified. Even in the HLA region types
several genes seem to be involved (see below). Most of
the other putative T1D loci comprise regions of 140 HLA-DQ alleles HLA-DR-alleles RR
centimorgans (cM) in size, corresponding roughly to 1
40 Mb, which may contain several genes. Mapping these Positive associations
(Susceptibility haplotypes)
genes will be a major challenge of the genome era. A1*0301-B1*0302 DRB1*04 2.59.5
Currently, little is known about the nature of genetic vari- A1*0501-B1*0201 DRB1*301 2.55.0
ation underlying T1D, which makes it difficult to be con- A1*0501-B1*0302 DRB1*301/DRB1*04 12.032.0
fident about strategies used to address this problem. One A1*0301-B1*0201 DRB1*301/DRB1*04
hypothesis proposes that the genetic basis of T1D will A1*0301-B1*0402 DRB1*04/DRB1*801 4.015.0
involve alleles that are themselves common in the popu- A1*0301-B1*0201 DRB1*701 8.013.0
A1*0301-B1*0201 DRB1*901 5.5
lation at large.31,32 Assumptions about genetic factors con- A1*0301-B1*0401 DRB1*04 3.54.5
tributing to T1D are relevant to the approach undertaken. A1*0301-B1*0303 DRB1*901 2.04.5
Under the common disease, common variant hypoth-
esis, it may be possible to generate a catalogue of com- Negative associations
mon SNPs and use association mapping to identify dis- (Protective haplotypes)
ease-susceptibility polymorphisms.3335 In this regard A1*0102-B1*0602 DRB1*1501 0.030.2
A1*0103-B1*0603 DRB1*1301 0.050.25
strategies to identify SNPs that delineate the different A1*0301-B1*0301 DRB1*04 0.20.5
haplotypes of a gene or a region of linkage disequilib- A1*0501-B1*0301 DRB1*1101 0.050.5
rium (LD)3639 seem most promising. Interestingly, very
recent studies suggest that much of the difficulty in map- Relative risk (RR) is for the combined DQ-DR haplotype and refers
ping T1D susceptibility genes results from inadequate to high-risk populations. There is significant variation between dif-
sample sizes and the study of mixed ethnic groups.21,40 ferent ethnic populations.

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with strong protection from the disease, even in the pres-
ence of T1D-associated autoantibodies and/or of high-
risk 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 protec-
tion.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 HLA-
DR4-associated DRB1 alleles are increased among T1D
patients.55 This has since been confirmed in larger studies
by other groups.5658 The varying risk conferred by differ-
ent HLA-DR4 haplotypes is illustrated in Table 2. There
is evidence that the different risk categories are determ-
ined by the predicted structure and action of the peptide-
binding 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 com-
mon to all these alleles that is central to disease suscepti-
bility, 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.5963 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 predis-
posing 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 com-
plexity 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 allo-
types, 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 sus-
ceptibility.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,6971 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-
Table 2 Critical polymorphic residues of the HLA-DRB1*04 beta chain associated with predisposition to type 1 diabetes
DRB1*04 allele
37 57 67
0401 Tyr Asp Leu
0402 Tyr Asp lle
0403 Tyr Asp Leu
0404 Tyr Asp Leu
0405 Tyr Ser Leu
0406 Ser Asp Leu
0407 Tyr Asp Leu
+ and indicate degree of predisposition, ie + + + confer the strongest susceptibility, whereas corresponds to strong protection.
Genetics of type 1 diabetes mellitus
F Pociot and MF McDermott
237
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.7476
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 HLA-
DQ/DR loci; however, in all these studies the number of
subjects/families was small. Subsequently, several stud-
ies 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 lympho-
toxin (TNFA and TNFB).78,8082 The strongest evidence for
susceptibility genes in the class I region comes from
recent systematic assessment of microsatellite markers
spanning this region.8389
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 gener-
ate 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 puta-
tive loci, approved by the Human Gene Nomenclature
Committee, are IDDM1IDDM18 (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 pre-
liminary 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
Polymorphic residues Disease predisposition
70 71 74 86
Gln Lys Ala Gly +++
Asp Glu Ala Val +/
Gln Arg Glu Val
Gln Arg Ala Val +/
Gln Arg Ala Gly +++
Gln Arg Glu Val
Gln Arg Glu Gly
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 Genetics of type 1 diabetes mellitus
F Pociot and MF McDermott

238
Table 3 Summary of previous linkage results

Locus Chromosome Markers Significance level (reference) Independent or overlapping

replication (reference)

1 D1S1644AGT **18
IDDM7-IDDM12 2 HOXD8D2S72CTLA4 ***150 *18,19,21,24,245
IDDM13 2 D2S137D2S301 **27 *18
IDDM9 3 D3S1279 *19
29
IDDM18 5 IL12B
IDDM15 6 D6S283 ***28 **20
** (not corrected for MHC)18,21
IDDM5 6 D6S476D6S473 ***26 *16,19
*18,21,125
IDDM8 6 D6S446D6S281 ***24 **24,125; *18,19,28
IDDM10 10 D10S191D10S220 ***19 **17
**21
IDDM17 10 D10S1750D10S1773 ***6 *21
IDDM2 11 INS **19
IDDM4 11 D11S1296FGF3 ***26 **16,17
14 D14S70D14S276 **19
IDDM11 14 D14S67 ***25
30
IDDM16 14 D14S292D14S293
IDDM3 15 D15S107 **22
16 D16S515D16S520 **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) 3, but an estimated sibling genetic risk ratio (s)
of only 1.12. Other locus-specific effects, excluding HLA,
range from 1.051.3. Power analyses suggest that 4.300
affected sib-pair families will be required to achieve 80%
power to detect a linkage at the suggested significance
level with P 2.2 105 90 at these levels of risk.
IDDM2the insulin gene (INS) region
The immune-mediated process leading to development
of T1D is highly specific to pancreatic beta cells. The insu-
lin gene, therefore, is a plausible candidate susceptibility
locus since insulin or insulin precursors may act as auto-
antigens. Alternatively, insulin levels could modulate the
interaction between the immune system and the beta
cells.
A unique minisatellite (VNTR), which arises from tan-
dem repetition of a 1415 bp oligonucleotide sequence, is
located in the 5 regulatory region of the human insulin
gene (INS) on chromosome 11p15.5. The number of tan-
dem repeats varies from about 26 to over 200, and VNTR
alleles occur in three discrete size classes: class I (2663
repeats), class II (mean of 80 repeats), and class III (141
209 repeats).9193 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 two-
to five-fold increase in risk of developing T1D, whereas
class III alleles seem to provide dominant protection.93102
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,
which followed this original mapping, presumed that the
4.1 kb was the minimal regionin other words haplo-
types were analysed within the 4.1 kb region and not out-
side it, and eventually provided substantial evidence for
the insulin VNTR being the primary locus. However,
without actually searching more thoroughly for associ-
ations 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 exist-
ing evidence for IDDM2 as a true locus comes from mul-
tiple replications of the disease association studies in both
case-control and family-based cohorts. High-resolution
genotyping has revealed that variable degrees of suscep-
tibility are associated with each VNTR allele and prob-
ably reflect sequence heterogeneity within the VNTR that
may affect its function and physical state.104108 There are
also data to suggest that the VNTR may modulate INS
transcription in pancreas and thymus93,101,109113 and that
INS class III alleles, as compared with class I alleles, cor-
relate with low INS mRNA levels in the pancreas but
with higher levels in the thymus (on average 23 fold).
Greater thymic expression of INS may explain the domi-
nant protective effect of class III VNTR alleles, reported
in T1D, by enhancing tolerance to the preproinsulin pro-
tein.114,115
IDDM3IDDM18
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 IDDM3IDDM18, 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 candi-
date genes have been further analyzed. IDDM3 [MIM
600318] was originally reported to be located near the

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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,1821,26
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 chro-
mosome 11q13, was reported simultaneously by two dif-
ferent 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 off-
spring 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 apop-
totic signal depends on association and interaction
between the intracellular death domain of Fas with
FADD. Recent experimental findings indicate that bind-
ing 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 recep-
tor 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 func-
tion is unknown. C11orf23 has sequence similarity to the
SIT4 (sporulation-induced transcript 4)-associated pro-
tein (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 screen-
ings. 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 repli-
cated 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
Genetics of type 1 diabetes mellitus
F Pociot and MF McDermott
239
IDDM5 maps to a region approximately 40 cM centrom-
eric 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 oxy-
gen radicals (FOR) in the immune-mediated beta-cell
destruction,31,127 and protection of beta cells from cyto-
kine exposure is correlated with superoxide dismutase
(MnSOD) expression/activity.128,129 Furthermore, poly-
morphisms 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 predis-
position 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 perfor-
med.133,134 In 1708 families from seven different countries,
a haplotype designated 1024 composed of the markers
129, II-IO43 and 56-D18S487 showed some positive evi-
dence of association with T1D.134 However, in an inde-
pendent 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 disease-
associated haplotype (allelic heterogeneity), which con-
founded the analysis of individual alleles by TDT133135
or simply indicates that the original observation of associ-
ation 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 = 5 106). 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.139141 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 sus-
ceptibility 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
IL1R1,144146 IL1B,130,147,148 and IL1RN130,149) HOXD8,150
GAD1,151 GALNT3,141 and NEUROD.152154 However, link-
age or association has not been convincingly demon-
strated 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
Genes and Immunity
 Genetics of type 1 diabetes mellitus
F Pociot and MF McDermott
240
other studies, using partially overlapping sets of famil-
ies.19,28,155 Combined evidence from these studies (non-
overlapping families), as well as results from the consen-
sus 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
3q21q25, 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 hetero-
zygous diabetic offspring.19 However, further studies are
needed for confirmation of this locus.
Linkage of T1D to chromosome 10p11q11 (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 sus-
ceptibility locus on 14q24.3q31, which was identified by
the finding of significant linkage to D14S67.25 Most sup-
port 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 het-
erogeneity between HLA-defined subsets of families sug-
gests that IDDM11 may be an important susceptibility
locus in families lacking strong HLA region predis-
position. However, no further studies have been able to
replicate this original observation. Two candidate genes
have been identified in the region. The ENSA gene en-
codes -endosulfine, an endogenous regulator of beta-cell
K (ATP) channels,158 and the recombinant -endosulfine
has been shown to inhibit sulfonylurea binding to beta-
cell 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,162164 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 can-
didate gene for IDDM11-conferred susceptibility. Fur-
thermore, 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 D2S72CTLA4D2S116 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 func-
tional 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 3UTR of the CTLA4 sequence, and several
polymorphisms have been detected at CTLA4.39 These
polymorphisms, in particular the exon 1 (49 GA) SNP,
have been investigated by TDT analysis in several popu-
lations,41,140,171186 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 auto-
immunity,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 Inter-
estingly, 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 costimu-
lator (ICOS),195,196 which is structurally and functionally
related to CD28 and CTLA-4, may be an additional candi-
date 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 knock-
outs197199 have demonstrated that ICOS is essential for
development of normal T cell help and plays a protective
role during induction of experimental autoimmune dis-
ease.197 These data suggest that there may be more auto-
immune disease genes at chromosome 2q33 and that the
immune response is a dynamic process, wherein there is
obviously a large potential for multiple costimulatory sig-
nals.
The IDDM13 [MIM 610318] locus maps to 2q34, and
the strongest evidence for linkage has been obtained for
the D2S137D2S164 region.27 Thus, IDDM12 and
IDDM13 are separated by only 1718 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 D2S1327D2S1471
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 disease-
associated mutations have been identified in these genes.
IDDM15 is a putative susceptibility locus that has been
mapped to 6q21, in the region of D6S283D6S1580,28
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 cosegre-
gation of IDDM15 with disease should take these gender
related recombination rates into account. In a recent gen-
ome scan of Scandinavian T1D families20 suggestive evi-
dence 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 popu-
lations.20 Taking into account the 95% confidence interval
for the estimate of the distance between HLA and

D6S283,28 it was estimated that the P value in the com-
bined family set would be 3 105 to 5 108 (7 107 for 5q31.1q33.1, close to the gene for the p40 subunit of the
the recombination rates given above).20 Additional sup-
port 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-sus-
ceptibility loci, apart from IDDM1 and IDDM2. Interest-
ingly, it has also been suggested that this region on chro-
mosome 6 contains a gene responsible for transient
neonatal diabetes mellitus, which could also be a candi-
date 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 allo-
types in T1D (reviewed in Dugoujon and Cambon-
Thomsen202). 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 stud-
ies 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 mark-
ers.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 self-
antigens, and it is therefore conceivable that genetically
controlled differences in immunoglobulin structure and
function could alter a persons immune response to such
antigens and affect T1D risk. Also, this locus needs repli-
cation 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 high-
risk 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 stud-
ies,204 and this particular region has not been identified in
other genome scans.1620 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 dis-
ease rather than a polygenic disease in some circum-
stances, 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
Genetics of type 1 diabetes mellitus
F Pociot and MF McDermott
241
605598], was identified and mapped to chromosome
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 differ-
entiation of T-lymphocytes into the Th1 subset, character-
ised 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 induc-
tion,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 auto-
reactive T cell responses might predispose to self-destruc-
tive immunity.211,212 Several polymorphisms have been
identified in the IL 12B locus.205,213 A 3UTR (untranslated
region) single base change showed strong linkage
disequilibrium with the T1D susceptibility locus in Aus-
tralian and British diabetes families,29 but this obser-
vation needs to be replicated in other populations.214
Other susceptibility loci
A number of additional chromosomal regions demon-
strating 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 desig-
nated 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 selec-
ted to cover the EIF2AK3 region, and evidence of linkage
at this locus increased to a LOD score of 2.6 in HLA-
DR3/4 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 WFS1,216218 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 Marker/position LOD score P-values
1 1q42 2.20a 7.4 104
2 D2S113 1.82b 0.002
4 D4S403 1.84b*
5 D5S407 2.16b*
12 D12S99 1.97b*
16 D16S405D16S287 2.80b 2 104
16 16p11p13 1.74a*
16 D16S3098 3.93a 2.2 105
17 17q25 1.81a*
19 19q11 1.80a*
*Corresponding P-values not reported.
Genes and Immunity
 Genetics of type 1 diabetes mellitus
F Pociot and MF McDermott
242
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 link-
age to Xp13-p11 in HLA-DR3/X affected sibpairs.20,219
There is also increasing evidence of the key role of vit-
amin D levels in T1D susceptibility.220222 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 poly-
morphisms and T1DM has been reported in South
Indian, German and Taiwanese populations,227229
although not necessarily with the same VDR polymor-
phisms.
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 identifi-
cation of such complex traits. Therefore new methods
have been developed. These include variance compo-
nents methods for quantitative trait loci (QTL);230,231 con-
ditional tests for QTL by multiple regression analy-
sis;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 analy-
sis,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 methods1621,239,240 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 stra-
tegies for detecting sets of marker loci, which are linked
to multiple interacting disease genes. At present, evi-
dence of statistical interactions between unlinked loci is
either calculated by evaluation of correlations between
family-specific LOD scores for pairs of loci237 or by con-
ditioning on other loci eg on specific HLA genotypes or
age-at-onset.1921 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 ident-
ifying new T1D susceptibility/resistance regions. Identi-
fication of syntenic regions, ie regions demonstrating cor-
respondence 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 identifi-
cation of similar genes in man. Characterisation of over-
lapping 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 predis-
pose to autoimmunity. Indeed, by correlating data from
existing genome scans in other human autoimmune dis-
ease, overlaps with already identified T1D susceptibility
loci are revealed (Table 5). This clustering of autoimmune
susceptibility loci suggests that there may be related gen-
etic backgrounds contributing to susceptibility of clini-
cally 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 suscepti-
bility 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 stud-
ies 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 fre-
quencies higher than 5%.
Table 5 IDDM loci for which susceptibility loci for other auto-
immune diseases have been mapped to the same region
Locus Other autoimmune diseases
IDDM1 All autoimmune diseases
IDDM2 MS246
IDDM3 CD247
IDDM5 RA248
IDDM6 RA249, AITD250, SLE135
IDDM8 RA248
IDDM9 RA249
IDDM12 (CTLA4) RA, MS, AITD, AD191
IDDM13 RA249
16q22q24 Psoriasis251, asthma252, CD253
DXS998 MS, RA249
MS = multiple sclerosis; CD = celiac disease; RA = rheumatoid
arthritis; AITD = autoimmune thyroid disease; AD = Addisons
disease.

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 con-
firmed. These studies are still difficult to perform due to
the fact that the human genome sequence is not com-
pleted, 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 con-
tinue 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 gen-
eration of transgenic and knockout animal models.
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