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AbstractType 1 diabetes (T1D) is a chronic immune-mediated disease, charac-terised by a selective loss of insulin-producing β-cells in the pancreatic islets. Susceptibility is determined by interactions of multiple genes with unknown environmental factors. Around 50% of the genetic risk of the disease is explained by HLA, although other genes with a smaller effect are also involved. Most of the known risk genes for T1D play a role in immunity, mostly through T-cell regulation (CTLA4, PTPN22, IL-2RA) and cytokine production or modulation (VDR, SUMO4). The insulin gene (INS) represents and exception to this, and is probably the only gene specifi cally associated with T1D and not with other autoimmune dis-eases. Ongoing genome-wide association studies are providing evi-dence of multiple known and previously unknown risk genes. New ana-lytical tools are continuously being developed to handle the vast amounts of data produced, as well as to account for multiple compari-sons and assess combined effects such as gene-gene and gene-envi-ronment interactions. In this review, we will give an overview of the most important genes identifi ed to date, analyse the genetic evidence sup-porting them as T1D susceptibility genes and discuss the mechanisms mediating their contribution to the pathogenesis of the disease.

Keywords: autoimmune, insuline-dependent, family risk, prediction.

IntroductionType 1 diabetes (T1D) is one of the most common chron-ic diseases in childhood, with an incidence ranging from

0.1 to 64/100 000 per year (China vs Finland) and in-creasing in most of the countries where it has been stud-ied DIAMOND and EURODIAB.1,2-5 In Spain, accord-ing to most studies, the incidence per 100,000 inhabitants and year ranges between 9.5 and 16.4 for children diag-nosed before the age of 15.6-13 An exception to these are represented by recent results from Castilla-Leon, show-ing an incidence of 22/100,000/yr,14 from Ciudad Real (26/100,000/yr)15 and data from the Canary Islands. The latter region has the highest rate of childhood T1D ever reported in Spain, with the most recent incidence (32/100,000/yr on the island of La Palma) approaching that of some Northern European countries.16,17 In addi-tion, some studies show an increasing trend in the inci-dence of T1D in Spain,12,16 whereas others do not.6

Type 1A diabetes (T1D) is a complex, multifactorial dis-ease, which leads to the autoimmune destruction of pancre-atic, insulin-producing, β-cells. Its ultimate cause is un-known, but both environmental and genetic factors have proved to play a role in its development. The present review will focus on the latter. Although only 10-12% of patients with T1D have a family history of the disease at diagnosis, with longer follow-up the frequency increases to up to 25%.18 In addition, having a Þ rst degree relative with the disease increases the risk from 2.5 to more than 100 times, depending on who the affected family member is (table 1).

The most established genetic locus contributing to T1D and many other autoimmune diseases is the major histo-compatibility complex (MHC), which includes the genes encoding the human leukocyte antigen gene (HLA), cru-cial in antigen presentation. In addition, several other genes have been established as contributing to the devel-opment of the disease, although to a smaller extent than HLA. More than 20 different loci have been proposed to account for the genetic risk of T1D (Þ gure 1), but only a minority had been confirmed until very recently. At

Revisión

Genetics of type 1 diabetes: recent progress and future perspectivesA.M. Wägner, J.C. WiebeEndocrinology Dept. Hospital Universitario Insular de Gran Canaria

Date received: 24th November 2008Date accepted: 7th May 2009

Correspondence: A.M. Wägner, MD PhD. Servicio de Endocrinología y Nutrición. Hospital Universitario Insular de Gran Canaria. Avda. Marítima del Sur, s/n. 35016 Las Palmas de Gran Canaria. E-mail: awagfah@gobiernodecanarias.org

Abbreviations:HLA: human leukocyte antigen; INS: insulin gene; IL-2: interleukin-2; IL-2RA: interleukin-2 receptor; Lyp: lymphoid protein tyrosine kinase; MHC: major compatibility complex; PTPN22: protein tyrosine phosphatase non-receptor type 22; SNP: single-nucleotide polymorphisms, SUMO: small ubiquitin-like modifier; T1D: type 1 diabetes; VDR: vitamin D receptor; VNTR: variable number of tandem repeat.

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present, we are witnessing an «explosion» of risk genes, thanks to the availability of new genotyping technolo-gies and bioinformatic tools.

Recent development in genetic researchThe genotyping and analytical tools made available in recent years have profoundly changed the way we under-stand genetics research. Genotyping methods have al-lowed for several hundreds of thousands genetic varia-tions to be studied, as opposed to only a few at a time with previous technology. This fact has also changed the strategy of studies, moving from directed, hypothesis-based search for candidate genes to non hypothesis-based, unbiased whole genome association studies which

complement the former. Sample sizes have increased from a few hundreds to many thousands of patients. In complex diseases like diabetes, this increase in sample size is crucial if we aim to identify genes with moderate effects on disease risk. In that sense, we have moved from competition to collaboration between research groups and large networks and consortia have been established: the Type 1 Diabetes Genetics Consortium –T1DGC–, the Wellcome Trust Case Control Consorti-um –WTCCC– and The Genetics Association Informa-tion Network –GAIN–.

Finally, new analytical tools have had to be developed in order to tackle the vast amounts of information delivered by high through-put genotyping technologies. Both link-age and association studies become more complex with increasing number of genes being simultaneously in-cluded. The risk of false positive results has to be ac-counted for, interaction analyses are necessary to eluci-date combined genetic effects, and new tools for analysis are in continuous development.19-21

Most established risk genesMajor Histocompatibility ComplexThe genetic region encoding the human MHC, HLA, also designated as IDDM1, is by far the most solidly estab-

Table 1. Risk of T1D for a given individual according to the family member affected18,170-172

Relative risk Absolute risk (%)

No family history 1 0,4

Mother 2.5-5 1-2

Father 12.5-15 5-6

Sibling 15-22.5 6-9

One sibling + one parent 62,5 25

HLA-identical sibling 50 20

Monozygotic twin 75-175 30-70

Image KeyGenome Wilde Associated Region Candidate Region

UnnamedChr1

IDDM7

IDDM12

IDDM13

IDDM10IDDM17

IDDM6

IDDM4

IDDM2

IDDM9 IDDM18

IDDM11

IDDM1IDDM15IDDM5IDDM8

IDDM3UnnamedChr16

Chr1 1p13 Chr2

Chr9

2q24

2q33

Chr10 10p15

Chr3

Chr11

Chr4 4q27

Chr1211p15

Chr5 Chr6 6p216p21

12q13

12q24

Chr13 Chr14

Chr7

Chr15

Chr8

Chr16 16p13

ChrYChrXChr22Chr21Chr20Chr19Chr18Chr17 18p11

18p22

Figure 1. Genomic regions linked or associated with type 1 diabetes. With permission from www.t1dbase.org

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lished risk locus for T1D.22-24 It is located on the short arm of chromosome 6 (6p21.3), a dense region of highly polymorphic genes extending for 3.5 Mb. The classical class I HLA loci (telomeric) comprise HLA-A, -B, and -C, and class II (centromeric) comprise HLA-DR (DRA, DRB), -DQ (DQA, DQB) and -DP (DPA, DPB). The class III HLA region (located between class I and class II) includes the complement genes C2, C4, Bf, heat shock proteins genes (HSP70), tumour necrosis factor genes (TNF), 21-hydroxylase (21-OH) and others (Þ gure 2).

HLA accounts for up to 50% of the genetic risk,25 with major effects attributed to certain DR and DQ genes. However, due to high linkage disequilibrium in the re-gion (DR and DQ alleles tend to be inherited together) it is difÞ cult to determine those responsible for the risk. In-deed, associations of HLA alleles with T1D should be considered haplotype speciÞ c rather than allele speciÞ c. A recent meta-analysis of 38 studies conÞ rmed that hap-lotypes comprised of DRB1*0401, *0402 or *0405 and DQB1*0301 (DR4-DQ8) were associated with the high-est risk of T1D, followed by DRB1*0301 DQB1*0200 (DR3-DQ2) and DRB1*0404 DQB1*0302. The highest risk of T1D is given by the combination of DR3 and

DR4 in one genotype. The “neutral” category of haplo-types includes DRB1*0800 DQB1*0402, DRB1*0901 DQB1*0303 (DR9) and DRB1*0100 DQB1*0501 (DR1) and the most protective includes DRB1*1400 DQB1*0503 and DRB1*1500 DQB1*0602 (DR2).26 Results from the T1DGC expand these haplotypes to in-clude DQA1, as well as DRB1 and DQB127 (table 2). Their results also indicate that the risk associated with certain HLA haplotypes can be inß uenced by the geno-typic context, as exempliÞ ed by the high risk conferred by the trans-complementing DQ heterodimer encoded by the DQA*0501 allele on DR3 and the DQB1*0302 on some DR4 haplotypes.27

In Spain, unlike in other European populations, DR3 seems to confer a higher risk of T1D than DR4 accord-ing to most,28,29 albeit not all of the studies.7 These Þ nd-ings may be due to the particularly high-risk haplotypes associated with DR3 in Spain.28,30

Although DR and DQ alleles confer most of the genetic risk for T1D, class I alleles and maybe other loci within the MHC region are also important in the development of the disease. Further genotyping of class I alleles in

Major Histocompatibility Complex (6p21.3)

0301040504020401

02000301

Alleles

Genes

Telomere Centromere

A C B

MIC

A

TNF

HSP7

0

C4A

CYP2

1B

DRA

DRB1

DQA1

DQB1

TAP2

LAP7

TAP1

LMP2

DPA1

DPB1

Frequentrecombination

Frequentrecombination

Inrequentrecombination

4000

kbp

2000

kbp

1000

kbp

0kbp

Class I Class III Class II

MHC

6p21

.3

Chr6

alleles + alleles haplotypesDRB1 *0401 DQB1 *0301

*0402 DR4-DQ8*0405

DRB1 *0301 DQB1 *0200 DR3-DQ2}}

Figure 2. Description of the MHC region on chromosome 6

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carriers of high-risk class II HLA haplotypes has given further insight into this matter.31,32 Siblings of patients with T1D, identical for their DR3/DR4-DQ8 genotypes, who share both HLA haplotypes (deÞ ned by HLA A and B, too) with the proband, have a 55% risk of developing T1D by the age of 12 (vs 5% of those sharing 1 or no haplotype).32 Furthermore, the remarkably conserved HLA A1-B8-DR3 haplotype33 seems to reduce the risk conferred by DR3-DQ2.34 Several other reports support an effect of HLA class I genes on disease susceptibility, in particular the HLA-A*2401, *0101 and *0302 and HLA-B*39 alleles.34-38 A highly conserved haplotype (B18 AH 18.2), particularly prevalent in the Spanish population, modulates the risk conferred by the DR3-DQ2 alleles. In fact, markers included in the HLA class III region (BAT-2*2 and TNFa2bI) have been found to predict risk in carriers of DR3-DQ2,30 though it is uncer-tain whether this effect persists after accounting for class I genes. In addition, a recent report from the T1DGC MCH Þ ne-mapping project identiÞ es additional risk sin-gle-nucleotide polymorphisms (SNPs) in the vicinity of HLA-G, COL11A2 and RING1.39 Other genes within the MHC region that have been reported to be associated with T1D include MIC-A40 and ITP3,41 but the results have not been replicated when LD with other class I and class II genes has been taken into account.42,43

Finally, a new locus telomeric to MHC (UBD/MAS1L) has shown to predict development of type 1 diabetes in-

dependently of class I and class II genes.44 Replication in other populations, as well as functional studies of the candidate genes should provide information about their role in the pathogenesis of the disease.

Non-MHC genesAlthough HLA is responsible for up to 50% of the genet-ic risk of T1D, other genes are involved, too, albeit with a weaker effect (odds ratios in the 1.15-1.3 range). Most of these genes play important roles in immunity and many are not speciÞ c to T1D, but also inß uence risk for other autoimmune diseases (table 3).

INSThe insulin gene (INS), located on chromosome 11p15.5 (IDDM2), is expressed in β-cells and in the human thy-mus, an expression site likely to be involved in immune tolerance. Two recent studies conÞ rmed that insulin is a major and primary target for autoreactive T-cells both in humans with T1D and in NOD mice.45,46 The susceptibil-ity locus IDDM2 maps to a minisatellite composed of a variable number of tandem repeat (VNTR) polymor-phism situated 0.5 kb upstream of INS, in the promoter region of the gene.47 In Caucasians, the main classes of VNTR region minisatellites are named VNTR I (26-63 repeating units) and VNTR III (140-210 units) alleles,48 where the former is associated with the highest risk of T1D,49,50 Although the precise function of the VNTR is still uncertain, the feature of the promoter region of INS may inß uence the binding of the AIRE transcription fac-tor. The latter regulates the expression of self antigens51 and controls the thymic expression of insulin and the de-letion of autoreactive T-cells during negative selection. The development of immune tolerance to insulin may be reduced through reduction of insulin transcription in thymic medullary epithelial cells.23,52 Indeed, the level of insulin expression in the human thymus correlates with the VNTR polymorphism, which in turn correlates with diabetes susceptibility.53,54 Recent studies of the INS lo-cus showed that the SNPs -2221MspI, -23HphI (A/T) and +1140 (A/C) confer the highest susceptibility to T1D. Because of their strong linkage disequilibrium with the VNTR, these polymorphism can even be used as markers of the latter.49,55-57

CTLA4The cytotoxic T lymphocyte antigen-4 (CTLA4) plays an important role in immune response regulation and is strongly associated with autoimmune diseases.58,59 This

Table 2. HLA class II haplotypes conferring the highest and the lowest risk of type 1 diabetes

Haplotype Risk of T1D (odds ratio)

High risk

DRB1*0405 DQA1*0301 DQB1*0302 (DR4) 11.37

DRB1*0401 DQA1*0301 DQB1*0302 (DR4) 8.39

DRB1*0301 DQA1*0501 DQB1*0201 (DR3) 3.64

DRB1*0402 DQA1*0301 DQB1*0302 (DR4) 3.63

DRB1*0801 DQA1*0401 DQB1*0402 (DR8) 1.59

Protection

DRB1*0701 DQA1*0201 DQB1*0303 (DR7) 0.02

DRB1*1401 DQA1*0101 DQB1*0503 (DR6) 0.02

DRB1*1501 DQA1*0102 DQB1*0602 (DR2) 0.03

DRB1*1104 DQA1*0501 DQB1*0301 (DR11) 0.07

DRB1*1303 DQA1*0501 DQB1*0301 0.08

Based on Erlich et al.27

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CD28 homologue is mapped to the genetic region of the human IDDM12 locus on chromosome 2q3160 and its ex-clusive expression on activated CD4+ and CD8+ T-cells carrying CD2861 in mice seems to be controlled by the Foxp3 gene.62-64 CTLA4 appears to attenuate immune re-sponses by several mechanisms. As a negative regulator of T-cell activation, CTLA4 inhibits T-cell co-stimula-tion through intercellular interaction, competing for CD28 ligands (CD80/CD86) that are expressed on the surface of antigen presenting cells (APCs). Unlike CD28, which contributes to T-cell activation and maintenance of T-cell response (two signal hypothesis),65,66 CTLA4 restricts the initiation and progression of T-cell immuni-ty.67-69 It also inhibits T-cell activation by different intra-cellular signalling pathways,70,71 mediates apoptosis of activated human T lymphocytes in an antigen-restricted way72,73 and has an effect on the suppressive activity of regulatory T-cells (Tregs).74-78 The latter are important for maintenance of self-tolerance and immune homeos-tasis in the absence of exogenous antigens (Ag) and for control of Ag-speciÞ c responses.79 SpeciÞ c deÞ ciency of CTLA4 in Tregs in knock-out mice impairs suppressive function of Tregs and results in spontaneous develop-ment of systemic lymphoproliferation and fatal T-cell-

mediated autoimmune disease with multiorgan lym-phocytic inÞ ltration and tissue destruction.58,80,81

The T1D-associated CTLA4 haplotype contains several polymorphisms in tight linkage disequilibrium (LD), any one of which or a combination thereof could determine the functional effect. The SNP +6230G>A (CT60 rs30807243), located in the 3’ ß anking region of CTLA4, has been associated with splicing or altered levels of steady state CTLA4 mRNA.59,60 However, recent re-sults82,83 deny the effect of this SNP on modulation of steady-state mRNA of any known CTLA4 isoform but do not rule out its potential role in the development of T1D. Promoter polymorphisms -319C>T and -1661A>G (the latter in Moroccan and Indian population) possibly con-tribute to T1D through transcriptional effects on expres-sion,60,84,85 and SNP +49A>G on exon 1 of CTLA486 causes a change in the signal peptide, resulting in less CTLA4 at the cell surface. This explains the reduced in-hibitory function of CTLA4 reported in individuals with the +49G allele and is associated with reduced control of T-cell proliferation.87,88 Both the CD28 and CTLA4 path-ways are targets for current immunomodulatory thera-pies.89

Table 3. Summary of genes associated with the risk of type 1 diabetes

Gene/region (IDDM)

Reference Location Functional studies

Role Causal variants Association to other AID

HLA (IDDM1) 173,174 6p21.3 Yes Antigen presentation Class II, Class I and others Yes

INS (IDDM2) 48,49,53 11p15.5 Yes Insulin gene VNTR I/III No

CTLA4 (IDDM12) 59,175 2q31 Yes Regulator of T-cell activation -319C>T, +49A>G, +6230G>A (CT60) Yes

PTPN22 90,176 1p13 Yes Inhibits T-cell receptor signalling Arg620Trp (+1 858C>T) Yes

IL2RA (IDDM10) 102,103 10p15-p14 Yes α-chain of IL-2 receptor CD25 rs706778 (A/G), rs3118470 (C/T), ss52580101, rs11594656

Yes

SUMO4 (IDDM5) 136 6p25 Yes Inhibits NFκB Met55Val (163A>G) Yes

VDR 122,123 12q13 Yes Vitamin D receptor. It mediates Class II MHC down-regulation and IL12 inhibition

FokI (ATG>ACG) Yes

IFIH1 (IDDM19) (mda-5 or Helicard)

138-140 2q24 Yes Is involved in antiviral immune response

rs13422767, rs2111485, rs1990760, (A946T) rs3747517

Controversial

KIAA0350(CLEC16A)

146,177 16p13 No Encodes a C-type lectin rs2903692, rs725613, rs17673553, rs887864

Yes

PTPN2 144,157 18p11 No encodes a T-cell protein tyrosine phosphatase

rs1893217, rs478582 ?

UBASH3A (TULA, CLIP4, STS-2)

22 21q22.3 No cellular regulator, may be involved in maintenance of immunological tolerance178

rs876498 ?

AID: autoimmune diseases. VNTR: variable number of tandem repeats. ?: not known at the time of the review.

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PTPN22Similar to CTLA4, PTPN22 (protein tyrosine phosphatase non-receptor type 22) is a diabetes susceptibility locus that is shared by several autoimmune diseases.90,91 It is lo-cated on chromosome 1p13 and encodes a lymphoid pro-tein tyrosine kinase (Lyp). Lyp is expressed in lymphoid T-cells, where it modulates the activation of protein ki-nases involved in early T-cell receptor (TCR) mediated signalling events,92 acting as a negative regulator of TCR signalling.92-94 The Arg620Trp (1858C/T) SNP in PTPN22 appears to promote autoimmunity in multiple ways, though there is only limited data regarding the mecha-nism by which variations in this gene contribute to the pathogenesis of T1D and how they affect immune func-tion in humans. The Arg620Trp variant has been reported to be associated with the development of insulin autoan-tibodies (in contrast to GAD and IA-2 antibody levels, which were not signiÞ cantly inß uenced by this polymor-phism) and an accelerated progression of the autoimmune process in T1D.95 According to two studies,93,96 the Ar-g620Trp variant causes a gain-of-inhibitory function that leads to enhanced suppression of TCR signal transduc-tion, a profound defect in T-cell responsiveness to antigen stimulation and decreased interleukin 2 (IL-2) secretion in T-cells. IL-2 is mainly produced by activated T-cells, promoting their proliferation and expansion.97 Homozy-gosity for the Arg620Trp variant is associated with reduced CD4+T-cell and B-cell activation and a shift in the mem-ory T- and B-cell populations to an increase in circulating memory T-cells and fewer and less effective memory B-cells.94,90 Lower T-cell signalling may allow the escape of self-reactive T-cells from thymic deletion and lead to im-paired self tolerance and reduced Treg development,96,98 and cause autoimmunity.52 There have been attempts to assess whether the SNPArg620Trp is the sole T1D suscep-tibility variant in PTPN22 and, although it seems to be the major risk variant for T1D in this chromosomic re-gion in European populations, the possibility still remains that a yet unidentiÞ ed variant could have a role in suscep-tibility to the disease.99-101

IL-2RAA polymorphism in Interleukin-2 receptor (IL-2RA), lo-cated on chromosome 10p15-p14,102 has recently shown an association with risk of T1D. IL-2RA encodes the α-chain of the high-afÞ nity heterodimeric IL-2 cytokine re-ceptor (CD25), highly expressed by activated Tregs.103,104 Genetic evidence also suggests a crucial role for IL-2 in T1D.102,103 Located on chromosome 4q27, IL-2 plays a

critical role in programming T-cells for activation-induced cell death and interferes with immune regulation.52 IL-2 or IL-2RA knock-out mice completely lack Tregs and suffer from a lymphoproliferative syndrome and spontaneous autoimmune disease.105 The association of IL-2 and IL-2RA to T1D is probably due to reduced proliferation of a variety of lymphocytes, including Tregs, whose depletion and altered function directly contribute to T1D pathogen-esis.106 Still, the precise role by which IL-2RA/IL-2 are in-volved in T1D susceptibility needs to be evaluated.

VDREpidemiological studies show differences in T1D inci-dence which are associated with geographical latitude and sun exposure107 and vitamin D intake before108 and during infancy109-112 seems to protect against the disease. In vitro, vitamin D suppresses the antigen-presenting ca-pacity of T-cells and dendritic cells.113 In fact, down-reg-ulation of MHC class II molecules and adhesion mole-cules114 and inhibition of IL-12 is seen after treatment with vitamin D or its analogues.115-119 The relationship between Vitamin D and autoimmune diseases has been thoroughly reviewed elsewhere.120,121

Vitamin D actions are mediated by the highly polymor-phic vitamin D receptor115 which is encoded by VDR, lo-cated on 12q12-14.122 The FokI polymorphism in exon 2 leads to a shorter and more active form of VDR protein, and displays a different distribution (P 0.0049) in sub-jects with T1D and controls.112 However, genetic studies are somewhat contradictory, with some showing an asso-ciation between VDR variations and T1D,122-131 whereas others do not.132-134 Population heterogeneity and differ-ences in exposure to ultraviolet radiation may account for these differences. A recent meta-analysis of 16 stud-ies in 19 regions showed an interaction with ambient winter ultraviolet radiation and association between cer-tain VDR alleles and T1D.135 This study supports the role of vitamin D in the development of T1D, though further studies combining genetic data and information on expo-sure to ultraviolet radiation and vitamin D status should further clarify this matter.

SUMO4The association of the small ubiquitin-like modifier (SUMO) gene, SUMO4, located in the IDDM5 locus on chromosome 6q25, has been conÞ rmed in Asian popula-tions despite controversial observations in Caucasians. A single amino acid substitution (163A>G, Met55Val) at an

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evolutionarily conserved residue of SUMO4 enhances NFκB transcriptional activity and IL-12B expression and is associated with increased risk for T1D.136,137

Other genes and regionsInterferon induced with helicase C domain 1 gene (IFIH1), involved in anti-viral response, is the most plau-sible risk gene for T1D in a linkage disequilibrium block on chromosome 2q24 (IDDM19),138-140 though its asso-ciation with other autoimmune diseases, like Graves’ disease141,142 and multiple sclerosis,143 is controversial.

A number of other associations with type 1 diabetes have been identiÞ ed and replicated for SNPs in two regions on chromosome 12, 12q24 near C12orf30 and 12q13 near erythroblastic leukemia viral oncogene homolog 3 (ERBB3), a region on 16p13 near C-type lectin domain family 16, member A (CLEC16A/KIAA0350), a region on 18p11 near protein tyrosine phosphatase, nonreceptor type 2 (PTPN2), a region on 2q12-22 encoding inter-leukin 1 receptor 1 and a region on 21q22.3 in the ubiq-uitin associated and SH3 domain containing, A (UBA-SH3A, STS/TULA family) locus.22,112,144-148 Many other chromosomic regions are likely to be discovered during ongoing analysis of the data obtained from the WTCCC, T1DGC and GAIN consortia. Detailed and updated in-formation about T1D associated loci can be found in T1DBase (www.t1dbase.org ).

Additional candidate genesA different approach to identifying new genes involved in T1D consists of trying to replicate results found in closely related diseases, such as T2D, autoimmune dia-betes presenting as part of a syndrome and other autoim-mune diseases.

Several attempts have been made at associating T2D genes to T1D, but most have been negative.149,150 Patients with autoimmune diabetes diagnosed after the age of 35 and with a clinical presentation more close to T2D (LA-DA) are an exception. These patients have features of both type 1 and type 2 diabetes, clinically as well as ge-netically.151-153

Autoimmune diabetes is also a minor component of se-vere monogenic syndromes such as APS-I or IPEX. APS1 (autoimmune polyglandular syndrome type 1)

or autoimmune polyendocrinopathy candidiasis ectoder-mal dystrophy (APECED)154-156 is a recessive disease caused by mutations of the AIRE gene,157 located on 21q22,158 which encodes a transcription factor with an important role in promoting tolerance and preventing au-toimmunity.159-161 Children with the IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropa-thy, X-linked), also termed the XPID syndrome (X-linked Polyendocrinopathy, Immune Dysfunction and Diarrhoea), present with severe multiorgan autoimmuni-ty (including diabetes) and lymphoproliferation which may lead to death in the Þ rst 2 years of life,162 caused by regulatory T-cell failure due to mutations in FOXP3, lo-cated on Xq11.23-Xq13.3.163-165

PerspectivesAt present, the clinically useful application of genetics in type 1 diabetes is limited to identifying monogenic forms of diabetes where an atypical clinical presentation of T1D (eg: in the Þ rst 6 months of life, with a strong fam-ily history of diabetes or as part of a distinct syndrome) suggests a monogenic etiology of the disease and where treatments other than insulin may be considered. In ad-dition, identiÞ cation of individuals at a high risk of de-veloping T1D may be of clinical interest in the future, if interventions that are presently being tested in clinical trials166-168 prove to be safe and effective.

HLA genotyping is a complex process, due to the highly polymorphic nature of the genetic region. Taking advan-tage of the high linkage disequilibrium in the HLA re-gion, high-risk HLA can be detected by simply analys-ing a few SNPs169 and thus, high-risk individuals, candidates for intervention, could be easily identiÞ ed. The already established markers of disease plus the dis-covery of additional ones may allow further deÞ nition in risk assessment. Nevertheless, for the time being, genet-ic counselling to families of patients with T1D cannot be accompanied by preventive measures.

ConclusionsT1D is a complex autoimmune disease with a proved ge-netic background. Most (around 50%) of its genetic risk is accounted for by class I and class II HLA haplotypes, although other genes with a smaller effect are also in-volved. Most of the known risk genes for T1D play a role in immunity, mostly through T-cell regulation (CT-

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LA4, PTPN22, IL-2RA) and cytokine production or mod-ulation (VDR, SUMO4). The insulin gene (INS) repre-sents and exception to this, and is probably the only gene speciÞ cally associated with T1D and not with other au-toimmune diseases.

Ongoing genome-wide association studies are providing evidence of multiple known and previously unknown risk genes. New analytical tools are continuously being developed to handle the vast amounts of data produced, as well as to account for multiple comparisons and as-sess combined effects such as gene-gene and gene-envi-ronment interactions. ■

Acknowledgements:JCW is being supported by a research grant from the EFSD/ JDRF/ Novo Nordisk Programme 2008.

Potential conß icts of interestThe authors are not aware of any conß icts of interest related to the subject of the review.

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Practical considerations

• Genetics can improve risk prediction in type 1 diabetes.

• HLA haplotypes can explain the main part of ge-netic risk in type 1 diabetes.

• Due to the lack of effi cient intervention protocols/measures, routine genotyping of type 1 diabetes patients and relatives is not recommended at present.

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