Hla‐dr4 Subtype and ‐b Alleles in Dqb1*0302‐positive Haplotypes Associated With Iddm

Reijonen, Helena; Nejentsev, S; Tuokko, Juha; Koskinen, Sinikka; Tuomilehto‐Wolf, Eva; Åkerblom, Hans K.; Ilonen, Jorma

doi:10.1046/j.1365-2370.1997.d01-108.x

Cited by 27 publications

(25 citation statements)

References 22 publications

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“…In the DR3/404-stratified group, we confirmed strong diabetes association of B39, previously shown by us (3,4), and of A24, shown by others (7,8). There was only one allele at each microsatellite locus associated with an increased risk for type 1 diabetes, and all of these alleles, as well as A24, were strongly associated with B39 ( Table 1).…”

supporting

confidence: 88%

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Non-class II HLA gene associated with type 1 diabetes maps to the 240-kb region near HLA-B.

Nejentsev¹,

Gombos²,

Laine³

et al. 2000

Diabetes

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Several studies provide evidence that in addition to the DQ-DR genes, HLA contains another uncharacterized gene or genes associated with type 1 diabetes. Our aim was to investigate the effect of this gene independently of the DQ-DR genes and to localize it with a matched case-control study. More than 1,400 patients and 30,000 control individuals from Finland were studied. They were first genotyped for the selected alleles of the HLA-DQB1, -DQA1, and -DRB1 genes. For the DR3/4(0404) genotype, 75 patients and 181 control subjects were stratified, and 241 patients and 354 controls were stratified for the DR3/4(0401) genotype. Ten microsatellite markers in the HLA class III and I regions (D6S273, TNFa, C12A, STR MICA, MIB, C125, C143, C245, C3211, and MOGc) and selected alleles of the HLA-A and HLA-B genes were studied. In the DR3/4(0404)-stratified group, we found that markers located between C12A and C143 near the HLA-B gene confer a strong additional diabetes association. This was confirmed by the population differentiation test in both DR3/4(0404)-and DR3/4(0401)-stratified groups. Our data indicate that an additional gene associated with type 1 diabetes is located in the 240-kb region near HLA-B. We excluded STR MICA polymorphism as a mutation responsible for diabetes association. Diabetes 49:2217-2221, 2000 H LA localization of the genes predisposing to type 1 diabetes is well established. DQB1, DQA1, and DRB1 genes are considered primary and major loci associated with type 1 diabetes. However, evidence is accumulating that the HLA class I-III region contains gene(s) associated with an increased risk for type 1 diabetes (1-4) or its earlier age at onset (5-8). We searched for an additional HLA gene associated with type 1 diabetes among Finnish patients and control subjects stratified for the DQ-DR alleles.Initially, samples from >1,400 type 1 diabetic patients and >30,000 control subjects were collected and genotyped for DQB1 (9). DQB1*02/0302 subjects were then studied for the DQA1*05 and *0201 alleles and DR4 subtypes (of which only DRB1*0401 and DRB1*0404 are frequent among Finns). Thus, a group stratified for the DQA1*05-DQB1*02/ DQB1*0302-DRB1*0404 [DR3/4(0404)] genotype (75 patients and 181 control subjects) and a group stratified for the DQA1*05-DQB1*02/DQB1*0302-DRB1*0401 [DR3/4(0401)] genotype (241 patients and 354 control subjects) were selected. These subjects are all DR3/DR4 haplotype heterozygotes: one group carries DR404 and the other DR401 haplotype. Thus, within each group we excluded the diabetogenic effect of the known DQ-DR markers.In these groups, selected alleles of the HLA-B and HLA-A genes and 10 microsatellites (D6S273, TNFa, C12A, STR MICA, MIB, C125, C143, C245, C3211, and MOGc) were studied to map a non-class II HLA gene associated with type 1 diabetes susceptibility. These cover distance of ~2,300 kb and include the whole HLA class I region and the class I-III boundary (Fig. 1).We found that in the DR3/404-and DR3/401-stratified groups there was only one allele at each microsatellit...

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supporting

confidence: 88%

“…associated with a conspicuously high risk on this haplotype (3,4). At the same time, it was shown that B39 is in linkage disequilibrium with the HLA-A24 allele on the DR404 haplotype (4).…”

Section: S Nejentsev and Associatesmentioning

confidence: 99%

Non-class II HLA gene associated with type 1 diabetes maps to the 240-kb region near HLA-B.

Nejentsev¹,

Gombos²,

Laine³

et al. 2000

Diabetes

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“…41 In addition, it is possible that the same single locus in the class II-centromeric class I region also explains the heterogeneity in risk reported for DQ8-DRB1*0404 haplotypes in Finland. 7,9 Zavattari et al 10 suggested that three markers, DMB, DOB and TNFc, were independently associated with T1D, but these data could be explained by a single extended susceptibility haplotype. Nonetheless, Sardinian haplotypes differ significantly centromeric of DQB1, and a third non-DQ/DR variant reducing the DQ2-DR3 haplotype susceptibility in this population is a possibility.…”

Section: Discussionmentioning

confidence: 99%

Evidence of at least two type 1 diabetes susceptibility genes in the HLA complex distinct from HLA-DQB1, -DQA1 and –DRB1

et al. 2003

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Susceptibility to, and protection against development of type 1 diabetes (T1D) are primarily associated with the highly polymorphic exon 2 sequences of the HLA class II genes: DQB1, DQA1 and DRB1. However, several studies have also suggested that additional genes in the HLA complex influence T1D risk, albeit to a lesser degree than the class II genes. We have previously shown that allele 3 of microsatellite marker D6S2223, 4.9 Mb telomeric of DQ in the extended class I region, is associated with a reduction in risk conferred by the DQ2-DR3 haplotype. Here we replicate this finding in two populations from Sweden and France. We also show that markers in the HLA class II, III and centromeric class I regions contribute to the DQ2-DR3 associated risk of T1D, independently of linkage disequilibrium (LD) with both the DQ/DR genes and the D6S2223 associated gene. The associated marker alleles are carried on the DQ2-DR3-B18 haplotype in a region of strong LD. By haplotype mapping, we have located the most likely location for this second DQ2-DR3 haplotype-modifying locus to the 2.35 Mb region between HLA-DOB and marker D6S2702, located 970 kb telomeric of HLA-B.

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“…Although most A Ã 24 alleles do show a predisposing effect, a study of T1D in a Filipino population showed that A Ã 24:07, which differs from A Ã 24:02 by the substitution of Gln for His at position 70, is not predisposing for T1D . B Ã 39 alleles appear to be the most highly predisposing class I alleles, with the B Ã 39:06 allele most commonly associated with T1D (Ilonen et al 1992;Nejentsev et al 1997;Reijonen et al 1997;Valdes et al 2005;Noble et al 2010). B Ã 3906 increases T1D risk for moderate susceptibility haplotypes, such as DR1, DR8, and even DR16 (a type of DR2) haplotypes Baschal et al 2011).…”

Section: Hla Class Imentioning

confidence: 99%

Genetics of Type 1 Diabetes

Noble¹,

Erlich²

2012

Cold Spring Harbor Perspectives in Medicine

253

157

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Hla‐dr4 Subtype and ‐b Alleles in Dqb1*0302‐positive Haplotypes Associated With Iddm

Cited by 27 publications

References 22 publications

Non-class II HLA gene associated with type 1 diabetes maps to the 240-kb region near HLA-B.

Non-class II HLA gene associated with type 1 diabetes maps to the 240-kb region near HLA-B.

Evidence of at least two type 1 diabetes susceptibility genes in the HLA complex distinct from HLA-DQB1, -DQA1 and –DRB1

Genetics of Type 1 Diabetes

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