Dataset Information

Haplotype-based search for SNPs associated with differential type 1 diabetes risk among chromosomes carrying a specific HLA DRB1-DQA1-DQB1 haplotype.

ABSTRACT: AIM:The aim of this study was to test chromosomes carrying the same DRB1-DQA1-DQB1 haplotype for single nucleotide polymorphisms (SNPs) in the major histocompatibility complex (MHC) that might mark subgroups of the haplotype with different risks for type 1 diabetes (T1D). METHODS:Chromosomes from T1D children, their parents and non-diabetic siblings in families of the Type 1 Diabetes Genetics Consortium (T1DGC) were analysed by two haplotype-based methods: (i) logistic regression analysis restricted to phased chromosomes carrying the same DRB1-DQA1-DQB1 haplotype but differentiated by the two alleles at MHC SNPs, which were individually tested for association with T1D and (ii) homozygous parent transmission disequilibrium test (TDT) for biased transmission of a SNP allele to diabetic children from parents who are heterozygous at the SNP but homozygous for the specific DRB1-DQA1-DQB1 haplotype being evaluated. RESULTS:A number of SNPs gave nominally significant (p < 0.05) evidence of marking two subsets of the 301-501-201 haplotype that might differ with respect to their diabetogenic potency. However, none of the SNPs achieved experiment-wide significance and hence may be false-positive associations. CONCLUSIONS:We discuss limitations and possible deficiencies of our study suggesting further work that might yield more robust SNP associations marking two subgroups of a DRB1-DQA1-DQB1 haplotype with different T1D risks.

SUBMITTER: McGinnis R

PROVIDER: S-EPMC2697815 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Haplotype-based search for SNPs associated with differential type 1 diabetes risk among chromosomes carrying a specific HLA DRB1-DQA1-DQB1 haplotype.

McGinnis R R McLaren W W Ranganath V V Whittaker P P Hunt S S Deloukas P P

Diabetes, obesity & metabolism 20090201

<h4>Aim</h4>The aim of this study was to test chromosomes carrying the same DRB1-DQA1-DQB1 haplotype for single nucleotide polymorphisms (SNPs) in the major histocompatibility complex (MHC) that might mark subgroups of the haplotype with different risks for type 1 diabetes (T1D).<h4>Methods</h4>Chromosomes from T1D children, their parents and non-diabetic siblings in families of the Type 1 Diabetes Genetics Consortium (T1DGC) were analysed by two haplotype-based methods: (i) logistic regression ...[more]

PMID: 19143810

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Project description:Multiple sclerosis (MS), a common central nervous system inflammatory disease, has a major heritable component. Susceptibility is associated with the MHC class II region, especially HLA-DRB5*0101-HLA-DRB1*1501-HLA-DQA1*0102-HLA-DQB1*0602 haplotypes(hereafter DR2), which dominate genetic contribution to MS risk. Marked linkage disequilibrium (LD) among these loci makes identification of a specific locus difficult. The once-leading candidate, HLA-DRB1*15, localizes to risk, neutral, and protective haplotypes. HLA-DRB1*15 and HLA-DQB1*0602, nearly always located together on a small ancestral chromosome segment, are strongly MS-associated. One intervening allele on this haplotype, viz. HLA-DQA1*0102, shows no primary MS association. Two Canadian cohorts (n = 830 and n = 438 trios) genotyped for HLA-DRB1, HLA-DQA1 and HLA-DQB1 alleles were tested for association using TDT. To evaluate epistasis involving HLA-DRB1*15, transmissions from HLA-DRB1*15-negative parents were stratified by the presence/absence of HLA-DRB1*15 in affected offspring. All 3 alleles contribute to MS susceptibility through novel epistatic interactions. HLA-DQA1*0102 increased disease risk when combined with HLA-DRB1*1501 in trans, thereby unambiguously implicating HLA-DQ in MS susceptibility. Three-locus haplotypes demonstrated that HLA-DRB1*1501 and HLA-DQB1*0602 each influence risk. Transmissions of rare morcellated DR2 haplotypes showed no interaction with HLA-DQA1*0102. Incomplete haplotypes bearing only HLA-DRB1*1501 or HLA-DQB1*0602 did not predispose to MS. Balanced reciprocal transmission distortion can mask epistatic allelic association. These findings implicate epistasis among HLA class II alleles in human immune responses generally, provide partial explanation for intense linkage disequilibrium in the MHC, have relevance to animal models, and demonstrate key roles for DR2-specific interactions in MS susceptibility. MHC disease associations may be more generally haplotypic or diplotypic.

Project description:ObjectiveSystemic sclerosis (SSc) is a rare disease that is particularly uncommon in children. Specific HLA alleles have been associated with SSc in adults. This study was undertaken to investigate HLA class II alleles in juvenile-onset SSc.MethodsDRB1, DQA1, and DQB1 alleles were determined by DNA-based HLA typing. Analyses were conducted comparing Caucasian patients with juvenile-onset SSc (n = 76) to healthy Caucasian controls (n = 581).ResultsInitial analyses focused on HLA class II associations previously reported in adult Caucasian patients with SSc. The frequency of DRB1*11 was not significantly increased in juvenile-onset SSc (22.4% of patients with juvenile-onset SSc versus 17.6% of controls; odds ratio [OR] 1.35, P = 0.34), nor were the specific DRB1*11:01 or *11:04 alleles. DQA1*05, a risk factor previously identified in adult men with SSc, was increased in patients with juvenile-onset SSc versus controls (57.9% versus 44.1%; OR 1.76, P = 0.027), as was DRB1*03 (34.2% versus 22.5%; OR 1.79, P = 0.031). Secondary analyses of all DRB1 allele groups revealed an association with DRB1*10 (10.5% of patients with juvenile-onset SSc versus 1.5% of controls; OR 7.48, P = 0.0002). As this is a new observation, correction was made for multiple comparisons of 13 different DRB1 allele groups; results nevertheless remained significant (P = 0.003). Also, a lower frequency of DRB1*01 was observed in patients with juvenile-onset SSc who were younger at disease onset (OR 0.06, P = 0.01) and in those with antibodies to topoisomerase (OR 0.14, P = 0.024).ConclusionAssociations of HLA alleles with juvenile-onset SSc differed from associations with SSc in women, but were similar to associations with SSc in men. Additionally, a novel association with DRB1*10 was observed in children. The greatest proportion of genetic risk of SSc is contributed by the HLA complex, and the current study reveals the importance of the association of HLA class II genes in juvenile-onset SSc.

Dataset Information

Haplotype-based search for SNPs associated with differential type 1 diabetes risk among chromosomes carrying a specific HLA DRB1-DQA1-DQB1 haplotype.

Publications

Haplotype-based search for SNPs associated with differential type 1 diabetes risk among chromosomes carrying a specific HLA DRB1-DQA1-DQB1 haplotype.

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