Genetic variation within the HLA class III influences T1D susceptibility conferred by high-risk HLA haplotypes

Abstract

Human leukocyte antigen (HLA) class II DRB1 and DQB1 represent the major type I diabetes (T1D) genetic susceptibility loci; however, other genes in the HLA region are also involved in T1D risk. We analyzed 1411 pedigrees (2865 affected individuals) from the type I diabetes genetics consortium genotyped for HLA classical loci and for 12 single-nucleotide polymorphisms (SNPs) in the class III region previously shown to be associated with T1D in a subset of 886 pedigrees. Using the transmission disequilibrium test, we compared the proportion of SNP alleles transmitted from within the high-risk DR3 and DR4 haplotypes to affected offspring. Markers rs4151659 (mapping to CFB) and rs7762619 (mapping 5' of LTA) were the most strongly associated with T1D on DR3 (P=1.2 x 10(-9) and P=2 x 10(-12), respectively) and DR4 (P=4 x 10(-15) and P=8 x 10(-8), respectively) haplotypes. They remained significantly associated after stratifying individuals in analyses for B*1801, A*0101-B*0801, DPB1*0301, DPB1*0202, DPB1*0401 or DPB1*0402. Rs7762619 and rs4151659 are in strong linkage disequilibrium (LD) (r(2)=0.82) with each other, but a joint analysis showed that the association for each SNP was not solely because of LD. Our data support a role for more than one locus in the class III region contributing to risk of T1D.

Figure 1

Genetic association between 12 MHC class II SNPs and T1D among (A) DR3 haplotypes (B) DR4 haplotypes. Empty circles are p-values only for samples not included in a previous study (15). Filled circles include all samples. DR3 = DRB1*0301 DQA1*0501 DQB1*0201 DR4= DRB1*0401/2/4/5 DQA1*0301 DQB1*0302, all other DR4 subtypes are excluded.

Figure 2

Forest plot of study-specific estimates and fixed effects summary transmitted/non-transmitted ratio (T/NTR) and 95% confidence interval (CI) for the association between the minor allele at (A) rs4151659 on DR4 haplotypes and (B) rs7762619 on DR3 haplotypes in the individual cohorts from the T1DGC collection.

Figure 3

Forest plot showing the effect of (A) rs4151659 on extended DR3 and DR4 haplotypes and (B) rs7762619 on extended DR3 and DR4 haplotypes. The p-value and number of informative transmissions for each comparison are shown.

Figure 4

Forest plot of study-specific estimates and fixed effects summary transmitted/non-transmitted ratio (T/NTR) and 95% confidence interval (CI) for the association on four different DRB1-DQB1 haplotypes between the minor allele at (A) rs4151659 and (B) rs7762619.