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

HLA class II DRB1 and DQB1 represent the major type 1 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 1 diabetes genetics consortium (T1DGC) genotyped for HLA classical loci and for 12 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 × 10(−9) and p=2 × 10(−12) respectively) and DR4 (p=4 × 10(−15) and p= 8 × 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 due to LD. Our data support a role for more than one locus in the class III region contributing to risk of T1D.