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

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 × 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 because of LD. Our data support a role for more than one locus in the class III region contributing to risk of T1D.