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 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.
Valdes
A M
AM
King's College London, Department of Twin Research and Genetic Epidemiology, UK. ana.valdes@kcl.ac.uk <ana.valdes@kcl.ac.uk>
Thomson
G
G
Barcellos
L F
LF
D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D006680:HLA Antigens