Genome-Wide Association Study Confirming a Strong Effect of HLA and Identifying Variants in <i>CSAD/lnc-ITGB7-1</i> on Chromosome 12q13.13 Associated With Susceptibility to Fulminant Type 1 Diabetes.

Abstract

The first genome-wide association study of fulminant type 1 diabetes was performed in Japanese individuals. As previously reported using a candidate gene approach, a strong association was observed with multiple single nucleotide polymorphisms (SNPs) in the HLA region, and the strongest association was observed with rs9268853 in the class II DR region (<i>P</i> = 1.56 × 10^-23, odds ratio [OR] 3.18). In addition, rs11170445 in <i>CSAD/lnc-ITGB7-1</i> on chromosome 12q13.13 showed an association at a genome-wide significance level (<i>P</i> = 7.58 × 10^-9, OR 1.96). Fine mapping of the region revealed that rs3782151 in <i>CSAD/lnc-ITGB7-1</i> showed the lowest <i>P</i> value (<i>P</i> = 4.60 × 10^-9, OR 1.97 [95% CI 1.57-2.48]). The risk allele of rs3782151 is a <i>cis</i> expression quantitative trait locus for <i>ITGB7</i> that significantly increases the expression of this gene. <i>CSAD/lnc-ITGB7-1</i> was found to be strongly associated with susceptibility to fulminant, but not classical, autoimmune type 1 diabetes, implicating this locus in the distinct phenotype of fulminant type 1 diabetes.