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

Diabetes. 2019 Mar;68(3):665-675. doi: 10.2337/db18-0314. Epub 2018 Dec 14.

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 (P = 1.56 × 10-23, odds ratio [OR] 3.18). In addition, rs11170445 in CSAD/lnc-ITGB7-1 on chromosome 12q13.13 showed an association at a genome-wide significance level (P = 7.58 × 10-9, OR 1.96). Fine mapping of the region revealed that rs3782151 in CSAD/lnc-ITGB7-1 showed the lowest P value (P = 4.60 × 10-9, OR 1.97 [95% CI 1.57-2.48]). The risk allele of rs3782151 is a cis expression quantitative trait locus for ITGB7 that significantly increases the expression of this gene. CSAD/lnc-ITGB7-1 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Diabetes Mellitus, Type 1 / genetics*
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study / methods*
  • Genotype
  • Humans
  • Integrin beta Chains / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Quantitative Trait Loci / genetics

Substances

  • Integrin beta Chains