T2D Genome-Wide Association Study Risk SNPs Impact Locus Gene Expression and Proliferation in Human Islets.

Genome-wide association studies link the locus with type 2 diabetes (T2D) risk, but mechanisms increasing risk remain unknown. The locus encodes cell cycle inhibitors , , and ; ; and , a long noncoding RNA. The goal of this study was to determine whether T2D risk SNPs impact locus gene expression, insulin secretion, or β-cell proliferation in human islets. Islets from donors without diabetes ( = 95) were tested for SNP genotype (rs10811661, rs2383208, rs564398, and rs10757283), gene expression (, , , , , , , and ), insulin secretion ( = 61), and β-cell proliferation ( = 47). Intriguingly, locus genes were coregulated in islets in two physically overlapping cassettes: -, which increased with age, and -, which did not. Risk alleles at rs10811661 and rs2383208 were differentially associated with expression of , but not , , or , in age-dependent fashion, such that younger homozygous risk donors had higher expression, equivalent to older donor levels. We identified several risk SNP combinations that may impact locus gene expression, suggesting possible mechanisms by which SNPs impact locus biology. Risk allele carriers at coding SNP rs564398 had reduced β-cell proliferation index. In conclusion, locus SNPs may impact T2D risk by modulating islet gene expression and β-cell proliferation.