CDKN2A/B T2D Genome-Wide Association Study Risk SNPs Impact Locus Gene Expression and Proliferation in Human Islets

Genome-wide association studies link the CDKN2A/B locus with type 2 diabetes (T2D) risk, but mechanisms increasing risk remain unknown. The CDKN2A/B locus encodes cell cycle inhibitors p14, p15, and p16; MTAP; and ANRIL, a long noncoding RNA. The goal of this study was to determine whether CDKN2A/B T2D risk SNPs impact locus gene expression, insulin secretion, or β-cell proliferation in human islets. Islets from donors without diabetes (n = 95) were tested for SNP genotype (rs10811661, rs2383208, rs564398, and rs10757283), gene expression (p14, p15, p16, MTAP, ANRIL, PCNA, KI67, and CCND2), insulin secretion (n = 61), and β-cell proliferation (n = 47). Intriguingly, locus genes were coregulated in islets in two physically overlapping cassettes: p14-p16-ANRIL, which increased with age, and MTAP-p15, which did not. Risk alleles at rs10811661 and rs2383208 were differentially associated with expression of ANRIL, but not p14, p15, p16, or MTAP, in age-dependent fashion, such that younger homozygous risk donors had higher ANRIL 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 ANRIL coding SNP rs564398 had reduced β-cell proliferation index. In conclusion, CDKN2A/B locus SNPs may impact T2D risk by modulating islet gene expression and β-cell proliferation.