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

Abstract

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