CDKN2A/B T2D GWAS Risk-SNPs Impact Locus Gene Expression and Proliferation in Human Islets
Department of Medicine, Diabetes Center of Excellence; Department of Quantitative Health Sciences; UMass Metabolic Network
Endocrinology | Endocrinology, Diabetes, and Metabolism | Genomics
Genome-wide association studies link the CDKN2A/B locus with T2D risk, but mechanisms increasing risk remain unknown. The CDKN2A/B locus encodes cell cycle inhibitors p14, p15, and p16, MTAP, and ANRIL, a lncRNA. The goal of this study was to determine whether CDKN2A/B T2D risk-SNPs impact locus gene expression, insulin secretion, or beta cell proliferation, in human islets. Islets from non-diabetic donors (n=95) were tested for SNP genotype (rs10811661, rs2383208, rs564398, rs10757283), gene expression (p14, p15, p16, MTAP, ANRIL, PCNA, KI67, CCND2), insulin secretion (n=61) and beta cell proliferation (n=47). Intriguingly, locus genes were co-regulated 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 haplotype 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 beta cell proliferation index. In conclusion, CDKN2A/B locus SNPs may impact T2D risk by modulating islet gene expression and beta cell proliferation.
DOI of Published Version
Diabetes. 2018 Feb 6. pii: db17-1055. doi: 10.2337/db17-1055. [Epub ahead of print] Link to article on publisher's site
Kong, Yahui; Sharma, Rohit B.; Ly, Socheata; Stamateris, Rachel E.; Jesdale, William M.; and Alonso, Laura C., "CDKN2A/B T2D GWAS Risk-SNPs Impact Locus Gene Expression and Proliferation in Human Islets" (2018). University of Massachusetts Medical School Faculty Publications. 1480.