CDKN2A/B T2D GWAS Risk-SNPs Impact Locus Gene Expression and Proliferation in Human Islets
Sharma, Rohit B.
Stamateris, Rachel E.
Jesdale, William M.
Alonso, Laura C.
UMass Chan AffiliationsUMass Metabolic Network
Department of Quantitative Health Sciences
Department of Medicine, Diabetes Center of Excellence
Document TypeJournal Article
MetadataShow full item record
AbstractGenome-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.
Diabetes. 2018 Feb 6. pii: db17-1055. doi: 10.2337/db17-1055. [Epub ahead of print] Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/29250