Type 2 Diabetes-Associated Genetic Variants Regulate Chromatin Accessibility in Human Islets

• Published in: Diabetes (New York, N.Y.) Vol. 67; no. 11; pp. 2466 - 2477
• Main Authors: Khetan, Shubham, Kursawe, Romy, Youn, Ahrim, Lawlor, Nathan, Jillette, Alexandria, Marquez, Eladio J, Ucar, Duygu, Stitzel, Michael L
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.11.2018
• Subjects: Alleles; Chromatin; Chromatin - genetics; Chromatin - metabolism; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Genetic diversity; Genetic Predisposition to Disease; Genetics; Genetics/Genomes/Proteomics/Metabolomics; Genome-wide association studies; Genomes; Genotype; Genotype & phenotype; Humans; Islets of Langerhans; Islets of Langerhans - metabolism; Pancreas; Polymorphism; Quantitative trait loci; Risk factors; Single-nucleotide polymorphism
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db18-0393

Type 2 diabetes (T2D) is a complex disorder in which both genetic and environmental risk factors contribute to islet dysfunction and failure. Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs), most of which are noncoding, in >200 loci to islet dysfunction and T2D. Identification of the putative causal variants and their target genes and whether they lead to gain or loss of function remains challenging. Here, we profiled chromatin accessibility in pancreatic islet samples from 19 genotyped individuals and identified 2,949 SNPs associated with in vivo -regulatory element use (i.e., chromatin accessibility quantitative trait loci [caQTL]). Among the caQTLs tested ( = 13) using luciferase reporter assays in MIN6 β-cells, more than half exhibited effects on enhancer activity that were consistent with in vivo chromatin accessibility changes. Importantly, islet caQTL analysis nominated putative causal SNPs in 13 T2D-associated GWAS loci, linking 7 and 6 T2D risk alleles, respectively, to gain or loss of in vivo chromatin accessibility. By investigating the effect of genetic variants on chromatin accessibility in islets, this study is an important step forward in translating T2D-associated GWAS SNP into functional molecular consequences.