Identification of <i>C2CD4A</i> as a human diabetes susceptibility gene with a role in β cell insulin secretion.

Abstract

Fine mapping and validation of genes causing β cell failure from susceptibility loci identified in type 2 diabetes genome-wide association studies (GWAS) poses a significant challenge. The <i>VPS13C-C2CD4A-C2CD4B</i> locus on chromosome 15 confers diabetes susceptibility in every ethnic group studied to date. However, the causative gene is unknown. FoxO1 is involved in the pathogenesis of β cell dysfunction, but its link to human diabetes GWAS has not been explored. Here we generated a genome-wide map of FoxO1 superenhancers in chemically identified β cells using 2-photon live-cell imaging to monitor FoxO1 localization. When parsed against human superenhancers and GWAS-derived diabetes susceptibility alleles, this map revealed a conserved superenhancer in <i>C2CD4A</i>, a gene encoding a β cell/stomach-enriched nuclear protein of unknown function. Genetic ablation of C2cd4a in β cells of mice phenocopied the metabolic abnormalities of human carriers of <i>C2CD4A</i>-linked polymorphisms, resulting in impaired insulin secretion during glucose tolerance tests as well as hyperglycemic clamps. C2CD4A regulates glycolytic genes, and notably represses key β cell "disallowed" genes, such as <i>lactate dehydrogenase A</i> We propose that <i>C2CD4A</i> is a transcriptional coregulator of the glycolytic pathway whose dysfunction accounts for the diabetes susceptibility associated with the chromosome 15 GWAS locus.