Metabolic effects of genetic variation in the human REPIN1 gene

Background Replication initiator 1 (Repin1) is a zinc finger protein highly expressed in liver and adipose tissue. The Repin1 resides within a quantitative trait locus (QTL) for body weight and triglyceride levels in the rat, and its hepatic deletion in mice results in improved insulin sensitivity and lower body weight. Here, we analyzed whether genetic variation within the Repin1 affects parameters of glucose and lipid metabolism. Methods We sequenced REPIN1 in 48 non-related Caucasian subjects. We discovered a 12 base pair deletion (12 bp del; rs3832490), which was subsequently genotyped in two well-characterized cohorts ( N = 3013) to test for associations with metabolic traits. Functional consequences of the variant were investigated in HepG2 cells in vitro. Results In human cohorts, we show that the 12 bp del associates with improved glucose metabolism (lower fasting plasma glucose, fasting plasma insulin, and HOMA IR). Cells transfected with the plasmid carrying the 12 bp del variant are characterized by increased GLUT2 and fatty acid translocase CD36 expression and more lipid droplets. Conclusion Our data suggest that genetic variation in human REPIN1 plays a role in glucose and lipid metabolism by differentially affecting the expression of REPIN1 target genes including glucose and fatty acid transporters.