Variation in glucose homeostasis traits associated with P2RX7 polymorphisms in mice and humans.

1. J Clin Endocrinol Metab. 2015 May;100(5):E688-96. doi: 10.1210/jc.2014-4160. Epub 2015 Feb 26. Variation in glucose homeostasis traits associated with P2RX7 polymorphisms in mice and humans. Todd JN(1), Poon W, Lyssenko V, Groop L, Nichols B, Wilmot M, Robson S, Enjyoji K, Herman MA, Hu C, Zhang R, Jia W, Ma R, Florez JC, Friedman DJ. Author information: (1)Division of Endocrinology (J.N.T.), Boston Children's Hospital, and Departments of Pediatrics (J.N.T.) and Medicine (S.R., K.E., M.A.H., J.C.F., D.J.F.), Harvard Medical School, and Department of Medicine (B.N., M.W., S.R., K.E., M.A.H., D.J.F.) and Center for Vascular Biology Research (B.N., M.W., D.J.F.), Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115; Center for Human Genetic Research (J.N.T., J.C.F.), and Diabetes Research Center (Diabetes Unit) (J.C.F.), Massachusetts General Hospital, Boston, Massachusetts 02114; Program in Medical and Population Genetics (J.C.F.), Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142; Department of Clinical Sciences, Diabetes, and Endocrinology (W.P., V.L., L.G.), Skåne University Hospital, Lund University, SE 205 02 Malmö, Sweden; Department of Translational Pathophysiology (V.L.), Steno Diabetes Center A/S, DK-2820 Gentofte, Denmark; Institute for Molecular Medicine Finland FIMM (L.G.), University of Helsinki, FI-00014 Helsinki, Finland; Shanghai Jiao Tong University Affiliated Sixth People's Hospital (C.H., R.Z., W.J.), Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai 200233, China; and Department of Medicine and Therapeutics (R.M.), Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong. CONTEXT: Extracellular nucleotide receptors are expressed in pancreatic B-cells. Purinergic signaling via these receptors may regulate pancreatic B-cell function. OBJECTIVE: We hypothesized that purinergic signaling might influence glucose regulation and sought evidence in human studies of glycemic variation and a mouse model of purinergic signaling dysfunction. DESIGN: In humans, we mined genome-wide meta-analysis data sets to examine purinergic signaling genes for association with glycemic traits and type 2 diabetes. We performed additional testing in two genomic regions (P2RX4/P2RX7 and P2RY1) in a cohort from the Prevalence, Prediction, and Prevention of Diabetes in Botnia (n = 3504), which includes more refined measures of glucose homeostasis. In mice, we generated a congenic model of purinergic signaling dysfunction by crossing the naturally hypomorphic C57BL6 P2rx7 allele onto the 129SvJ background. RESULTS: Variants in five genes were associated with glycemic traits and in three genes with diabetes risk. In the Prevalence, Prediction, and Prevention of Diabetes in Botnia study, the minor allele in the missense functional variant rs1718119 (A348T) in P2RX7 was associated with increased insulin sensitivity and secretion, consistent with its known effect on increased pore function. Both male and female P2x7-C57 mice demonstrated impaired glucose tolerance compared with matched P2x7-129 mice. Insulin tolerance testing showed that P2x7-C57 mice were also less responsive to insulin than P2x7-129 mice. CONCLUSIONS: We show association of the purinergic signaling pathway in general and hypofunctioning P2X7 variants in particular with impaired glucose homeostasis in both mice and humans. DOI: 10.1210/jc.2014-4160 PMCID: PMC4422893 PMID: 25719930 [Indexed for MEDLINE]