Evidence of an Association Between the Arg72 Allele of the Peptide YY and Increased Risk of Type 2 Diabetes

Evidence of an Association Between the Arg72 Allele of the Peptide YY and Increased Risk of Type 2 Diabetes Signe S. Torekov 1 2 , Lesli H. Larsen 1 3 , Charlotte Glümer 1 4 , Knut Borch-Johnsen 1 4 5 , Torben Jørgensen 4 , Jens J. Holst 6 , Ole D. Madsen 1 2 , Torben Hansen 1 and Oluf Pedersen 1 5 1 Steno Diabetes Center and Hagedorn Research Institute, Gentofte, Denmark 2 Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark 3 Danish Epidemiology Science Centre and Research Unit for Dietary Studies at the Institute of Preventive Medicine, Copenhagen University Hospital, Copenhagen, Denmark 4 Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark 5 Faculty of Health Science, University of Aarhus, Aarhus, Denmark 6 Department of Medical Physiology, University of Copenhagen, Denmark Address correspondence and reprint requests to Signe S. Torekov, MSc, Steno Diabetes Center, Niels Steensens Vej 2, DK-2820, Gentofte, Denmark. E-mail: skto{at}steno.dk Abstract We tested the hypothesis that variants in the gene encoding the prepropeptide YY ( PYY ) associate with type 2 diabetes and/or obesity. Mutation analyses of DNA from 84 patients with obesity and familial type 2 diabetes identified two polymorphisms, IVS3 + 68C>T and Arg72Thr, and one rare variant, +151C>A of PYY . The common allele of the Arg72Thr variant associated with type 2 diabetes with an allele frequency of the Arg allele of 0.667 (95% CI 0.658–0.677) among 4,639 glucose-tolerant subjects and 0.692 (0.674–0.710) among 1,326 patients with type 2 diabetes ( P = 0.005, odds ratio 1.19 [95% CI 1.05–1.35]). The same polymorphism associated with overweight (25 ≤ BMI < 30 kg/m 2 ) ( P = 0.018, 1.15 [1.02–1.28]). In quantitative trait analyses of a population-based sample of 6,022 subjects, the Arg allele was associated with an increased plasma glucose level 2 h after an oral glucose tolerance test (OGTT) ( P = 0.03), an increased area under the curve for the post-OGTT plasma glucose level ( P = 0.03), and a lower insulinogenic index ( P = 0.01). In conclusion, the common Arg allele of the PYY Arg72Thr variant modestly associates with type 2 diabetes and with type 2 diabetes–related quantitative traits. HPLC, high-performance liquid chromatography OGTT, oral glucose tolerance test NPY, neuropeptide Y PYY, peptide YY UTR, untranslated region Footnotes O.D.M. is employed by, holds stock in, and has received grant support from Novo Nordisk. Accepted Apri