Brief Genetics Report Common Variants in the ENPP1 Gene Are Not Reproducibly Associated With Diabetes or Obesity Helen N. Lyon, 1,2,3 Jose C. Florez, 2,4,5,6 Todd Bersaglieri, 1,2 Richa Saxena, 2,6 Wendy Winckler, 2,5 Peter Almgren, 7 Ulf Lindblad, 8 Tiinamaija Tuomi, 9,10 Daniel Gaudet, 11 Xiaofeng Zhu, 12 Richard Cooper, 12 Kristin G. Ardlie, 13 Mark J. Daly, 5,6 David Altshuler, 2,4,5,6,14 Leif Groop, 7,9 and Joel N. Hirschhorn 1,2,14 The common missense single nucleotide polymorphism (SNP) K121Q in the ectoenzyme nucleotide pyrophosphate phosphodiesterase (ENPP1) gene has recently been asso- ciated with type 2 diabetes in Italian, U.S., and South-Asian populations. A three-SNP haplotype, including K121Q, has also been associated with obesity and type 2 diabetes in French and Austrian populations. We set out to confirm these findings in several large samples. We genotyped the haplotype K121Q (rs1044498), rs1799774, and rs7754561 in 8,676 individuals of European ancestry with and without type 2 diabetes, in 1,900 obese and 930 lean individuals of European ancestry from the U.S. and Poland, and in 1,101 African-American individuals. Neither the K121Q missense polymorphism nor the putative risk haplotype were signif- icantly associated with type 2 diabetes or BMI. Two SNPs showed suggestive evidence of association in a meta-anal- ysis of our European ancestry samples. These SNPs were rs7754561 with type 2 diabetes (odds ratio for the G-allele, 0.85 [95% CI 0.78 – 0.92], P  0.00003) and rs1799774 with BMI (homozygotes of the delT-allele, 0.6 [0.42– 0.88], P  0.007). However, these findings are not supported by other studies. We did not observe a reproducible association between these three ENPP1 variants and BMI or type 2 diabetes. Diabetes 55:3180 –3184, 2006 E ctoenzyme nucleotide pyrophosphate phospho- diesterase (ENPP1), also known as plasma cell membrane glycoprotein 1 (PC-1), downregu- lates insulin signaling by inhibiting the insulin receptor’s tyrosine kinase activity. This inhibition is pro- posed to confer insulin resistance in mammals. The ENPP1 gene is located on 6q22-23, a locus linked to obesity and diabetes in several studies (1– 4). Recent studies of variation in the ENPP1 gene have found an association of the common missense single nucleotide polymorphism (SNP) K121Q (rs1044498) and of a three- marker haplotype (which includes K121Q) with the risk of diabetes and obesity. Abate et al. (5) reported that the Q-allele was associated with diabetes in South-Asian and Caucasian populations. Meyre et al. (6) described a three- SNP risk haplotype in the ENPP1 gene (formed by the three minor alleles of rs1044498 K-allele, rs1799774 delT- allele, and rs7754561 G-allele) that was associated with increased risk of diabetes and obesity in adults and obese children. Bacci et al. (7) also reported an association of the minor allele in K121Q with insulin resistance and athero- genesis in diabetic individuals. Their meta-analysis of 4,425 control subjects and 2,834 patients with type 2 diabetes showed an odds ratio (OR) of 1.29 ([95% CI 1.09 –1.53], P = 0.003) under a dominant model. In con- trast, Matsuoka et al. (8) found that the Q-allele was not associated with diabetes and that the K-allele rather than the Q-allele was associated with obesity in both Cauca- sians and African Americans. Given this cumulative yet conflicting evidence for association with diabetes and obesity, we tested whether the K121Q variant or the risk haplotype (Q-delT-G) are associated with diabetes and/or obesity in several large case-control and family-based cohorts ascertained for both phenotypes. RESEARCH DESIGN AND METHODS Obese and lean individuals from the U.S. and Poland (Table 1) were selected from a collection of 60,000 subjects recruited by Genomics Collaborative for a diverse set of disease studies, including healthy people and groups with osteoarthritis, rheumatoid arthritis, asthma, hypertension, coronary artery disease, myocardial infarction, hyperlipidemia, stroke, type 2 diabetes, or From the 1 Divisions of Genetics and Endocrinology, Program in Genomics, Children’s Hospital, Boston, Massachusetts; the 2 Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massa- chusetts; the 3 Department of Pediatrics, Harvard Medical School, Boston, Massachusetts; the 4 Department of Medicine, Harvard Medical School, Bos- ton, Massachusetts; the 5 Center for Human Genetic Research, Massachusets General Hospital, Boston, Massachusetts; the 6 Department of Medicine, Massachusetts General Hospital; Boston, Massachusetts; the 7 Department of Endocrinology, University Hospital MAS, Lund University, Malmo ¨ , Sweden; the 8 Department of Clinical Science, University Hospital MAS, Lund Univer- sity, Malmo ¨ , Sweden; the 9 Department of Medicine, Helsinki University Central Hospital and Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland; 10 Folkha ¨ lsan Research Center, Helsinki, Finland; the 11 Community Genomic Medicine Center, Montreal University and Lipid Clinic, Chicoutimi Hospital, Quebec, Canada; the 12 Department of Preventive Medicine and Epidemiology, Loyola University Medical Center, Maywood, Illinois; the 13 Genomics Collaborative Division, SeraCare LifeSciences, Cam- bridge, Massachusetts; and the 14 Department of Genetics, Harvard Medical School, Boston, Massachusetts. Address correspondence and reprint requests to Joel N. Hirschhorn, Divi- sion of Genetics, Children’s Hospital Boston, Enders 561, 300 Longwood Ave., Boston, MA 02115. E-mail: joelh@broad.mit.edu. Received for publication 27 March 2006 and accepted in revised form 26 July 2006. H.N.L. and J.C.F. contributed equally to this work. L.G. and J.N.H. jointly supervised the project. W.W. is currently affiliated with the Biological and Biomedical Sciences Program, Harvard University, Boston, Massachusetts, and K.G.A. is currently affiliated with the Biological Samples Platform, Broad Institute of Harvard and MIT, Cambridge, Massachusetts. K.G.A. is employed by Genomics Collaborative, which owns a sample repository of samples that were used in this study. Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org. SNP, single nucleotide polymorphism. DOI: 10.2337/db06-0407 © 2006 by the American Diabetes Association. 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