Journal Article

Haplotype Structure of the ENPP1 Gene and Nominal Association of the K121Q Missense Single Nucleotide Polymorphism With Glycemic Traits in the Framingham Heart Study

Jarred B. McAteer, Josée Dupuis, Elliot S. Stolerman, Alisa K. Manning, James B. Meigs, Caroline S. Fox, Jose C. Florez, L. Adrienne Cupples

2008

Overview

Haplotype Structure of the ENPP1 Gene and Nominal Association of the K121Q Missense Single Nucleotide Polymorphism With Glycemic Traits in the Framingham Heart Study Elliot S. Stolerman 1 2 3 , Alisa K. Manning 4 , Jarred B. McAteer 1 2 , Josée Dupuis 4 , Caroline S. Fox 5 6 , L. Adrienne Cupples 4 , James B. Meigs 3 7 and Jose C. Florez 1 2 3 1 Center for Human Genetic Research and Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 2 Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 3 Department of Medicine, Harvard Medical School, Boston, Massachusetts 4 Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 5 Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 6 National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts 7 General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts Corresponding author: Jose C. Florez, jcflorez{at}partners.org Abstract OBJECTIVE— A recent meta-analysis demonstrated a nominal association of the ectonucleotide pyrophosphatase phosphodiesterase 1 ( ENPP1 ) K→Q missense single nucleotide polymorphism (SNP) at position 121 with type 2 diabetes. We set out to confirm the association of ENPP1 K121Q with hyperglycemia, expand this association to insulin resistance traits, and determine whether the association stems from K121Q or another variant in linkage disequilibrium with it. RESEARCH DESIGN AND METHODS— We characterized the haplotype structure of ENPP1 and selected 39 tag SNPs that captured 96% of common variation in the region (minor allele frequency ≥5%) with an r 2 value ≥0.80. We genotyped the SNPs in 2,511 Framingham Heart Study participants and used age- and sex-adjusted linear mixed effects (LME) models to test for association with quantitative metabolic traits. We also examined whether interaction between K121Q and BMI affected glycemic trait levels. RESULTS— The Q allele of K121Q (rs1044498) was associated with increased fasting plasma glucose (FPG), A1C, fasting insulin, and insulin resistance by homeostasis model assessment (HOMA-IR; all P = 0.01–0.006). Two noncoding SNPs (rs7775386 and rs7773477) demonstrated similar associations, but LME models indicated that their effects were not independent from K121Q. We found no association of K121Q with obesity, but interaction models suggested that the effect of the Q allele on FPG and HOMA-IR was stronger in those with a higher BMI ( P = 0.008 and 0.01 for interaction, respectively). CONCLUSIONS— The Q allele of ENPP1 K121Q is associated with hyperglycemia and insulin resistance in whites. We found an adiposity-SNP interaction, with a stronger association of K121Q with diabetes-related quantitative traits in people with a higher BMI. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 21 April 2008. J.B.M. serves on consultancy boards for GlaxoSmithKline, sanofi-aventis, Interleukin Genetics, Kalypsis, and Outcomes Sciences. J.C.F. has received a consulting honorarium from Publicis Healthcare Communications Group, a global advertising agency engaged by Amylin Pharmaceuticals. Readers may use this article as long as the work is properly cited, the use is educational and not for profit,and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted April 16, 2008. Received February 22, 2008. DIABETES

• Publisher: American Diabetes Association
• Subject: Amino Acid Substitution / Biological and medical sciences / Blood Glucose - metabolism / Cardiovascular Diseases - epidemiology / Cardiovascular Diseases - genetics / Diabetes / Diabetes Mellitus, Type 2 - genetics / Diabetes. Impaired glucose tolerance / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Female / Genetic aspects / Genetic polymorphisms / Genetic Variation / Genetics / Glucose / Glycoproteins / Haplotypes / Homeostasis / Humans / Hyperglycemia / Hyperglycemia - genetics / Insulin resistance / Insulin Resistance - genetics / Kinases / Linkage Disequilibrium / Male / Massachusetts / Medical sciences / Middle Aged / Mutation, Missense / Obesity / Phosphoric Diester Hydrolases - genetics / Physiological aspects / Polymorphism / Polymorphism, Single Nucleotide / Population / Pyrophosphatases - genetics / Quantitative Trait Loci / Research design / Risk Factors / Type 2 diabetes / White People