Novel Association of HK1 with Glycated Hemoglobin in a Non-Diabetic Population: A Genome-Wide Evaluation of 14,618 Participants in the Women’s Genome Health Study Guillaume Pare´ 1,2.*, Daniel I. Chasman1,2., Alexander N. Parker3, David M. Nathan4, Joseph P. Miletich3, Robert Y. Zee1,2, Paul M. Ridker1,2 1 Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America, 2 Donald W. Reynolds Center for Cardiovascular Research, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America, 3 Amgen, Inc., Cambridge, Massachusetts, United States of America, 4 Diabetes Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America Abstract Type 2 diabetes is a leading cause of morbidity and mortality. While genetic variants have been found to influence the risk of type 2 diabetes mellitus, relatively few studies have focused on genes associated with glycated hemoglobin, an index of the mean blood glucose concentration of the preceding 8–12 weeks. Epidemiologic studies and randomized clinical trials have documented the relationship between glycated hemoglobin levels and the development of long-term complications in diabetes; moreover, higher glycated hemoglobin levels in the subdiabetic range have been shown to predict type 2 diabetes risk and cardiovascular disease. To examine the common genetic determinants of glycated hemoglobin levels, we performed a genome-wide association study that evaluated 337,343 SNPs in 14,618 apparently healthy Caucasian women. The results show that glycated hemoglobin levels are associated with genetic variation at the GCK (rs730497; P = 2.8610212), SLC30A8 (rs13266634; P = 9.861028), G6PC2 (rs1402837; P = 6.8610210), and HK1 (rs7072268; P = 6.461029) loci. While associations at the GCK, SLC30A8, and G6PC2 loci are confirmatory, the findings at HK1 are novel. We were able to replicate this novel association in an independent validation sample of 455 additional non-diabetic men and women. HK1 encodes the enzyme hexokinase, the first step in glycolysis and a likely candidate for the control of glucose metabolism. This observed genetic association between glycated hemoglobin levels and HK1 polymorphisms paves the way for further studies of the role of HK1 in hemoglobin glycation, glucose metabolism, and diabetes. Citation: Pare´ G, Chasman DI, Parker AN, Nathan DM, Miletich JP, et al. (2008) Novel Association of HK1 with Glycated Hemoglobin in a Non-Diabetic Population: A Genome-Wide Evaluation of 14,618 Participants in the Women’s Genome Health Study. PLoS Genet 4(12): e1000312. doi:10.1371/journal.pgen.1000312 Editor: David B. Allison, University of Alabama at Birmingham, United States of America Received August 12, 2008; Accepted November 18, 2008; Published December 19, 2008 Copyright: 2008 Pare´ et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported by grants from the National Heart Lung and Blood Institute and the National Cancer Institute (Bethesda, MD; grants HL080467, HL043851 and CA047988), the Donald W Reynolds Foundation (Las Vegas, NV), the Doris Duke Charitable Foundation, and the Foundation Leducq (Paris, FR), with collaborative scientific and genotypic support provided by Amgen, Inc. GP is a recipient of a Fonds de la Recherche en Sante du Que´bec scholarship. Competing Interests: The authors have declared that no competing interests exist. * E-mail: gpare@rics.bwh.harvard.edu . These authors contributed equally to this work. Introduction Type 2 diabetes is a leading cause of morbidity and mortality. While genetic variants influence the risk of type 2 diabetes mellitus [1], relatively little is known about the role of genetic variations in the regulation of glucose concentration in healthy individuals. Indeed, only two genes, glucokinase (GCK) [2–4] and G6PC2 [5,6], have been unequivocally associated with fasting blood glucose concentration in healthy subjects. Other genes, such as SLC30A8, have been linked to glucose metabolism without ever having been associated with blood glucose concentration per se [7]. Glycated proteins are formed post-translationally from the slow, non-enzymatic attachment of glucose to N-terminal valine and internal lysine amino groups [8]. The concentration of glycated hemoglobin is a function of the concentration of glucose to which the erythrocytes are exposed over their lifespan (120 days on average). The glycated hemoglobin assay reflects the integrated blood glucose concentration of the preceding 8–12 weeks [9], provides a better estimate of mean glycemia than routine determinations of blood glucose concentration, and is the most widely used index of chronic glycemia [10,11]. Clinical trials have documented the relationship between glycated hemoglobin levels and the development of long-term complications in type 1 and type 2 diabetes [12,13], and higher glycated hemoglobin levels in the subdiabetic range have been shown to predict type 2 diabetes risk [14] and cardiovascular disease [14–17]. Despite considerable effort to decipher the genetic basis of type 2 diabetes, relatively few studies have focused on the genetic basis of glycated hemoglobin levels. To examine the common genetic determinants of glycated hemoglobin levels, we performed a genome-wide association study evaluating 337,343 SNPs in 14,618 apparently healthy non-diabetic women of Caucasian ancestry. PLoS Genetics | www.plosgenetics.org 1 December 2008 | Volume 4 | Issue 12 | e1000312