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

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...

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Published in:	PLoS genetics Vol. 4; no. 12; p. e1000312
Main Authors:	Paré, Guillaume, Chasman, Daniel I., Parker, Alexander N., Nathan, David M., Miletich, Joseph P., Zee, Robert Y., Ridker, Paul M.
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 01.12.2008 Public Library of Science (PLoS)
Subjects:	Cohort Studies Continental Population Groups - genetics Diabetes Diabetes and Endocrinology/Type 2 Diabetes Diabetes Mellitus, Type 2 - epidemiology Diabetes Mellitus, Type 2 - genetics Diabetes Mellitus, Type 2 - metabolism Female Genetics and Genomics/Complex Traits Genome, Human Genome-Wide Association Study Glucose Glycated Hemoglobin A - genetics Glycated Hemoglobin A - metabolism Hemoglobin Hexokinase - genetics Hexokinase - metabolism Humans Middle Aged Physiology/Endocrinology Polymorphism, Single Nucleotide Risk Factors United States - epidemiology Womens health
ISSN:	1553-7404, 1553-7390, 1553-7404
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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 = 2.8 x 10(-12)), SLC30A8 (rs13266634; P = 9.8 x 10(-8)), G6PC2 (rs1402837; P = 6.8 x 10(-10)), and HK1 (rs7072268; P = 6.4 x 10(-9)) 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.
AbstractList	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 = 2.8×10−12), SLC30A8 (rs13266634; P = 9.8×10−8), G6PC2 (rs1402837; P = 6.8×10−10), and HK1 (rs7072268; P = 6.4×10−9) 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. Type 2 diabetes is a leading cause of morbidity and mortality in both the developed and developing world. Because the main metabolic characteristic of diabetes is increased blood glucose concentration, we sought to uncover the genetic determinants of glycated hemoglobin, an index of the mean blood glucose concentration of the preceding 8–12 weeks. Taking advantage of new technologies allowing us to interrogate genetic variation on a whole-genome basis, we found that variations in the GCK, SLC30A8, G6PC2, and HK1 genes are important determinants of glycated hemoglobin concentrations. While associations with the GCK, SLC30A8, and G6PC2 genes have previously been identified in genetic studies of diabetes and blood glucose concentration, the findings at HK1 are novel. HK1 encodes the enzyme hexokinase, responsible for the first step in glucose utilization and a likely candidate for the control of glucose metabolism. This observed genetic association between glycated hemoglobin levels and HK1 genetic variants paves the way for further studies of the role of HK1 in glucose metabolism and diabetes. 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 = 2.8 x 10(-12)), SLC30A8 (rs13266634; P = 9.8 x 10(-8)), G6PC2 (rs1402837; P = 6.8 x 10(-10)), and HK1 (rs7072268; P = 6.4 x 10(-9)) 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. 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=2.810 super(-12)), SLC30A8 (rs13266634; P=9.810 super(-8)), G6PC2 (rs1402837; P=6.810 super(-10)), and HK1 (rs7072268; P=6.410 super(-9)) 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. Author Summary Type 2 diabetes is a leading cause of morbidity and mortality in both the developed and developing world. Because the main metabolic characteristic of diabetes is increased blood glucose concentration, we sought to uncover the genetic determinants of glycated hemoglobin, an index of the mean blood glucose concentration of the preceding 8-12 weeks. Taking advantage of new technologies allowing us to interrogate genetic variation on a whole-genome basis, we found that variations in the GCK, SLC30A8, G6PC2, and HK1 genes are important determinants of glycated hemoglobin concentrations. While associations with the GCK, SLC30A8, and G6PC2 genes have previously been identified in genetic studies of diabetes and blood glucose concentration, the findings at HK1 are novel. HK1 encodes the enzyme hexokinase, responsible for the first step in glucose utilization and a likely candidate for the control of glucose metabolism. This observed genetic association between glycated hemoglobin levels and HK1 genetic variants paves the way for further studies of the role of HK1 in glucose metabolism and diabetes. 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 = 2.8 x 10(-12)), SLC30A8 (rs13266634; P = 9.8 x 10(-8)), G6PC2 (rs1402837; P = 6.8 x 10(-10)), and HK1 (rs7072268; P = 6.4 x 10(-9)) 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.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 = 2.8 x 10(-12)), SLC30A8 (rs13266634; P = 9.8 x 10(-8)), G6PC2 (rs1402837; P = 6.8 x 10(-10)), and HK1 (rs7072268; P = 6.4 x 10(-9)) 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. 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 = 2.8×10-12), SLC30A8 (rs13266634; P = 9.8×10-8), G6PC2 (rs1402837; P = 6.8×10-10), and HK1 (rs7072268; P = 6.4×10-9) 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.
Author	Parker, Alexander N. Miletich, Joseph P. Paré, Guillaume Zee, Robert Y. Chasman, Daniel I. Ridker, Paul M. Nathan, David M.
AuthorAffiliation	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 4 Diabetes Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America 3 Amgen, Inc., Cambridge, Massachusetts, United States of America University of Alabama at Birmingham, United States of America
AuthorAffiliation_xml	– name: 1 Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America – name: 4 Diabetes Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America – name: University of Alabama at Birmingham, United States of America – name: 3 Amgen, Inc., Cambridge, Massachusetts, United States of America – name: 2 Donald W. Reynolds Center for Cardiovascular Research, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
Author_xml	– sequence: 1 givenname: Guillaume surname: Paré fullname: Paré, Guillaume – sequence: 2 givenname: Daniel I. surname: Chasman fullname: Chasman, Daniel I. – sequence: 3 givenname: Alexander N. surname: Parker fullname: Parker, Alexander N. – sequence: 4 givenname: David M. surname: Nathan fullname: Nathan, David M. – sequence: 5 givenname: Joseph P. surname: Miletich fullname: Miletich, Joseph P. – sequence: 6 givenname: Robert Y. surname: Zee fullname: Zee, Robert Y. – sequence: 7 givenname: Paul M. surname: Ridker fullname: Ridker, Paul M.
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/19096518$$D View this record in MEDLINE/PubMed
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Copyright	Paré et al. 2008 2008 Paré 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: Paré 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
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Snippet	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,... 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,...
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SubjectTerms	Cohort Studies Continental Population Groups - genetics Diabetes Diabetes and Endocrinology/Type 2 Diabetes Diabetes Mellitus, Type 2 - epidemiology Diabetes Mellitus, Type 2 - genetics Diabetes Mellitus, Type 2 - metabolism Female Genetics and Genomics/Complex Traits Genome, Human Genome-Wide Association Study Glucose Glycated Hemoglobin A - genetics Glycated Hemoglobin A - metabolism Hemoglobin Hexokinase - genetics Hexokinase - metabolism Humans Middle Aged Physiology/Endocrinology Polymorphism, Single Nucleotide Risk Factors United States - epidemiology Womens health
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Title	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
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