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
Online Access:Get full text
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Summary: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.
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Conceived and designed the experiments: GP DIC DMN PMR. Performed the experiments: GP ANP. Analyzed the data: GP. Contributed reagents/materials/analysis tools: DIC JPM RYZ PMR. Wrote the paper: GP.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1000312