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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
- Source :
- PLoS Genetics, PLoS Genetics, Vol 4, Iss 12, p e1000312 (2008)
- Publication Year :
- 2008
- Publisher :
- Public Library of Science (PLoS), 2008.
-
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 = 2.8×10−12), 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.<br />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.
- Subjects :
- Cancer Research
medicine.medical_specialty
lcsh:QH426-470
Population
030209 endocrinology & metabolism
Genome-wide association study
Type 2 diabetes
Genetics and Genomics/Complex Traits
Biology
Polymorphism, Single Nucleotide
Cohort Studies
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Risk Factors
Hexokinase
Diabetes mellitus
Internal medicine
Genetics
medicine
Humans
Diabetes and Endocrinology/Type 2 Diabetes
education
Molecular Biology
Genetics (clinical)
Ecology, Evolution, Behavior and Systematics
030304 developmental biology
Glycated Hemoglobin
0303 health sciences
education.field_of_study
SLC30A8
Physiology/Endocrinology
Genome, Human
Racial Groups
Type 2 Diabetes Mellitus
Middle Aged
medicine.disease
United States
3. Good health
lcsh:Genetics
Endocrinology
Diabetes Mellitus, Type 2
chemistry
biology.protein
Female
Glycated hemoglobin
Hemoglobin
Research Article
Genome-Wide Association Study
Subjects
Details
- ISSN :
- 15537404
- Volume :
- 4
- Database :
- OpenAIRE
- Journal :
- PLoS Genetics
- Accession number :
- edsair.doi.dedup.....5406200b09f3dc33cc7557d8ab665df2