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Open Access Highly Accessed Research article

Studies of a genetic variant in HK1 in relation to quantitative metabolic traits and to the prevalence of type 2 diabetes

Anette P Gjesing1*, Aneta A Nielsen2, Ivan Brandslund23, Cramer Christensen4, Anneli Sandbæk5, Torben Jørgensen67, Daniel Witte8, Amélie Bonnefond9, Phillippe Froguel109, Torben Hansen111 and Oluf Pedersen1121314

Author Affiliations

1 The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 1-3, 2100 Copenhagen, Denmark

2 Department of Clinical Biochemistry, Vejle Hospital, Kabbeltoft 25, 7100 Vejle, Denmark

3 Institute of Regional Health Research, University of Southern Denmark, J.B. Winsloews Vej 9B, 5000 Odense, Denmark

4 Department of Internal Medicine and Endocrinology, Vejle Hospital, Kabbeltoft 25, 7100 Vejle, Denmark

5 Department of General Practice, University of Aarhus, Vennelyst Boulevard 6, 8000 Aarhus, Denmark

6 Research Centre for Prevention and Health, Glostrup University Hospital, Nordre Ringvej, 2600 Glostrup, Denmark

7 Faculty of Health Science, University of Copenhagen, Blegdamsvej, 2200 Copenhagen, Denmark

8 Steno Diabetes Center, Niels Steensens Vej 2, 2800 Gentofte, Denmark

9 CNRS-UMR-8199, Lille Pasteur Institute, Univ Lille Nord de France, rue du Pr. Calmette, 59000 Lille, France

10 Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, Du Cane Rd., London W12 0NN, UK

11 Faculty of Health Sciences, University of Southern Denmark, J.B. Winsloews Vej 19, 5000 Odense, Denmark

12 Hagedorn Research Institute, Niels Steensens Vej 1, 2820 Gentofte, Denmark

13 Institute of Biomedical Science, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark

14 Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark

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BMC Medical Genetics 2011, 12:99  doi:10.1186/1471-2350-12-99

Published: 25 July 2011

Abstract

Background

Single nucleotide polymorphisms (SNPs) within the gene encoding Hexokinase 1 (HK1) are associated with changes in glycated haemoglobin (HbA1c) levels. Our aim was to investigate the effect of HK1 rs7072268 on measures of glucose- and lipid-metabolism in a Danish non-diabetic population and combine the outcome of these analyses in a meta-analysis with previously published results. Furthermore, our aim was to perform a type 2 diabetes case-control analysis and meta-analysis with two previous case-control studies.

Methods

SNP rs7072268 was genotyped in 9,724 Danes. The quantitative trait study included 5,604 non-diabetic individuals from the Inter99 cohort. The case-control study included 4,449 glucose tolerant individuals and 3,398 patients with type 2 diabetes. Meta-analyses on quantitative traits included 24,560 Caucasian individuals and 30,802 individuals were included in the combined analysis of present and previous type 2 diabetes case-control studies.

Results

Using an additive model, we confirmed that the T-allele of rs7072268 associates with increased HbA1c of 0.6% (CI: 0.4 - 0.9), p = 3*10-7 per allele. The same allele associated with an increased area under the curve (AUC) for glucose of 5.0 mmol/l*min (0.1 - 10.0), p = 0.045 following an oral glucose tolerance test (OGTT) and increased fasting levels of cholesterol of 0.06 mmol/l (0.03 - 1.0), p = 0.001 and triglycerides of 2.0% (0.2 - 3.8), p = 0.03 per allele in the same study sample of non-diabetic individuals from the Inter99 cohort. However, the T-allele did not show any association with estimates of insulin release or insulin sensitivity neither in Inter99 nor in combined analyses. The prevalence of type 2 diabetes was increased among carriers of the rs7072268 T-allele both in the Danish study-population with an OR of 1.11 (1.02-1.21) and in a meta-analysis including the two additional sample sets with an OR of 1.06 (1.02-1.11). However, after Bonferroni correction the T-allele only remained associated to HbA1c and fasting cholesterol.

Conclusions

The present study provides suggestive evidence of an association of the rs7072268 T-allele in HK1 with increased AUC glucose following an OGTT in non-diabetic individuals and a nominal association with type 2 diabetes prior to Bonferroni correction. The latter was confirmed in combined analyses involving 16,445 cases and 14,357 control subjects.

Keywords:
Hexokinase 1; Glycated Haemoglobin A1c; Type 2 diabetes; Genetics