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

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.