Abstract
BackgroundSingle 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.MethodsSNP 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.ResultsUsing 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.ConclusionsThe 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.
Highlights
Single nucleotide polymorphisms (SNPs) within the gene encoding Hexokinase 1 (HK1) are associated with changes in glycated haemoglobin (HbA1c) levels
HK1 is responsible for the first step in glucose utilization and it has been hypothesized that HK1 variants may affect glucose metabolism and thereby risk of Type 2 Diabetes (T2DM) [1]
The T-allele associated with an increase in Glycated Haemoglobin 1c (HbA1c) of 0.6% per allele (0.4 - 0.9); p = 3 × 10-7, an increase of 5.0 mmol/l×min per allele (0.1 10.0); p = 0.045 for area under the curve (AUC) for glucose under an oral glucose tolerance test (OGTT), an increase of 0.06 mmol/l per allele (0.03 - 1.0); p = 0.001 in fasting total plasma cholesterol, and an increase of 2.0% per allele (0.2 - 3.8); p = 0.03 in fasting plasma triglycerides (Table 2)
Summary
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. The T-allele of rs7072268, located in intron 7 of the gene encoding the hexokinase 1 (HK1), has previously been associated with higher glycated haemoglobin levels (HbA1c) in a genome-wide association study (GWAS) among more than 14,000 women [1]. The aim of present study was to validate the previously observed outcome of the rs7072268 within HK1 on 1) quantitative metabolic traits in a random sample of 5,604 adult Danish non-diabetic individuals with available data on glucose homeostasis and lipid variables and 2) on prevalence of T2DM in a case-control study including 4,449 glucose tolerant individuals and 3,398 patients with T2DM. We combined the outcomes of the present analyses with previously published results in a meta-analysis
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