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

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.

Correlations between islet autoantibody specificity and theSLC30A8genotype withHLA-DQB1and metabolic control in new onset type 1 diabetes

“…These findings have subsequently been replicated [11,12]. The C allele of rs13266634 has been associated with functional effects in β-cells such as decreased insulin release [13,14], proinsulin to insulin conversion [15], first phase insulin response 4 [16] and HbA1c levels [17]. We and others have been unable to demonstrate an association for rs13266634 with the risk of T1D [18][19][20][21].…”

“…Given that rs13266634 changes an amino acid in ZnT8 which is important for insulin secretion and has documented effects on type 2 diabetes related traits [13][14][15][16][17], we hypothesised that the SNP could have an effect on β-cell function and the rate of β-cell destruction in T1D. In the absence of stimulated C-peptide measurements, we used IDAA1c as a proxy with values taken less than 1 year after diagnosis.…”

Type 2 Diabetes Prevention: Implications of Hemoglobin A1c Genetics

“…Seven (FN3K, HFE, TMPRSS6, ANK1, SPTA1, ATP11A, and HK1) were first reported in European populations [16,17], and the remaining four (TMEN79, HB21L/MYB, MYO9B, and CYBA) were reported in Asian populations [20]. These genomic loci were either not strongly associated with FG, remained associated with HbA1c even after adjustment for FG in mediation analyses, or were strongly associated with red blood cell traits (e.g.…”

“…In 2008, Pare and colleagues conducted a GWAS on 14,618 nondiabetic participants of European ancestry in the Women's Genome Health Study [16]. They reported that HbA1c was associated with genetic variation at four genomic loci (GCK, rs730497, p = 2.8 x 10 -12 ; SLC30A8, rs13266634, p = 9.8 x10 -8 , G6PC2/ ABCB11, rs1402837, p = 6.8 x 10 -10…”

“…For instance, HK1, encoding hexokinase, was considered "glycemic" when it was first reported by ) [16]. Hexokinase is an enzyme that phosphorylates glucose to produce glucose-6-phosphate, the initial step in glucose metabolism.…”