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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.

Paré G, Chasman DI, Parker AN, Nathan DM, Miletich JP, Zee RY, Ridker PM - PLoS Genet. (2008)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. gpare@rics.bwh.harvard.edu

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 x 10(-12)), SLC30A8 (rs13266634; P = 9.8 x 10(-8)), G6PC2 (rs1402837; P = 6.8 x 10(-10)), and HK1 (rs7072268; P = 6.4 x 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.

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Related in: MedlinePlus

Quantile-Quantile plot of Glycated Hemoglobin Association P-Values.The quantile-quantile plot of glycated hemoglobin association P-values is shown on the left. On the right, the same quantile-quantile plot is shown, but after adjusting glycated hemoglobin values for the additive genetic effect of the 5 SNPs retained by the model selection algorithm (rs1402837, rs730497, rs13266634, rs7072268 and rs2305198; see text for details).
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pgen-1000312-g002: Quantile-Quantile plot of Glycated Hemoglobin Association P-Values.The quantile-quantile plot of glycated hemoglobin association P-values is shown on the left. On the right, the same quantile-quantile plot is shown, but after adjusting glycated hemoglobin values for the additive genetic effect of the 5 SNPs retained by the model selection algorithm (rs1402837, rs730497, rs13266634, rs7072268 and rs2305198; see text for details).

Mentions: To define further the extent of genetic associations at these 4 loci, we applied a forward model selection algorithm to each of them, identifying SNPs that were non-redundantly associated with glycated hemoglobin. Briefly, 38 SNPs at GCK, 31 at SLC30A8, 41 at HK1 and 44 at G6PC2 were initially assessed for possible inclusion in a multiple linear regression model. Using a P-value cut-off of 3×10−4 to account for the 154 SNPs considered, 5 SNPs were selected, representing the lead SNP at each of the 4 loci considered plus one SNP (rs2305198; located at 70799 Kb on chromosome 10) at the HK1 locus (see Table 2). Interestingly, this later SNP (rs2305198; HK1) was marginally significant in univariable analysis (p = 0.02), illustrating that its inclusion in the model and significant association are conditional on the genotypes at rs7072268 (HK1). Multiple regression beta coefficients and P-values of the 5 SNPs selected are shown in Table 2 and range from 5.4×10−8 to 1.8×10−25. Shown in Figure 2 are the quantile-quantile plots of association P-values before and after adjusting glycated hemoglobin concentration for the combined effect of these 5 SNPs. Among these SNPs, there was no strong evidence for non-additive effects of the minor allele as judged by lack of significance for a likelihood ratio test comparing the additive regression model to an alternative genotype model with an additional degree of freedom. No pairwise gene-gene interaction was observed between any of the model selected SNPs. That is, we tested every possible 2-SNPs combination among these 5 SNPs.


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.

Paré G, Chasman DI, Parker AN, Nathan DM, Miletich JP, Zee RY, Ridker PM - PLoS Genet. (2008)

Quantile-Quantile plot of Glycated Hemoglobin Association P-Values.The quantile-quantile plot of glycated hemoglobin association P-values is shown on the left. On the right, the same quantile-quantile plot is shown, but after adjusting glycated hemoglobin values for the additive genetic effect of the 5 SNPs retained by the model selection algorithm (rs1402837, rs730497, rs13266634, rs7072268 and rs2305198; see text for details).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2596965&req=5

pgen-1000312-g002: Quantile-Quantile plot of Glycated Hemoglobin Association P-Values.The quantile-quantile plot of glycated hemoglobin association P-values is shown on the left. On the right, the same quantile-quantile plot is shown, but after adjusting glycated hemoglobin values for the additive genetic effect of the 5 SNPs retained by the model selection algorithm (rs1402837, rs730497, rs13266634, rs7072268 and rs2305198; see text for details).
Mentions: To define further the extent of genetic associations at these 4 loci, we applied a forward model selection algorithm to each of them, identifying SNPs that were non-redundantly associated with glycated hemoglobin. Briefly, 38 SNPs at GCK, 31 at SLC30A8, 41 at HK1 and 44 at G6PC2 were initially assessed for possible inclusion in a multiple linear regression model. Using a P-value cut-off of 3×10−4 to account for the 154 SNPs considered, 5 SNPs were selected, representing the lead SNP at each of the 4 loci considered plus one SNP (rs2305198; located at 70799 Kb on chromosome 10) at the HK1 locus (see Table 2). Interestingly, this later SNP (rs2305198; HK1) was marginally significant in univariable analysis (p = 0.02), illustrating that its inclusion in the model and significant association are conditional on the genotypes at rs7072268 (HK1). Multiple regression beta coefficients and P-values of the 5 SNPs selected are shown in Table 2 and range from 5.4×10−8 to 1.8×10−25. Shown in Figure 2 are the quantile-quantile plots of association P-values before and after adjusting glycated hemoglobin concentration for the combined effect of these 5 SNPs. Among these SNPs, there was no strong evidence for non-additive effects of the minor allele as judged by lack of significance for a likelihood ratio test comparing the additive regression model to an alternative genotype model with an additional degree of freedom. No pairwise gene-gene interaction was observed between any of the model selected SNPs. That is, we tested every possible 2-SNPs combination among these 5 SNPs.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. gpare@rics.bwh.harvard.edu

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 x 10(-12)), SLC30A8 (rs13266634; P = 9.8 x 10(-8)), G6PC2 (rs1402837; P = 6.8 x 10(-10)), and HK1 (rs7072268; P = 6.4 x 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.

Show MeSH
Related in: MedlinePlus