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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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Genetic Context of Significant Associations.Genomic context for each of four loci with significant association with glycated hemoglobin levels. (A) G6PC2 locus (2q24.3); (B) GCK locus (19p13.2); (C) SLC30A8 locus (8q24.11); (D) HK1 locus (10q21.3). Upper panel: Genes from RefSeq release 25. Only one isoform is shown when multiple splicing variants are known. Lower Panel: SNPs are shown according to their physical location and −log10 P-values for association with glycated hemoglobin. At each locus, the SNP with the lowest P-value is represented by a black dot. The color of each other SNP was determined according to its linkage disequilibrium (r2) with the SNP with the lowest P-value, with colors varying from blue (r2 = 0) to red (r2 = 1). In Figure 1-D, the chromosomal position of rs2305198 is shown as this SNP was selected by the model selection algorithm in addition to the SNP with the lowest P-value (see text for details). The red line represents the genome-wide significance threshold of 5×10−8. Also shown is the genetic distance in cM from the lowest P-value SNP (light grey line) along with the position of recombination hotspots (light grey vertical bars). Recombination rates and hotspots are based on HapMap data, as described by McVean et al.[46] and Winckler et al.[47].
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pgen-1000312-g001: Genetic Context of Significant Associations.Genomic context for each of four loci with significant association with glycated hemoglobin levels. (A) G6PC2 locus (2q24.3); (B) GCK locus (19p13.2); (C) SLC30A8 locus (8q24.11); (D) HK1 locus (10q21.3). Upper panel: Genes from RefSeq release 25. Only one isoform is shown when multiple splicing variants are known. Lower Panel: SNPs are shown according to their physical location and −log10 P-values for association with glycated hemoglobin. At each locus, the SNP with the lowest P-value is represented by a black dot. The color of each other SNP was determined according to its linkage disequilibrium (r2) with the SNP with the lowest P-value, with colors varying from blue (r2 = 0) to red (r2 = 1). In Figure 1-D, the chromosomal position of rs2305198 is shown as this SNP was selected by the model selection algorithm in addition to the SNP with the lowest P-value (see text for details). The red line represents the genome-wide significance threshold of 5×10−8. Also shown is the genetic distance in cM from the lowest P-value SNP (light grey line) along with the position of recombination hotspots (light grey vertical bars). Recombination rates and hotspots are based on HapMap data, as described by McVean et al.[46] and Winckler et al.[47].

Mentions: Clinical characteristics of the 14,618 non-diabetic women in the primary WGHS analysis and of the 455 non-diabetic men and women in the external validation cohort are provided in Supplementary Table S1. Results of the genome-wide association analysis of adjusted baseline glycated hemoglobin concentration are presented in Table 1, which includes all SNPs with P-value lower than 10−6. Six SNPs at three different loci – G6PC2, GCK and HK1 - had an association P-value lower than our previously defined genome-wide significance threshold of 5×10−8: rs1402837, rs560887 and rs6709087 at G6PC2; rs730497 and rs4607517 at GCK; rs7072268 at HK1. In addition, two SNPs, one at the HK1 locus and one at the SCL30A8 locus, had association P-values just above this threshold level (5.5×10−8 and 9.8×10−8, respectively). Genetic context of all these loci is presented in Figure 1 along with the −log10 transformed P-values.


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)

Genetic Context of Significant Associations.Genomic context for each of four loci with significant association with glycated hemoglobin levels. (A) G6PC2 locus (2q24.3); (B) GCK locus (19p13.2); (C) SLC30A8 locus (8q24.11); (D) HK1 locus (10q21.3). Upper panel: Genes from RefSeq release 25. Only one isoform is shown when multiple splicing variants are known. Lower Panel: SNPs are shown according to their physical location and −log10 P-values for association with glycated hemoglobin. At each locus, the SNP with the lowest P-value is represented by a black dot. The color of each other SNP was determined according to its linkage disequilibrium (r2) with the SNP with the lowest P-value, with colors varying from blue (r2 = 0) to red (r2 = 1). In Figure 1-D, the chromosomal position of rs2305198 is shown as this SNP was selected by the model selection algorithm in addition to the SNP with the lowest P-value (see text for details). The red line represents the genome-wide significance threshold of 5×10−8. Also shown is the genetic distance in cM from the lowest P-value SNP (light grey line) along with the position of recombination hotspots (light grey vertical bars). Recombination rates and hotspots are based on HapMap data, as described by McVean et al.[46] and Winckler et al.[47].
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Related In: Results  -  Collection

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pgen-1000312-g001: Genetic Context of Significant Associations.Genomic context for each of four loci with significant association with glycated hemoglobin levels. (A) G6PC2 locus (2q24.3); (B) GCK locus (19p13.2); (C) SLC30A8 locus (8q24.11); (D) HK1 locus (10q21.3). Upper panel: Genes from RefSeq release 25. Only one isoform is shown when multiple splicing variants are known. Lower Panel: SNPs are shown according to their physical location and −log10 P-values for association with glycated hemoglobin. At each locus, the SNP with the lowest P-value is represented by a black dot. The color of each other SNP was determined according to its linkage disequilibrium (r2) with the SNP with the lowest P-value, with colors varying from blue (r2 = 0) to red (r2 = 1). In Figure 1-D, the chromosomal position of rs2305198 is shown as this SNP was selected by the model selection algorithm in addition to the SNP with the lowest P-value (see text for details). The red line represents the genome-wide significance threshold of 5×10−8. Also shown is the genetic distance in cM from the lowest P-value SNP (light grey line) along with the position of recombination hotspots (light grey vertical bars). Recombination rates and hotspots are based on HapMap data, as described by McVean et al.[46] and Winckler et al.[47].
Mentions: Clinical characteristics of the 14,618 non-diabetic women in the primary WGHS analysis and of the 455 non-diabetic men and women in the external validation cohort are provided in Supplementary Table S1. Results of the genome-wide association analysis of adjusted baseline glycated hemoglobin concentration are presented in Table 1, which includes all SNPs with P-value lower than 10−6. Six SNPs at three different loci – G6PC2, GCK and HK1 - had an association P-value lower than our previously defined genome-wide significance threshold of 5×10−8: rs1402837, rs560887 and rs6709087 at G6PC2; rs730497 and rs4607517 at GCK; rs7072268 at HK1. In addition, two SNPs, one at the HK1 locus and one at the SCL30A8 locus, had association P-values just above this threshold level (5.5×10−8 and 9.8×10−8, respectively). Genetic context of all these loci is presented in Figure 1 along with the −log10 transformed P-values.

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