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

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• 作者：Anette P Gjesing (1)
  Aneta A Nielsen (2)
  Ivan Brandslund (2) (3)
  Cramer Christensen (4)
  Anneli Sandb?k (5)
  Torben J?rgensen (6) (7)
  Daniel Witte (8)
  Amélie Bonnefond (9)
  Phillippe Froguel (10) (9)
  Torben Hansen (1) (11)
  Oluf Pedersen (1) (12) (13) (14)
  
• 关键词：Hexokinase 1 ; Glycated Haemoglobin A1c ; Type 2 diabetes ; Genetics
• 刊名：BMC Medical Genetics
• 出版年：2011
• 出版时间：December 2011
• 年：2011
• 卷：12
• 期：1
• 全文大小：307KB
• 参考文献：1. Paré G, Chasman DI, Parker AN, Nathan DM, Miletich JP, Zee RY, Ridker PM: 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. / PLoS Genet 2008, 4:e1000312. CrossRef
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  3. Soranzo N, Sanna S, Wheeler E, Gieger C, Radke D, Dupuis J, Bouatia-Naji N, Langenberg C, Prokopenko I, Stolerman E, Sandhu MS, Heeney MM, Devaney JM, Reilly MP, Ricketts SL: Common variants at ten genomic loci influence hemoglobin A _1c levels via glycemic and non-glycemic pathways. / Diabetes 2010, 59:3229-9. CrossRef
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  11. Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, Wheeler E, Glazer NL, Bouatia-Naji N, Gloyn AL, Lindgren CM, M?gi R, Morris AP, Randall J, Johnson T, Elliott P, Rybin D, Thorleifsson G, Steinthorsdottir V, Henneman P, Grallert H, Dehghan A, Hottenga JJ, Franklin CS, Navarro P, Song K, Goel A, Perry JR, Egan JM, Lajunen T, / et al.: New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. / Nat Genet 2010, 42:105-6. CrossRef
  12. Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, McCulloch LJ, Ferreira T, Grallert H, Amin N, Wu G, Willer CJ, Raychaudhuri S, McCarroll SA, Langenberg C, Hofmann OM, Dupuis J, Qi L, Segrè AV, van Hoek M, Navarro P, Ardlie K, Balkau B, Benediktsson R, Bennett AJ, Blagieva R, Boerwinkle E, / et al.: Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. / Nat Genet 2010,42(7):579-9. CrossRef
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  20. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/12/99/prepub
  
• 作者单位：Anette P Gjesing (1)
  Aneta A Nielsen (2)
  Ivan Brandslund (2) (3)
  Cramer Christensen (4)
  Anneli Sandb?k (5)
  Torben J?rgensen (6) (7)
  Daniel Witte (8)
  Amélie Bonnefond (9)
  Phillippe Froguel (10) (9)
  Torben Hansen (1) (11)
  Oluf Pedersen (1) (12) (13) (14)
  
  1. The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 1-3, 2100, Copenhagen, Denmark
  2. Department of Clinical Biochemistry, Vejle Hospital, Kabbeltoft 25, 7100, Vejle, Denmark
  3. Institute of Regional Health Research, University of Southern Denmark, J.B. Winsloews Vej 9B, 5000, Odense, Denmark
  4. Department of Internal Medicine and Endocrinology, Vejle Hospital, Kabbeltoft 25, 7100, Vejle, Denmark
  5. Department of General Practice, University of Aarhus, Vennelyst Boulevard 6, 8000, Aarhus, Denmark
  6. Research Centre for Prevention and Health, Glostrup University Hospital, Nordre Ringvej, 2600, Glostrup, Denmark
  7. Faculty of Health Science, University of Copenhagen, Blegdamsvej, 2200, Copenhagen, Denmark
  8. Steno Diabetes Center, Niels Steensens Vej 2, 2800, Gentofte, Denmark
  9. CNRS-UMR-8199, Lille Pasteur Institute, Univ Lille Nord de France, rue du Pr. Calmette, 59000, Lille, France
  10. Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, Du Cane Rd, London, W12 0NN, UK
  11. Faculty of Health Sciences, University of Southern Denmark, J.B. Winsloews Vej 19, 5000, Odense, Denmark
  12. Hagedorn Research Institute, Niels Steensens Vej 1, 2820, Gentofte, Denmark
  13. Institute of Biomedical Science, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark
  14. Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark
  
• ISSN：1471-2350

文摘

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.