Genetic Variant in HK1 Is Associated With a Proanemic State and A1C but Not Other Glycemic Control–Related Traits
- Amélie Bonnefond1,
- Martine Vaxillaire1,
- Yann Labrune1,
- Cécile Lecoeur1,
- Jean-Claude Chèvre1,
- Nabila Bouatia-Naji1,
- Stéphane Cauchi1,
- Beverley Balkau2,
- Michel Marre3,4,
- Jean Tichet5,
- Jean-Pierre Riveline6,
- Samy Hadjadj7,
- Yves Gallois8,
- Sébastien Czernichow9,
- Serge Hercberg9,
- Marika Kaakinen10,11,
- Susanne Wiesner12,13,
- Guillaume Charpentier6,
- Claire Lévy-Marchal14,15,
- Paul Elliott16,
- Marjo-Riitta Jarvelin9,16,
- Fritz Horber12,13,
- Christian Dina1,
- Oluf Pedersen17,18,19,
- Robert Sladek20,21,
- David Meyre1 and
- Philippe Froguel1,22
- 1CNRS-UMR-8090, Institute of Biology and Lille 2 University, Pasteur Institute, Lille, France;
- 2INSERM U780, Villejuif, France, and University Paris-Sud, Orsay, France;
- 3Department of Endocrinology, Diabetology and Nutrition, Bichat-Claude Bernard University Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France;
- 4INSERM U695, Université Paris 7, Paris, France;
- 5Institut Inter-Régional Pour la Santé, La Riche, France;
- 6Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Essonnes, France;
- 7CHU de Poitiers, Endocrinologie Diabétologie, CIC INSERM 0802, INSERM U927, Université de Poitiers, UFR Médecine Pharmacie, Poitiers, France;
- 8CHU d'Angers, the Biochemistry Laboratory, Angers, France;
- 9Unité de Recherche en Epidémiologie Nutritionnelle, INSERM U557, INRA U1125, CNAM, UP13, CRNH-IdF, and the Public Health Department, Hôpital Avicenne (AP-HP), Bobigny, France;
- 10Institute of Health Sciences, University of Oulu, Oulu, Finland;
- 11Biocenter Oulu, University of Oulu, Oulu, Finland;
- 12Klinik Lindberg, Winterthur, Switzerland;
- 13University Berne, Berne, Switzerland;
- 14INSERM U690, Robert Debré Hospital, Paris, France;
- 15Paris Diderot University, Paris, France;
- 16Department of Epidemiology and Public Health, Imperial College London, London, U.K.;
- 17Steno Diabetes Center, Gentofte, Denmark;
- 18Department of Health Sciences, University of Aarhus, Aarhus, Denmark;
- 19Department of Health Sciences, University of Copenhagen, Copenhagen, Denmark;
- 20Department of Human Genetics, McGill University, Montreal, Canada;
- 21Genome Quebec Innovation Centre, Montreal, Canada;
- 22Genomic Medicine, Hammersmith Hospital, Imperial College London, London, U.K.
- Corresponding author: Philippe Froguel, p.froguel{at}imperial.ac.uk.
Abstract
OBJECTIVE A1C is widely considered the gold standard for monitoring effective blood glucose levels. Recently, a genome-wide association study reported an association between A1C and rs7072268 within HK1 (encoding hexokinase 1), which catalyzes the first step of glycolysis. HK1 deficiency in erythrocytes (red blood cells [RBCs]) causes severe nonspherocytic hemolytic anemia in both humans and mice.
RESEARCH DESIGN AND METHODS The contribution of rs7072268 to A1C and the RBC-related traits was assessed in 6,953 nondiabetic European participants. We additionally analyzed the association with hematologic traits in 5,229 nondiabetic European individuals (in whom A1C was not measured) and 1,924 diabetic patients. Glucose control–related markers other than A1C were analyzed in 18,694 nondiabetic European individuals. A type 2 diabetes case-control study included 7,447 French diabetic patients.
RESULTS Our study confirms a strong association between the rs7072268–T allele and increased A1C (β = 0.029%; P = 2.22 × 10−7). Surprisingly, despite adequate study power, rs7072268 showed no association with any other markers of glucose control (fasting- and 2-h post-OGTT–related parameters, n = 18,694). In contrast, rs7072268–T allele decreases hemoglobin levels (n = 13,416; β = −0.054 g/dl; P = 3.74 × 10−6) and hematocrit (n = 11,492; β = −0.13%; P = 2.26 × 10−4), suggesting a proanemic effect. The T allele also increases risk for anemia (836 cases; odds ratio 1.13; P = 0.018).
CONCLUSIONS HK1 variation, although strongly associated with A1C, does not seem to be involved in blood glucose control. Since HK1 rs7072268 is associated with reduced hemoglobin levels and favors anemia, we propose that HK1 may influence A1C levels through its anemic effect or its effect on glucose metabolism in RBCs. These findings may have implications for type 2 diabetes diagnosis and clinical management because anemia is a frequent complication of the diabetes state.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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See accompanying commentary, p. 2444..
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- Received May 1, 2009.
- Accepted July 15, 2009.
- © 2009 American Diabetes Association
