A genetic variant in HK1 is associated with pro-anemic state and HbA1c 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,
- Jean Tichet4,
- Jean-Pierre Riveline5,
- Samy Hadjadj6,
- Yves Gallois7,
- Sébastien Czernichow8,
- Serge Hercberg8,
- Marika Kaakinen9,
- Susanne Wiesner10,
- Guillaume Charpentier5,
- Claire Lévy-Marchal11,
- Paul Elliott12,
- Marjo-Riitta Jarvelin8,12,
- Fritz Horber10,
- Christian Dina1,
- Oluf Pedersen13,
- Robert Sladek14,
- David Meyre1 and
- Philippe Froguel (p.froguel{at}imperial.ac.uk)1,15
- 1CNRS-UMR-8090, Institute of Biology and Lille 2 University, Pasteur Institute, Lille, France
- 2INSERM U780, Villejuif, and University Paris-Sud, Orsay, France
- 3Department of Endocrinology, Diabetology and Nutrition, Bichat-Claude Bernard University Hospital, Assistance Publique des Hôpitaux de Paris, Paris, and INSERM U695, Université Paris 7, Paris, France
- 4Institut inter-régional pour la santé (IRSA), La Riche, France
- 5Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Essonnes, France
- 6CHU de Poitiers, Endocrinologie Diabétologie, CIC INSERM 0802, INSERM U927, Université de Poitiers, UFR Médecine Pharmacie, Poitiers, France
- 7CHU d'Angers, Biochemistry laboratory, Angers, France
- 8Unité de Recherche en Epidémiologie Nutritionnelle, INSERM U557, INRA U1125, CNAM, UP13, CRNH-IdF, Bobigny, and Public Health Department, Hôpital Avicenne (AP-HP), Bobigny, France
- 9Institute of Health Sciences, University of Oulu, Oulu, and Biocenter Oulu, University of Oulu, Oulu, Finland
- 10Klinik Lindberg, Winterthur and University Berne, Berne, Switzerland
- 11INSERM U690, Robert Debré hospital, Paris, and Paris Diderot University, Paris, France
- 12Department of Epidemiology and Public Health, Imperial College London, London, UK
- 13Steno Diabetes Center, Gentofte, and Faculty of Health Sciences, University of Aarhus, Aarhus, and Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
- 14Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, and Genome Quebec Innovation Centre, Montreal, Canada
- 15Genomic Medicine, Hammersmith Hospital, Imperial College London, London, UK.
Abstract
Objective: HbA1c is widely considered as a gold standard for monitoring effective blood glucose levels. Recently, a genome-wide association study reported an association between HbA1c and rs7072268 within HK1 (encoding Hexokinase 1) which catalyzes the first step of glycolysis. HK1 deficiency in red blood cells (RBC) causes severe nonspherocytic hemolytic anemia in both humans and mice.
Research Design and Methods: The contribution of rs7072268 to HbA1c and the RBC-related traits was assessed in 6,953 non-diabetic (ND) European participants. We additionally analyzed the association with hematologic traits in 5,229 ND European individuals (where HbA1c was not measured) and 1,924 diabetic patients. Other glucose control related markers than HbA1c were analyzed in 18,694 ND European individuals. A type 2 diabetes case-control study included 7,447 French diabetic patients.
Results: Our study confirms a strong association between rs7072268-T allele and increased HbA1c (β=0.029%HbA1c,P=2.22×10−7). Surprisingly, despite an adequate study power, rs7072268 showed no association with any other marker of glucose control (fasting- and 2h-post-OGTT-related parameters;N=18,694). In contrast, rs7072268-T allele decreases hemoglobin levels (N=13,416;β=−0.054g/dl,P=3.74×10−6) and hematocrit (N=11,492;β=−0.13%Hematocrit,P=2.26×10−4), suggesting a pro-anemic effect. The T-allele also increases risk for anemia (Ncases=846,OR=1.13,P=0.018).
Conclusions: HK1 variation although strongly associated with HbA1c 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 HbA1c levels through its anemic effect and/or its effect on glucose metabolism in RBC. These findings may have implications for T2D diagnosis and clinical management, as anemia is a frequent complication of the diabetic state.
Footnotes
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- Received May 1, 2009.
- Accepted July 15, 2009.
- Copyright © American Diabetes Association
