TY - JOUR

T1 - Genetic variant in HK1 is associated with a proanemic state and A1C but not other glycemic control-related traits

AU - Bonnefond, Amélie

AU - Vaxillaire, Martine

AU - Labrune, Yann

AU - Lecoeur, Cécile

AU - Chèvre, Jean-Claude

AU - Bouatia-Naji, Nabila

AU - Cauchi, Stéphane

AU - Balkau, Beverley

AU - Marre, Michel

AU - Tichet, Jean

AU - Riveline, Jean-Pierre

AU - Hadjadj, Samy

AU - Gallois, Yves

AU - Czernichow, Sébastien

AU - Hercberg, Serge

AU - Kaakinen, Marika

AU - Wiesner, Susanne

AU - Charpentier, Guillaume

AU - Lévy-Marchal, Claire

AU - Elliott, Paul

AU - Jarvelin, Marjo-Riitta

AU - Horber, Fritz

AU - Dina, Christian

AU - Pedersen, Oluf

AU - Sladek, Robert

AU - Meyre, David

AU - Froguel, Philippe

N1 - Keywords: Adult; Blood Glucose; Cohort Studies; Diabetes Mellitus, Type 2; Europe; European Continental Ancestry Group; Female; Genetic Variation; Genome-Wide Association Study; Genotype; Glucose; Hemoglobin A, Glycosylated; Hexokinase; Homeostasis; Humans; Infant, Newborn; Infant, Small for Gestational Age; Male; Middle Aged; Obesity; Switzerland; Young Adult

PY - 2009

Y1 - 2009

N2 - 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 (beta = 0.029%; P = 2.22 x 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; beta = -0.054 g/dl; P = 3.74 x 10(-6)) and hematocrit (n = 11,492; beta = -0.13%; P = 2.26 x 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.

AB - 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 (beta = 0.029%; P = 2.22 x 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; beta = -0.054 g/dl; P = 3.74 x 10(-6)) and hematocrit (n = 11,492; beta = -0.13%; P = 2.26 x 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.

U2 - 10.2337/db09-0652

DO - 10.2337/db09-0652

M3 - Journal article

C2 - 19651813

VL - 58

SP - 2687

EP - 2697

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 11

ER -