Genetic variant in HK1 is associated with a proanemic state and A1C but not other glycemic control-related traits
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Genetic variant in HK1 is associated with a proanemic state and A1C but not other glycemic control-related traits. / Bonnefond, Amélie; Vaxillaire, Martine; Labrune, Yann; Lecoeur, Cécile; Chèvre, Jean-Claude; Bouatia-Naji, Nabila; Cauchi, Stéphane; Balkau, Beverley; Marre, Michel; Tichet, Jean; Riveline, Jean-Pierre; Hadjadj, Samy; Gallois, Yves; Czernichow, Sébastien; Hercberg, Serge; Kaakinen, Marika; Wiesner, Susanne; Charpentier, Guillaume; Lévy-Marchal, Claire; Elliott, Paul; Jarvelin, Marjo-Riitta; Horber, Fritz; Dina, Christian; Pedersen, Oluf; Sladek, Robert; Meyre, David; Froguel, Philippe.
In: Diabetes, Vol. 58, No. 11, 2009, p. 2687-97.Research output: Contribution to journal › Journal article › Research › peer-review
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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 -
ID: 18765195