title: Genetic variant in HK1 is associated with a proanemic state and A1C but not other glycemic control-related traits.
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.
  
  
  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.
authors: CNRS-UMR-8090, Institute of Biology and Lille 2 University, Pasteur Institute, Lille, France.
authors: Amélie
authors: A
authors: Bonnefond
authors: Martine
authors: M
authors: Vaxillaire
authors: Yann
authors: Y
authors: Labrune
authors: Cécile
authors: C
authors: Lecoeur
authors: Jean-Claude
authors: JC
authors: Chèvre
authors: Nabila
authors: N
authors: Bouatia-Naji
authors: Stéphane
authors: S
authors: Cauchi
authors: Beverley
authors: B
authors: Balkau
authors: Michel
authors: M
authors: Marre
authors: Jean
authors: J
authors: Tichet
authors: Jean-Pierre
authors: JP
authors: Riveline
authors: Samy
authors: S
authors: Hadjadj
authors: Yves
authors: Y
authors: Gallois
authors: Sébastien
authors: S
authors: Czernichow
authors: Serge
authors: S
authors: Hercberg
authors: Marika
authors: M
authors: Kaakinen
authors: Susanne
authors: S
authors: Wiesner
authors: Guillaume
authors: G
authors: Charpentier
authors: Claire
authors: C
authors: Lévy-Marchal
authors: Paul
authors: P
authors: Elliott
authors: Marjo-Riitta
authors: MR
authors: Jarvelin
authors: Fritz
authors: F
authors: Horber
authors: Christian
authors: C
authors: Dina
authors: Oluf
authors: O
authors: Pedersen
authors: Robert
authors: R
authors: Sladek
authors: David
authors: D
authors: Meyre
authors: Philippe
authors: P
authors: Froguel
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism*; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D005060:Europe; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006593:Hexokinase / Q000235:genetics*; D006706:Homeostasis; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D013557:Switzerland / Q000453:epidemiology; D044465:White People; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D005947:Glucose; D006442:Glycated Hemoglobin; D006593:Hexokinase; C472074:HK1 protein, human