Genetic variant in HK1 is associated with a proanemic state and A1C but not other glycemic control-related traits.
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.
Bonnefond
Amélie
A
CNRS-UMR-8090, Institute of Biology and Lille 2 University, Pasteur Institute, Lille, France.
Vaxillaire
Martine
M
Labrune
Yann
Y
Lecoeur
Cécile
C
Chèvre
Jean-Claude
JC
Bouatia-Naji
Nabila
N
Cauchi
Stéphane
S
Balkau
Beverley
B
Marre
Michel
M
Tichet
Jean
J
Riveline
Jean-Pierre
JP
Hadjadj
Samy
S
Gallois
Yves
Y
Czernichow
Sébastien
S
Hercberg
Serge
S
Kaakinen
Marika
M
Wiesner
Susanne
S
Charpentier
Guillaume
G
Lévy-Marchal
Claire
C
Elliott
Paul
P
Jarvelin
Marjo-Riitta
MR
Horber
Fritz
F
Dina
Christian
C
Pedersen
Oluf
O
Sladek
Robert
R
Meyre
David
D
Froguel
Philippe
P
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
D001786:Blood Glucose; D005947:Glucose; D006442:Glycated Hemoglobin; D006593:Hexokinase; C472074:HK1 protein, human