Genetic variant in HK1 is associated with a proanemic state and A1C but not other glycemic control-related traits.
Genetic variant in HK1 is associated with a proanemic state and A1C but not other glycemic control-related traits.
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作者：
Bonnefond A;Vaxillaire M;Labrune Y;Lecoeur C;Chèvre JC;Bouatia-Naji N;Cauchi S;Balkau B;Marre M;Tichet J;Riveline JP;Hadjadj S;Gallois Y;Czernichow S;Hercberg S;Kaakinen M;Wiesner S;Charpentier G;Lévy-Marchal C;Elliott P;Jarvelin MR;Horber F;Dina C;Pedersen O;Sladek R;Meyre D;Froguel P
糖化血红蛋白被广泛认为是监测有效血糖水平的金标准。最近，一项全基因组关联研究报道了A1C与HK1（编码己糖激酶1）中的rs7072268之间的关联，该酶催化糖酵解的第一步。红细胞（红细胞[rbc]）中HK1缺乏导致人类和小鼠严重的非球型溶血性贫血。在6,953名非糖尿病欧洲参与者中评估了rs7072268对A1C和红细胞相关性状的贡献。我们还分析了5229名欧洲非糖尿病患者（未测量A1C）和1924名糖尿病患者与血液学特征的关系。分析了18694名非糖尿病欧洲人的糖化血红蛋白以外的血糖控制相关标志物。一项2型糖尿病病例对照研究包括7,447名法国糖尿病患者。我们的研究证实rs7072268-T等位基因与A1C升高有很强的相关性（β = 0.029%; P = 2.22 × 10−7）。令人惊讶的是，尽管有足够的研究能力，rs7072268显示与任何其他葡萄糖控制标志物（空腹和ogtt后2小时相关参数，n = 18,694）没有关联。相反，rs7072268-T等位基因降低血红蛋白水平（n = 13,416; β = - 0.054 g/dl; P = 3.74 × 10 - 6）和红细胞压积（n = 11,492; β = - 0.13%; P = 2.26 × 10 - 4），提示其具有促贫血作用。T等位基因也增加贫血的风险（836例；优势比1.13;P = 0.018）。HK1变异虽然与糖化血红蛋白密切相关，但似乎与血糖控制无关。由于HK1 rs7072268与血红蛋白水平降低有关，有利于贫血，我们认为HK1可能通过其贫血作用或对红细胞葡萄糖代谢的影响来影响A1C水平。这些发现可能对2型糖尿病的诊断和临床管理有意义，因为贫血是糖尿病状态的常见并发症。
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. 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. Our study confirms a strong association between the rs7072268–T allele and increased A1C (β = 0.029%; P = 2.22 × 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; β = −0.054 g/dl; P = 3.74 × 10−6) and hematocrit (n = 11,492; β = −0.13%; P = 2.26 × 10−4), suggesting a proanemic effect. The T allele also increases risk for anemia (836 cases; odds ratio 1.13; P = 0.018). 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.