Novel association of HK1 with glycated hemoglobin in a non-diabetic population: a genome-wide evaluation of 14,618 participants in the Women's Genome Health Study.
Novel association of HK1 with glycated hemoglobin in a non-diabetic population: a genome-wide evaluation of 14,618 participants in the Women's Genome Health Study.
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HK1与糖化血红蛋白在非糖尿病人群中的新型关联：对女性基因组健康研究中14,618名参与者的全基因组评估。
DOI：
10.1371/journal.pgen.1000312
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发表时间：
2008-12
期刊：
影响因子：
4.5
通讯作者：
Ridker PM
中科院分区：
文献类型：
--
作者：
Paré G;Chasman DI;Parker AN;Nathan DM;Miletich JP;Zee RY;Ridker PM
2型糖尿病是发病率和死亡率的主要原因。虽然已经发现遗传变异会影响2型糖尿病的风险，但相对较少的研究集中在与糖化血红蛋白相关的基因上，糖化血红蛋白是前8-12周平均血糖浓度的指标。流行病学研究和随机临床试验证明了糖化血红蛋白水平与糖尿病长期并发症的发生之间的关系；此外，亚糖尿病范围内较高的糖化血红蛋白水平已被证明可以预测2型糖尿病和心血管疾病的风险。为了检查糖化血红蛋白水平的共同遗传决定因素，我们进行了一项全基因组关联研究，评估了14,618名明显健康的高加索女性的337,343个snp。结果表明，糖化血红蛋白水平与GCK （rs730497; P = 2.8×10−12）、SLC30A8 （rs13266634; P = 9.8×10−8）、G6PC2 （rs1402837; P = 6.8×10−10）和HK1 （rs7072268; P = 6.4×10−9）位点的遗传变异相关。虽然GCK、SLC30A8和G6PC2位点的关联是确定的，但HK1位点的发现是新的。我们能够在另外455名非糖尿病男性和女性的独立验证样本中复制这种新的关联。HK1编码己糖激酶，这是糖酵解的第一步，可能是控制葡萄糖代谢的候选者。这种观察到的糖化血红蛋白水平和HK1多态性之间的遗传关联为进一步研究HK1在血红蛋白糖化、葡萄糖代谢和糖尿病中的作用铺平了道路。2型糖尿病是发达国家和发展中国家发病率和死亡率的主要原因。由于糖尿病的主要代谢特征是血糖浓度升高，我们试图揭示糖化血红蛋白的遗传决定因素，糖化血红蛋白是前8-12周平均血糖浓度的指标。利用新技术使我们能够在全基因组的基础上询问遗传变异，我们发现GCK、SLC30A8、G6PC2和HK1基因的变异是糖化血红蛋白浓度的重要决定因素。虽然与GCK、SLC30A8和G6PC2基因的关联已经在糖尿病和血糖浓度的遗传研究中被发现，但在HK1的发现是新的。HK1编码己糖激酶，负责葡萄糖利用的第一步，可能是控制葡萄糖代谢的候选者。这种观察到的糖化血红蛋白水平和HK1遗传变异之间的遗传关联为进一步研究HK1在葡萄糖代谢和糖尿病中的作用铺平了道路。
Type 2 diabetes is a leading cause of morbidity and mortality. While genetic variants have been found to influence the risk of type 2 diabetes mellitus, relatively few studies have focused on genes associated with glycated hemoglobin, an index of the mean blood glucose concentration of the preceding 8–12 weeks. Epidemiologic studies and randomized clinical trials have documented the relationship between glycated hemoglobin levels and the development of long-term complications in diabetes; moreover, higher glycated hemoglobin levels in the subdiabetic range have been shown to predict type 2 diabetes risk and cardiovascular disease. To examine the common genetic determinants of glycated hemoglobin levels, we performed a genome-wide association study that evaluated 337,343 SNPs in 14,618 apparently healthy Caucasian women. The results show that glycated hemoglobin levels are associated with genetic variation at the GCK (rs730497; P = 2.8×10−12), SLC30A8 (rs13266634; P = 9.8×10−8), G6PC2 (rs1402837; P = 6.8×10−10), and HK1 (rs7072268; P = 6.4×10−9) loci. While associations at the GCK, SLC30A8, and G6PC2 loci are confirmatory, the findings at HK1 are novel. We were able to replicate this novel association in an independent validation sample of 455 additional non-diabetic men and women. HK1 encodes the enzyme hexokinase, the first step in glycolysis and a likely candidate for the control of glucose metabolism. This observed genetic association between glycated hemoglobin levels and HK1 polymorphisms paves the way for further studies of the role of HK1 in hemoglobin glycation, glucose metabolism, and diabetes. Type 2 diabetes is a leading cause of morbidity and mortality in both the developed and developing world. Because the main metabolic characteristic of diabetes is increased blood glucose concentration, we sought to uncover the genetic determinants of glycated hemoglobin, an index of the mean blood glucose concentration of the preceding 8–12 weeks. Taking advantage of new technologies allowing us to interrogate genetic variation on a whole-genome basis, we found that variations in the GCK, SLC30A8, G6PC2, and HK1 genes are important determinants of glycated hemoglobin concentrations. While associations with the GCK, SLC30A8, and G6PC2 genes have previously been identified in genetic studies of diabetes and blood glucose concentration, the findings at HK1 are novel. HK1 encodes the enzyme hexokinase, responsible for the first step in glucose utilization and a likely candidate for the control of glucose metabolism. This observed genetic association between glycated hemoglobin levels and HK1 genetic variants paves the way for further studies of the role of HK1 in glucose metabolism and diabetes.
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影响因子：
8.2
作者：
Nathan DM;Turgeon H;Regan S
通讯作者：
Regan S
影响因子：
64.8
作者：
Frazer, Kelly A.;Ballinger, Dennis G.;Cox, David R.;Hinds, David A.;Stuve, Laura L.;Gibbs, Richard A.;Belmont, John W.;Boudreau, Andrew;Hardenbol, Paul;Leal, Suzanne M.;Pasternak, Shiran;Wheeler, David A.;Willis, Thomas D.;Yu, Fuli;Yang, Huanming;Zeng, Changqing;Gao, Yang;Hu, Haoran;Hu, Weitao;Li, Chaohua;Lin, Wei;Liu, Siqi;Pan, Hao;Tang, Xiaoli;Wang, Jian;Wang, Wei;Yu, Jun;Zhang, Bo;Zhang, Qingrun;Zhao, Hongbin;Zhao, Hui;Zhou, Jun;Gabriel, Stacey B.;Barry, Rachel;Blumenstiel, Brendan;Camargo, Amy;Defelice, Matthew;Faggart, Maura;Goyette, Mary;Gupta, Supriya;Moore, Jamie;Nguyen, Huy;Onofrio, Robert C.;Parkin, Melissa;Roy, Jessica;Stahl, Erich;Winchester, Ellen;Ziaugra, Liuda;Altshuler, David;Shen, Yan;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
影响因子：
7.7
作者：
Freathy RM;Timpson NJ;Lawlor DA;Pouta A;Ben-Shlomo Y;Ruokonen A;Ebrahim S;Shields B;Zeggini E;Weedon MN;Lindgren CM;Lango H;Melzer D;Ferrucci L;Paolisso G;Neville MJ;Karpe F;Palmer CN;Morris AD;Elliott P;Jarvelin MR;Smith GD;McCarthy MI;Hattersley AT;Frayling TM
通讯作者：
Frayling TM
影响因子：
56.9
作者：
McVean, GAT;Myers, SR;Donnelly, P
通讯作者：
Donnelly, P
影响因子：
15.8
作者：
Lawlor DA;Fraser A;Ebrahim S;Smith GD
通讯作者：
Smith GD