Common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, and HHEX/IDE genes are associated with type 2 diabetes and impaired fasting glucose in a Chinese Han population.
Common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, and HHEX/IDE genes are associated with type 2 diabetes and impaired fasting glucose in a Chinese Han population.
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CDKAL1，CDKN2A/B，IGF2BP2，SLC30A8和HHEX/IDE基因中的常见变体与中国han种群中的2型糖尿病和禁食葡萄糖有关。
作者：
Wu, Ying;Li, Huaixing;Loos, Ruth J. F.;Yu, Zhijie;Ye, Xingwang;Chen, Lihua;Pan, An;Hu, Frank B.;Lin, Xu
目的：全基因组关联研究已经确定了CDKAL1、CDKN2A/B、IGF2BP2、SLC30A8、HHEX/IDE、EXT2和LOC387761位点的常见变异，这些位点显著增加了2型糖尿病的风险。我们的目的是在基于人群的中国汉族队列中重复这些观察结果，并检查这些变异与2型糖尿病和糖尿病相关表型的关联。研究设计和方法：我们在3210名无血缘关系的中国汉族中对17个单核苷酸多态性（snp）进行了基因分型，其中包括424名2型糖尿病患者，878名空腹血糖受损（IFG）患者和1908名正常空腹血糖患者。结果：我们证实了2型糖尿病与CDKAL1（比值比1.49 [95% CI 1.27-1.75]; P = 8.91 × 10−7）和CDKN2A/B（比值比1.31 [1.12-1.54];P = 1.0 × 10−3）附近变异之间的关联。我们观察到IGF2BP2 snp （1.17 [1.03-1.32], P = 0.014）和SLC30A8 snp （1.12 [1.01-1.25], P = 0.033）与合并IFG/ 2型糖尿病显著相关。CDKAL1、IGF2BP2和SLC30A8中的snp也与β细胞功能受损有关，通过稳态模型评估β细胞功能。当合并时，CDKAL1-rs9465871、CDKN2A/B-rs10811661、IGF2BP2-rs4402960和SLC30A8-rs13266634每增加一个风险等位基因，2型糖尿病的风险增加1.24倍（P = 2.85 × 10−7），IFG/ 2型糖尿病的风险增加1.21倍（P = 6.31 × 10−11）。EXT2或LOC387761的snp均未显示与2型糖尿病或IFG有显著关联。HHEX/IDE snp与2型糖尿病仅在上海个体中有显著相关性（P < 0.013），而在北京个体中无显著相关性（P < 0.33）。结论：我们的研究结果表明，在中国汉族中，CDKAL1、CDKN2A/B、IGF2BP2和SLC30A8基因座的常见变异可能通过β细胞功能障碍介导，独立或附加地促进2型糖尿病风险。
OBJECTIVE— Genome-wide association studies have identified common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, HHEX/IDE, EXT2, and LOC387761 loci that significantly increase the risk of type 2 diabetes. We aimed to replicate these observations in a population-based cohort of Chinese Hans and examine the associations of these variants with type 2 diabetes and diabetes-related phenotypes. RESEARCH DESIGN AND METHODS— We genotyped 17 single nucleotide polymorhisms (SNPs) in 3,210 unrelated Chinese Hans, including 424 participants with type 2 diabetes, 878 with impaired fasting glucose (IFG), and 1,908 with normal fasting glucose. RESULTS— We confirmed the associations between type 2 diabetes and variants near CDKAL1 (odds ratio 1.49 [95% CI 1.27–1.75]; P = 8.91 × 10−7) and CDKN2A/B (1.31 [1.12–1.54]; P = 1.0 × 10−3). We observed significant association of SNPs in IGF2BP2 (1.17 [1.03–1.32]; P = 0.014) and SLC30A8 (1.12 [1.01–1.25]; P = 0.033) with combined IFG/type 2 diabetes. The SNPs in CDKAL1, IGF2BP2, and SLC30A8 were also associated with impaired β-cell function estimated by homeostasis model assessment of β-cell function. When combined, each additional risk allele from CDKAL1-rs9465871, CDKN2A/B-rs10811661, IGF2BP2-rs4402960, and SLC30A8-rs13266634 increased the risk for type 2 diabetes by 1.24-fold (P = 2.85 × 10−7) or for combined IFG/type 2 diabetes by 1.21-fold (P = 6.31 × 10−11). None of the SNPs in EXT2 or LOC387761 exhibited significant association with type 2 diabetes or IFG. Significant association was observed between the HHEX/IDE SNPs and type 2 diabetes in individuals from Shanghai only (P < 0.013) but not in those from Beijing (P > 0.33). CONCLUSIONS— Our results indicate that in Chinese Hans, common variants in CDKAL1, CDKN2A/B, IGF2BP2, and SLC30A8 loci independently or additively contribute to type 2 diabetes risk, likely mediated through β-cell dysfunction.
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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：
168.9
作者：
Ioannidis, JPA;Trikalinos, TA;Contopoulos-Ioannidis, DG
通讯作者：
Contopoulos-Ioannidis, DG
影响因子：
7.7
作者：
Palmer, Nicholette D.;Goodarzi, Mark O.;Bowden, Donald W.
通讯作者：
Bowden, Donald W.
影响因子：
7.7
作者：
Mori, Shintaro;Tanaka, Yasushi;Maeda, Shiro
通讯作者：
Maeda, Shiro
影响因子：
3.5
作者：
Zeggini, E
通讯作者：
Zeggini, E