迄今,最大型的II型糖尿病(T2D)遗传学研究已确定与常见代谢性疾病风险相关的新基因变异。一个研究多种族人群的国际科学协会,发现可指出开发更有效T2D药物的生物学靶标的基因。
多种基因和环境因素与T2D相互作用,这影响了全世界近3亿人。大部分基因变体还未被发现。
研究在多民族中鉴定基因变异
"科学家已确定约只有10%的基因变体促成T2D,且大多数以前的研究一直以欧洲血统的人为基础",此研究的通讯作者、费城儿童医院应用基因组中心的Brendan J. Keating博士说。这项国际性研究发现,许多与T2D相关的基因变体与多个族群重叠。目前的此项研究包括非裔美国人、西班牙裔、亚洲和欧洲血统的受试者。
研究最近在线发表在期刊American Journal of Human Genetics上。这项研究的另一个高级合著者是Richa Saxena博士,他来自马萨诸塞州总医院和哈佛医学院。
此研究协会开展了一项多种族的39项现存研究的meta-分析,包含超过17000例T2D患者与70000名对照受试者。这个大规模遗传筛查使用了一种定制的基因分析工具来检查2100个与心血管和代谢功能相关的已知基因上的50000个遗传变异。
研究人员确定了4个与T2D相关的以前未知的基因变异,在已知T2D基因中发现了6个新的独立遗传标志,并验证了16个先前已被报道的T2D相关变体。发现近40个总基因变异提高或降低T2D的风险。Keating说,目前研究的大量多种族样本中的全基因组筛选方法在发现与多种族人群相关的更多的糖尿病基因变异应该是有效的。
关于II型糖尿病
T2D,以前被称为非胰岛素依赖型或成年型糖尿病,占所有糖尿病的90%至95%。它是一种慢性代谢性疾病,在这个疾病中机体产生足够的胰岛素或变得不能正确处理它自身产生的胰岛素。而通常随着年龄增长而提高的T2D风险,这种疾病在儿童和青少年中已大大增加。
"当我们继续寻找与T2D相关的更多基因,我们期望其特异生物学功能的进一步调查研究将指导研究人员向预防和治疗这种疾病的新疗法开展研究", Keating说。
资助这一研究的2个主要团体是美国国立卫生研究院的国立心、肺和血液研究所通过候选基因关联资源(CARe)研究和英国心脏基金会。许多其他的资金来源支持了为这个meta-分析提供数据的39个研究。费城儿童医院的其他高级调查员有:应用基因组学中心主任Hakon Hakonarson博士与此中心副主任Struan F.A. Grant博士。(生物谷bioon.com)
doi:10.1016/j.ajhg.2011.12.022
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Large-Scale Gene-Centric Meta-Analysis across 39 studies Identifies Type 2 Diabetes Loci
Richa Saxena, Clara C. Elbers, Yiran Guo, Inga Peter, Tom R. Gaunt,Jessica L. Mega, Matthew B. Lanktree, Archana Tare, Berta Almoguera Castillo, Yun R. Li,Toby Johnson, Marcel Bruinenberg, Diane Gilbert-Diamond, Ramakrishnan Rajagopalan,Benjamin F. Voight, Ashok Balasubramanyam, John Barnard, Florianne Bauer, Jens Baumert, Tushar Bhangale,
Bernhard O. Böhm, Peter S. Braund, Paul R. Burton, Hareesh R. Chandrupatla, Robert Clarke, Rhonda M. Cooper-DeHoff, Errol D. Crook, George Davey-Smith, Ian N. Day, Anthonius de Boer, Mark C.H. de Groot, Fotios Drenos, Jane Ferguson,Caroline S. Fox, Clement E. Furlong, Quince Gibson, Christian Gieger, Lisa A. Gilhuijs-Pederson, Joseph T. Glessner, Anuj Goel, Yan Gong, Struan F.A. Grant, Diederick E. Grobbee,Claire Hastie, Steve E. Humphries, Cecilia E. Kim, Mika Kivimaki, Marcus Kleber,Christa Meisinger, Meena Kumari, Taimour Y. Langaee, Debbie A. Lawlor, Mingyao Li,Maximilian T. Lobmeyer, Anke-Hilse Maitland-van der Zee, Matthijs F.L. Meijs, Cliona M. Molony, David A. Morrow, Gurunathan Murugesan, Solomon K. Musani, Christopher P. Nelson, Stephen J. Newhouse, Jeffery R. O'Connell, Sandosh Padmanabhan, Jutta Palmen, Sanjey R. Patel, Carl J. Pepine, Mary Pettinger, Thomas S. Price, Suzanne Rafelt, Jane Ranchalis, Asif Rasheed, Elisabeth Rosenthal, Ingo Ruczinski, Sonia Shah, Haiqing Shen, Günther Silbernagel, Erin N. Smith, Annemieke W.M. Spijkerman, Alice Stanton,Michael W. Steffes, Barbara Thorand, Mieke Trip, Pim van der Harst, Daphne L. van der A,Erik P.A. van Iperen, Jessica van Setten, Jana V. van Vliet-Ostaptchouk, Niek Verweij,Bruce H.R. Wolffenbuttel, Taylor Young, M. Hadi Zafarmand, Joseph M. Zmuda, the Look AHEAD Research Group, DIAGRAM consortium, Michael Boehnke, David Altshuler, Mark McCarthy, W.H. Linda Kao, James S. Pankow, Thomas P. Cappola, Mark Caulfield,Anna Dominiczak, Denis C. Shields, Deepak Bhatt, Li Zhang, Sean P. Curtis, John Danesh, Juan P. Casas, Yvonne T. van der Schouw, N. Charlotte Onland-Moret, Pieter A. Doevendans, Gerald W. Dorn II, Martin Farrall, Garret A. FitzGerald, Anders Hamsten,Robert Hegele, Aroon D. Hingorani, Marten H. Hofker, Gordon S. Huggins, Thomas Illig,Gail P. Jarvik, Julie A. Johnson, Olaf H. Klungel, William C. Knowler, Wolfgang Koenig, Winfried März, James B. Meigs, Olle Melander, Patricia B. Munroe, Braxton D. Mitchell, Susan J. Bielinski, Daniel J. Rader, Muredach P. Reilly, Stephen S. Rich, Jerome I. Rotter, Danish Saleheen, Nilesh J. Samani, Eric E. Schadt, Alan R. Shuldiner, Roy Silverstein, Kandice Kottke-Marchant, Philippa J. Talmud, Hugh Watkins, Folkert Asselbergs, Paul I.W. de Bakker, Jeanne McCaffery, Cisca Wijmenga, Marc S. Sabatine, James G. Wilson, Alex Reiner, Donald W. Bowden, Hakon Hakonarson, David S. Siscovick, Brendan J. Keating
Abstract To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ?50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ?2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10?9) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10?6). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10?7) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10?15). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10?8). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.