迄今,，最大型的II型糖尿病(T2D)遺傳學(xué)研究已確定與常見(jiàn)代謝性疾病風(fēng)險(xiǎn)相關(guān)的新基因變異,。一個(gè)研究多種族人群的國(guó)際科學(xué)協(xié)會(huì),，發(fā)現(xiàn)可指出開(kāi)發(fā)更有效T2D藥物的生物學(xué)靶標(biāo)的基因,。
多種基因和環(huán)境因素與T2D相互作用，這影響了全世界近3億人,。大部分基因變體還未被發(fā)現(xiàn),。
研究在多民族中鑒定基因變異
"科學(xué)家已確定約只有10%的基因變體促成T2D，且大多數(shù)以前的研究一直以歐洲血統(tǒng)的人為基礎(chǔ)",，此研究的通訊作者,、費(fèi)城兒童醫(yī)院應(yīng)用基因組中心的Brendan J. Keating博士說(shuō)。這項(xiàng)國(guó)際性研究發(fā)現(xiàn),，許多與T2D相關(guān)的基因變體與多個(gè)族群重疊,。目前的此項(xiàng)研究包括非裔美國(guó)人、西班牙裔,、亞洲和歐洲血統(tǒng)的受試者,。
研究最近在線發(fā)表在期刊American Journal of Human Genetics上。這項(xiàng)研究的另一個(gè)高級(jí)合著者是Richa Saxena博士,，他來(lái)自馬薩諸塞州總醫(yī)院和哈佛醫(yī)學(xué)院,。
此研究協(xié)會(huì)開(kāi)展了一項(xiàng)多種族的39項(xiàng)現(xiàn)存研究的meta-分析，包含超過(guò)17000例T2D患者與70000名對(duì)照受試者,。這個(gè)大規(guī)模遺傳篩查使用了一種定制的基因分析工具來(lái)檢查2100個(gè)與心血管和代謝功能相關(guān)的已知基因上的50000個(gè)遺傳變異,。
研究人員確定了4個(gè)與T2D相關(guān)的以前未知的基因變異,，在已知T2D基因中發(fā)現(xiàn)了6個(gè)新的獨(dú)立遺傳標(biāo)志,，并驗(yàn)證了16個(gè)先前已被報(bào)道的T2D相關(guān)變體。發(fā)現(xiàn)近40個(gè)總基因變異提高或降低T2D的風(fēng)險(xiǎn),。Keating說(shuō),，目前研究的大量多種族樣本中的全基因組篩選方法在發(fā)現(xiàn)與多種族人群相關(guān)的更多的糖尿病基因變異應(yīng)該是有效的。
關(guān)于II型糖尿病
T2D,，以前被稱為非胰島素依賴型或成年型糖尿病,，占所有糖尿病的90%至95%。它是一種慢性代謝性疾病,，在這個(gè)疾病中機(jī)體產(chǎn)生足夠的胰島素或變得不能正確處理它自身產(chǎn)生的胰島素,。而通常隨著年齡增長(zhǎng)而提高的T2D風(fēng)險(xiǎn)，這種疾病在兒童和青少年中已大大增加,。
"當(dāng)我們繼續(xù)尋找與T2D相關(guān)的更多基因,，我們期望其特異生物學(xué)功能的進(jìn)一步調(diào)查研究將指導(dǎo)研究人員向預(yù)防和治療這種疾病的新療法開(kāi)展研究"， Keating說(shuō),。
資助這一研究的2個(gè)主要團(tuán)體是美國(guó)國(guó)立衛(wèi)生研究院的國(guó)立心,、肺和血液研究所通過(guò)候選基因關(guān)聯(lián)資源(CARe)研究和英國(guó)心臟基金會(huì),。許多其他的資金來(lái)源支持了為這個(gè)meta-分析提供數(shù)據(jù)的39個(gè)研究。費(fèi)城兒童醫(yī)院的其他高級(jí)調(diào)查員有：應(yīng)用基因組學(xué)中心主任Hakon Hakonarson博士與此中心副主任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.
