近日,，國(guó)際糖尿病研究領(lǐng)域權(quán)威雜志Diabetes《糖尿病學(xué)》在線發(fā)表了迄今為止在中國(guó)漢族人群中所開(kāi)展的最大規(guī)模的2型糖尿病全基因組關(guān)聯(lián)研究，研究樣本達(dá)到4萬(wàn)3千多人,。該項(xiàng)目為科技部863計(jì)劃重點(diǎn)項(xiàng)目課題“中國(guó)漢族人群2型糖尿病全基因組關(guān)聯(lián)研究”,，由中科院生海生科院營(yíng)養(yǎng)所林旭研究員主持，合作單位包括：中科院系統(tǒng)生物學(xué)重點(diǎn)實(shí)驗(yàn)室,、北京大學(xué)人民醫(yī)院,、復(fù)旦大學(xué)附屬華山醫(yī)院,、中國(guó)醫(yī)學(xué)科學(xué)院基礎(chǔ)醫(yī)學(xué)研究所、中南大學(xué),、華中科技大學(xué),、上海交通大學(xué)附屬第六人民醫(yī)院和衛(wèi)生部北京老年醫(yī)學(xué)研究所。該項(xiàng)目相關(guān)研究結(jié)果還在亞洲（AGEN- T2D）和歐洲（DIAGRAM）兩個(gè)最大的全基因組關(guān)聯(lián)研究合作聯(lián)盟的人群數(shù)據(jù)中進(jìn)行了驗(yàn)證,。
目前,，已經(jīng)報(bào)道的2型糖尿病基因易感位點(diǎn)有近60個(gè)，但是絕大多數(shù)都是在歐美和其他亞洲人群中發(fā)現(xiàn)的,。我國(guó)近三十年來(lái)2型糖尿病的患病率逐年快速增加,，現(xiàn)有研究表明包括中國(guó)漢族人群在內(nèi)的東亞人群對(duì)2型糖尿病的易感性顯著高于西方人群，但是其遺傳學(xué)基礎(chǔ)尚不清楚,。
在本項(xiàng)目中,，上海生科院營(yíng)養(yǎng)科學(xué)研究所林旭研究團(tuán)隊(duì)的黎懷星研究員，博士研究生甘蔚和博士后魯玲等人發(fā)現(xiàn)：1）在已報(bào)道的58個(gè)2型糖尿病基因易感位點(diǎn)中,，有52個(gè)位點(diǎn)與2型糖尿病的關(guān)聯(lián)關(guān)系與本研究結(jié)果是一致的,，其中的23個(gè)位點(diǎn)被本研究證實(shí)為中國(guó)漢族人群的2型糖尿病基因易感位點(diǎn)；2）首次發(fā)現(xiàn)了兩個(gè)新的2型糖尿病基因易感位點(diǎn)RASGRP1-rs7403531和G蛋白偶聯(lián)受體激酶5 （GRK5）-rs10886471,，而且后者為東亞人群所特有,。這兩個(gè)基因易感位點(diǎn)所在基因區(qū)域的遺傳結(jié)構(gòu)在中國(guó)漢族人群和歐美人群之間存在著顯著的差異。RASGRP1-rs7403531位點(diǎn)的危險(xiǎn)等位基因還分別與糖化血紅蛋白水平的升高和β細(xì)胞功能指數(shù)（HOMA-B）的降低有顯著的關(guān)聯(lián)關(guān)系,；而GRK5-rs10886471位點(diǎn)的危險(xiǎn)等位基因則分別與血漿胰島素水平升高和胰島素敏感指數(shù)（HOMA-S）的降低有著顯著的關(guān)聯(lián)關(guān)系,。提示這兩個(gè)位點(diǎn)可能是分別通過(guò)損傷β細(xì)胞的功能和降低胰島素的敏感性來(lái)增加2型糖尿病發(fā)病風(fēng)險(xiǎn)的。進(jìn)一步研究發(fā)現(xiàn)還2型糖尿病患者外周血液中GRK5基因的mRNA水平顯著高于非糖尿病正常對(duì)照,，而且攜帶GRK5-rs10886471危險(xiǎn)等位基因的個(gè)體的GRK5-mRNA水平也要顯著高于不攜帶該等位基因的個(gè)體,。提示GRK5-rs10886471的危險(xiǎn)等位基因可能通過(guò)改變GRK5基因的轉(zhuǎn)錄水平進(jìn)而影響2型糖尿病發(fā)病風(fēng)險(xiǎn)。這些研究成果不僅為解析與2型糖尿病易感性相關(guān)的致病基因的結(jié)構(gòu),、基因功能和生物學(xué)機(jī)理,、種族間的差異奠定了堅(jiān)實(shí)的基礎(chǔ)；而且該項(xiàng)目所建立的人群數(shù)據(jù)庫(kù)和生物樣本庫(kù)也將為揭示調(diào)控致病基因的主要營(yíng)養(yǎng)和其它環(huán)境因素,，發(fā)展和建立對(duì)高危個(gè)體的預(yù)測(cè)模型提供了研究平臺(tái),。本項(xiàng)目的完成對(duì)建立符合中國(guó)人特點(diǎn)的2型糖尿病的早期風(fēng)險(xiǎn)評(píng)估體系和個(gè)體化干預(yù)策略，推動(dòng)我國(guó)在該領(lǐng)域的研究進(jìn)入國(guó)際前沿,，具有重要意義,。
該工作獲得了科技部863計(jì)劃重點(diǎn)項(xiàng)目，科技部973計(jì)劃,、自然科學(xué)基金委以及中科院等科研基金的資助,。（生物谷Bioon.com）
doi: 10.2337/db12-0454
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A Genome-Wide Association Study Identifies GRK5 and RASGRP1 as Type 2 Diabetes Loci in Chinese Hans
Huaixing Li, Wei Gan, Ling Lu, Xiao Dong, Xueyao Han, Cheng Hu, Zhen Yang, Liang Sun, Wei Bao, Pengtao Li, Meian He, Liangdan Sun, Yiqin Wang, Jingwen Zhu, Qianqian Ning, Yong Tang, Rong Zhang, Jie Wen5, Di Wang, Xilin Zhu, Kunquan Guo, Xianbo Zuo, Xiaohui Guo, Handong Yang, Xianghai Zhou, DIAGRAM Consortium, AGEN-T2D Consortium, Xuejun Zhang, Lu Qi, Ruth J.F. Loos, Frank B. Hu, Tangchun Wu, Ying Liu, Liegang Liu, Ze Yang, Renming Hu, Weiping Jia, Linong Ji, Yixue Li and Xu Lin
Substantial progress has been made in identification of type 2 diabetes (T2D) risk loci in the past few years, but our understanding of the genetic basis of T2D in ethnically diverse populations remains limited. We performed a genome-wide association study and a replication study in Chinese Hans comprising 8,569 T2D case subjects and 8,923 control subjects in total, from which 10 single nucleotide polymorphisms were selected for further follow-up in a de novo replication sample of 3,410 T2D case and 3,412 control subjects and an in silico replication sample of 6,952 T2D case and 11,865 control subjects. Besides confirming seven established T2D loci (CDKAL1, CDKN2A/B, KCNQ1, CDC123, GLIS3, HNF1B, and DUSP9) at genome-wide significance, we identified two novel T2D loci, including G-protein–coupled receptor kinase 5 (GRK5) (rs10886471: P = 7.1 × 10-9) and RASGRP1 (rs7403531: P = 3.9 × 10-9), of which the association signal at GRK5 seems to be specific to East Asians. In nondiabetic individuals, the T2D risk-increasing allele of RASGRP1-rs7403531 was also associated with higher HbA1c and lower homeostasis model assessment of β-cell function (P = 0.03 and 0.0209, respectively), whereas the T2D risk-increasing allele of GRK5-rs10886471 was also associated with higher fasting insulin (P = 0.0169) but not with fasting glucose. Our findings not only provide new insights into the pathophysiology of T2D, but may also shed light on the ethnic differences in T2D susceptibility.
