血液中的脂質(zhì)濃度是冠狀動(dòng)脈疾病的一大風(fēng)險(xiǎn)因素,，也是一個(gè)可以作為治療干預(yù)目標(biāo)的因素,。在對(duì)超過(guò)10萬(wàn)名歐洲裔人所做的一項(xiàng)全基因組關(guān)聯(lián)研究(GWAS)中,，研究人員識(shí)別出了與血脂相關(guān)的95個(gè)基因變異體,。所識(shí)別出的基因位點(diǎn)包括那些參與膽固醇代謝（降膽固醇藥物的已知作用目標(biāo)）的位點(diǎn),，以及對(duì)脂質(zhì)特征的正常變化有貢獻(xiàn)的新位點(diǎn)及對(duì)極端脂質(zhì)表現(xiàn)型有貢獻(xiàn)的新位點(diǎn),。在本項(xiàng)研究中被識(shí)別出與血液低密度脂蛋白膽固醇和冠狀動(dòng)脈疾病都相關(guān)的一個(gè)位點(diǎn)構(gòu)成本期Nature上另一篇論文的關(guān)注焦點(diǎn),。在染色體1p13上的這個(gè)位點(diǎn)被發(fā)現(xiàn)生成一個(gè)C/EBP轉(zhuǎn)錄因子結(jié)合點(diǎn)，并且改變肝臟中的SORT1基因的表達(dá),。
改變小鼠肝臟中SORT1的水平,，會(huì)改變血液脂蛋白水平，這一點(diǎn)有可能解釋為什么這個(gè)位點(diǎn)上的變化與心臟病相關(guān),。這一發(fā)現(xiàn)將“sortilin”通道識(shí)別為治療干預(yù)的一個(gè)可能目標(biāo),，并且說(shuō)明了GWAS結(jié)果何以可用作藥物目標(biāo)的一個(gè)生產(chǎn)線。（生物谷Bioon.com）
生物谷推薦原文出處：
Nature doi:10.1038/nature09270
Biological, clinical and population relevance of 95 loci for blood lipids
Tanya M. Teslovich,Kiran Musunuru,Albert V. Smith,Andrew C. Edmondson,Ioannis M. Stylianou,Masahiro Koseki,James P. Pirruccello,Samuli Ripatti,Daniel I. Chasman,Cristen J. Willer,Christopher T. Johansen,Sigrid W. Fouchier,Aaron Isaacs,Gina M. Peloso,Maja Barbalic,Sally L. Ricketts,Joshua C. Bis,Yurii S. Aulchenko,Gudmar Thorleifsson,Mary F. Feitosa,John Chambers,Marju Orho-Melander,Olle Melander,Toby Johnson,Xiaohui Li,et al
Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P?<?5?×?10?8), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes—GALNT2, PPP1R3B and TTC39B—with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
