From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus.
From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus.
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作者：
近期的全基因组关联研究（GWAS）已确定1号染色体1p13位点与人类血清低密度脂蛋白胆固醇（LDL - C）和心肌梗死（MI）密切相关。在此，我们通过对人类队列以及人源肝细胞的一系列研究表明，1p13位点上常见的非编码多态性rs12740374产生了一个C/EBP转录因子结合位点，并改变了SORT1基因在肝脏中的表达。通过在小鼠肝脏中进行小干扰RNA（siRNA）敲低和病毒过表达实验，我们证明Sort1通过调节肝脏极低密度脂蛋白（VLDL）的分泌来改变血浆LDL - C和VLDL颗粒水平。因此，我们为脂蛋白代谢的一种新的调控途径提供了功能证据，并表明对该途径的调节可能改变人类心肌梗死的风险。我们还证明了由GWAS鉴定出的常见非编码DNA变异可直接导致临床表型的产生。
Recent genome-wide association studies (GWASs) have identified a locus on chromosome 1p13 as strongly associated with both serum low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) in humans. Here we show through a series of studies in human cohorts and human-derived hepatocytes that a common noncoding polymorphism at the 1p13 locus, rs12740374, creates a C/EBP transcription factor binding site and alters the hepatic expression of the SORT1 gene. With siRNA knockdown and viral overexpression in mouse liver, we demonstrate that Sort1 alters plasma LDL-C and very low-density lipoprotein (VLDL) particle levels by modulating hepatic VLDL secretion. Thus, we provide functional evidence for a novel regulatory pathway for lipoprotein metabolism and suggest that modulation of this pathway may alter risk for MI in humans. We also demonstrate that common noncoding DNA variants identified by GWASs can directly contribute to clinical phenotypes.
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DOI：
10.1056/nejmoa072366
发表时间：
2007-08-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Samani NJ;Erdmann J;Hall AS;Hengstenberg C;Mangino M;Mayer B;Dixon RJ;Meitinger T;Braund P;Wichmann HE;Barrett JH;König IR;Stevens SE;Szymczak S;Tregouet DA;Iles MM;Pahlke F;Pollard H;Lieb W;Cambien F;Fischer M;Ouwehand W;Blankenberg S;Balmforth AJ;Baessler A;Ball SG;Strom TM;Braenne I;Gieger C;Deloukas P;Tobin MD;Ziegler A;Thompson JR;Schunkert H;WTCCC and the Cardiogenics Consortium
通讯作者：
WTCCC and the Cardiogenics Consortium
影响因子：
9.8
作者：
Schadt EE;Molony C;Chudin E;Hao K;Yang X;Lum PY;Kasarskis A;Zhang B;Wang S;Suver C;Zhu J;Millstein J;Sieberts S;Lamb J;GuhaThakurta D;Derry J;Storey JD;Avila-Campillo I;Kruger MJ;Johnson JM;Rohl CA;van Nas A;Mehrabian M;Drake TA;Lusis AJ;Smith RC;Guengerich FP;Strom SC;Schuetz E;Rushmore TH;Ulrich R
通讯作者：
Ulrich R
与人类血液低密度脂蛋白胆固醇、高密度脂蛋白胆固醇或甘油三酯相关的六个新位点。
影响因子：
30.8
作者：
Kathiresan, Sekar;Melander, Olle;Guiducci, Candace;Surti, Aarti;Burtt, Noel P.;Rieder, Mark J.;Cooper, Gregory M.;Roos, Charlotta;Voight, Benjamin F.;Havulinna, Aki S.;Wahlstrand, Bjorn;Hedner, Thomas;Corella, Dolores;Tai, E. Shyong;Ordovas, Jose M.;Berglund, Goran;Vartiainen, Erkki;Jousilahti, Pekka;Hedblad, Bo;Taskinen, Marja-Riitta;Newton-Cheh, Christopher;Salomaa, Veikko;Peltonen, Leena;Groop, Leif;Altshuler, David M.;Orho-Melander, Marju
通讯作者：
Orho-Melander, Marju
影响因子：
4.8
作者：
Olive, M;Williams, SC;Vinson, C
通讯作者：
Vinson, C
影响因子：
64.8
作者：
Soutschek, J;Akinc, A;Vornlocher, HP
通讯作者：
Vornlocher, HP