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Biological, clinical and population relevance of 95 loci for blood lipids.

ABSTRACT: 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 x 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.

SUBMITTER: Teslovich TM

PROVIDER: S-EPMC3039276 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Biological, clinical and population relevance of 95 loci for blood lipids.

Teslovich Tanya M TM Musunuru Kiran K Smith Albert V AV Edmondson Andrew C AC Stylianou Ioannis M IM Koseki Masahiro M Pirruccello James P JP Ripatti Samuli S Chasman Daniel I DI Willer Cristen J CJ Johansen Christopher T CT Fouchier Sigrid W SW Isaacs Aaron A Peloso Gina M GM Barbalic Maja M Ricketts Sally L SL Bis Joshua C JC Aulchenko Yurii S YS Thorleifsson Gudmar G Feitosa Mary F MF Chambers John J Orho-Melander Marju M Melander Olle O Johnson Toby T Li Xiaohui X Guo Xiuqing X Li Mingyao M Shin Cho Yoon Y Jin Go Min M Jin Kim Young Y Lee Jong-Young JY Park Taesung T Kim Kyunga K Sim Xueling X Twee-Hee Ong Rick R Croteau-Chonka Damien C DC Lange Leslie A LA Smith Joshua D JD Song Kijoung K Hua Zhao Jing J Yuan Xin X Luan Jian'an J Lamina Claudia C Ziegler Andreas A Zhang Weihua W Zee Robert Y L RY Wright Alan F AF Witteman Jacqueline C M JC Wilson James F JF Willemsen Gonneke G Wichmann H-Erich HE Whitfield John B JB Waterworth Dawn M DM Wareham Nicholas J NJ Waeber Gérard G Vollenweider Peter P Voight Benjamin F BF Vitart Veronique V Uitterlinden Andre G AG Uda Manuela M Tuomilehto Jaakko J Thompson John R JR Tanaka Toshiko T Surakka Ida I Stringham Heather M HM Spector Tim D TD Soranzo Nicole N Smit Johannes H JH Sinisalo Juha J Silander Kaisa K Sijbrands Eric J G EJ Scuteri Angelo A Scott James J Schlessinger David D Sanna Serena S Salomaa Veikko V Saharinen Juha J Sabatti Chiara C Ruokonen Aimo A Rudan Igor I Rose Lynda M LM Roberts Robert R Rieder Mark M Psaty Bruce M BM Pramstaller Peter P PP Pichler Irene I Perola Markus M Penninx Brenda W J H BW Pedersen Nancy L NL Pattaro Cristian C Parker Alex N AN Pare Guillaume G Oostra Ben A BA O'Donnell Christopher J CJ Nieminen Markku S MS Nickerson Deborah A DA Montgomery Grant W GW Meitinger Thomas T McPherson Ruth R McCarthy Mark I MI McArdle Wendy W Masson David D Martin Nicholas G NG Marroni Fabio F Mangino Massimo M Magnusson Patrik K E PK Lucas Gavin G Luben Robert R Loos Ruth J F RJ Lokki Marja-Liisa ML Lettre Guillaume G Langenberg Claudia C Launer Lenore J LJ Lakatta Edward G EG Laaksonen Reijo R Kyvik Kirsten O KO Kronenberg Florian F König Inke R IR Khaw Kay-Tee KT Kaprio Jaakko J Kaplan Lee M LM Johansson Asa A Jarvelin Marjo-Riitta MR Janssens A Cecile J W AC Ingelsson Erik E Igl Wilmar W Kees Hovingh G G Hottenga Jouke-Jan JJ Hofman Albert A Hicks Andrew A AA Hengstenberg Christian C Heid Iris M IM Hayward Caroline C Havulinna Aki S AS Hastie Nicholas D ND Harris Tamara B TB Haritunians Talin T Hall Alistair S AS Gyllensten Ulf U Guiducci Candace C Groop Leif C LC Gonzalez Elena E Gieger Christian C Freimer Nelson B NB Ferrucci Luigi L Erdmann Jeanette J Elliott Paul P Ejebe Kenechi G KG Döring Angela A Dominiczak Anna F AF Demissie Serkalem S Deloukas Panagiotis P de Geus Eco J C EJ de Faire Ulf U Crawford Gabriel G Collins Francis S FS Chen Yii-der I YD Caulfield Mark J MJ Campbell Harry H Burtt Noel P NP Bonnycastle Lori L LL Boomsma Dorret I DI Boekholdt S Matthijs SM Bergman Richard N RN Barroso Inês I Bandinelli Stefania S Ballantyne Christie M CM Assimes Themistocles L TL Quertermous Thomas T Altshuler David D Seielstad Mark M Wong Tien Y TY Tai E-Shyong ES Feranil Alan B AB Kuzawa Christopher W CW Adair Linda S LS Taylor Herman A HA Borecki Ingrid B IB Gabriel Stacey B SB Wilson James G JG Holm Hilma H Thorsteinsdottir Unnur U Gudnason Vilmundur V Krauss Ronald M RM Mohlke Karen L KL Ordovas Jose M JM Munroe Patricia B PB Kooner Jaspal S JS Tall Alan R AR Hegele Robert A RA Kastelein John J P JJ Schadt Eric E EE Rotter Jerome I JI Boerwinkle Eric E Strachan David P DP Mooser Vincent V Stefansson Kari K Reilly Muredach P MP Samani Nilesh J NJ Schunkert Heribert H Cupples L Adrienne LA Sandhu Manjinder S MS Ridker Paul M PM Rader Daniel J DJ van Duijn Cornelia M CM Peltonen Leena L Abecasis Gonçalo R GR Boehnke Michael M Kathiresan Sekar S

Nature 20100801 7307

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 x 10(-8)), with 59 showing genome-wide significant association with ...[more]

PMID: 20686565

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Project description:Monounsaturated fatty acids (MUFA) are emerging health biomarkers, and in particular the ratio between palmitoleic acid (9cis-16:1) and palmitic acid (16:0) affords the delta-9 desaturase index that is increased in obesity. Recently, other positional and geometrical MUFA isomers belonging to the hexadecenoic family (C16 MUFA) were found in circulating lipids, such as sapienic acid (6cis-16:1), palmitelaidic acid (9trans-16:1) and 6trans-16:1. In this work we report: i) the identification of sapienic acid as component of human erythrocyte membrane phospholipids with significant increase in morbidly obese patients (n = 50) compared with age-matched lean controls (n = 50); and ii) the first comparison of erythrocyte membrane phospholipids (PL) and plasma cholesteryl esters (CE) in morbidly obese patients highlighting that some of their fatty acid levels have opposite trends: increases of both palmitic and sapienic acids with the decrease of linoleic acid (9cis,12cis-18:2, omega-6) in red blood cell (RBC) membrane PL were reversed in plasma CE, whereas the increase of palmitoleic acid was similar in both lipid species. Consequentially, desaturase enzymatic indexes gave different results, depending on the lipid class used for the fatty acid content. The fatty acid profile of morbidly obese subjects also showed significant increases of stearic acid (C18:0) and C20 omega-6, as well as decreases of oleic acid (9cis-18:1) and docosahexaenoic acid (C22:6 omega-3) as compared with lean healthy controls. Trans monounsaturated and polyunsaturated fatty acids were also measured and found significantly increased in both lipid classes of morbidly obese subjects. These results highlight the C16 MUFA isomers as emerging metabolic marker provided that the assignment of the double bond position and geometry is correctly performed, thus identifying the corresponding lipidomic pathway. Since RBC membrane PL and plasma CE have different fatty acid trends, caution must also be used in the choice of lipid species for the interpretation of lipidomic profiles.

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Biological, clinical and population relevance of 95 loci for blood lipids.

Publications

Biological, clinical and population relevance of 95 loci for blood lipids.

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