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Common variants associated with plasma triglycerides and risk for coronary artery disease.

ABSTRACT: Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

SUBMITTER: Do R

PROVIDER: S-EPMC3904346 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Common variants associated with plasma triglycerides and risk for coronary artery disease.

Do Ron R Willer Cristen J CJ Schmidt Ellen M EM Sengupta Sebanti S Gao Chi C Peloso Gina M GM Gustafsson Stefan S Kanoni Stavroula S Ganna Andrea A Chen Jin J Buchkovich Martin L ML Mora Samia S Beckmann Jacques S JS Bragg-Gresham Jennifer L JL Chang Hsing-Yi HY Demirkan Ayşe A Den Hertog Heleen M HM Donnelly Louise A LA Ehret Georg B GB Esko Tõnu T Feitosa Mary F MF Ferreira Teresa T Fischer Krista K Fontanillas Pierre P Fraser Ross M RM Freitag Daniel F DF Gurdasani Deepti D Heikkilä Kauko K Hyppönen Elina E Isaacs Aaron A Jackson Anne U AU Johansson Asa A Johnson Toby T Kaakinen Marika M Kettunen Johannes J Kleber Marcus E ME Li Xiaohui X Luan Jian'an J Lyytikäinen Leo-Pekka LP Magnusson Patrik K E PK Mangino Massimo M Mihailov Evelin E Montasser May E ME Müller-Nurasyid Martina M Nolte Ilja M IM O'Connell Jeffrey R JR Palmer Cameron D CD Perola Markus M Petersen Ann-Kristin AK Sanna Serena S Saxena Richa R Service Susan K SK Shah Sonia S Shungin Dmitry D Sidore Carlo C Song Ci C Strawbridge Rona J RJ Surakka Ida I Tanaka Toshiko T Teslovich Tanya M TM Thorleifsson Gudmar G Van den Herik Evita G EG Voight Benjamin F BF Volcik Kelly A KA Waite Lindsay L LL Wong Andrew A Wu Ying Y Zhang Weihua W Absher Devin D Asiki Gershim G Barroso Inês I Been Latonya F LF Bolton Jennifer L JL Bonnycastle Lori L LL Brambilla Paolo P Burnett Mary S MS Cesana Giancarlo G Dimitriou Maria M Doney Alex S F AS Döring Angela A Elliott Paul P Epstein Stephen E SE Eyjolfsson Gudmundur Ingi GI Gigante Bruna B Goodarzi Mark O MO Grallert Harald H Gravito Martha L ML Groves Christopher J CJ Hallmans Göran G Hartikainen Anna-Liisa AL Hayward Caroline C Hernandez Dena D Hicks Andrew A AA Holm Hilma H Hung Yi-Jen YJ Illig Thomas T Jones Michelle R MR Kaleebu Pontiano P Kastelein John J P JJ Khaw Kay-Tee KT Kim Eric E Klopp Norman N Komulainen Pirjo P Kumari Meena M Langenberg Claudia C Lehtimäki Terho T Lin Shih-Yi SY Lindström Jaana J Loos Ruth J F RJ Mach François F McArdle Wendy L WL Meisinger Christa C Mitchell Braxton D BD Müller Gabrielle G Nagaraja Ramaiah R Narisu Narisu N Nieminen Tuomo V M TV Nsubuga Rebecca N RN Olafsson Isleifur I Ong Ken K KK Palotie Aarno A Papamarkou Theodore T Pomilla Cristina C Pouta Anneli A Rader Daniel J DJ Reilly Muredach P MP Ridker Paul M PM Rivadeneira Fernando F Rudan Igor I Ruokonen Aimo A Samani Nilesh N Scharnagl Hubert H Seeley Janet J Silander Kaisa K Stančáková Alena A Stirrups Kathleen K Swift Amy J AJ Tiret Laurence L Uitterlinden Andre G AG van Pelt L Joost LJ Vedantam Sailaja S Wainwright Nicholas N Wijmenga Cisca C Wild Sarah H SH Willemsen Gonneke G Wilsgaard Tom T Wilson James F JF Young Elizabeth H EH Zhao Jing Hua JH Adair Linda S LS Arveiler Dominique D Assimes Themistocles L TL Bandinelli Stefania S Bennett Franklyn F Bochud Murielle M Boehm Bernhard O BO Boomsma Dorret I DI Borecki Ingrid B IB Bornstein Stefan R SR Bovet Pascal P Burnier Michel M Campbell Harry H Chakravarti Aravinda A Chambers John C JC Chen Yii-Der Ida YD Collins Francis S FS Cooper Richard S RS Danesh John J Dedoussis George G de Faire Ulf U Feranil Alan B AB Ferrières Jean J Ferrucci Luigi L Freimer Nelson B NB Gieger Christian C Groop Leif C LC Gudnason Vilmundur V Gyllensten Ulf U Hamsten Anders A Harris Tamara B TB Hingorani Aroon A Hirschhorn Joel N JN Hofman Albert A Hovingh G Kees GK Hsiung Chao Agnes CA Humphries Steve E SE Hunt Steven C SC Hveem Kristian K Iribarren Carlos C Järvelin Marjo-Riitta MR Jula Antti A Kähönen Mika M Kaprio Jaakko J Kesäniemi Antero A Kivimaki Mika M Kooner Jaspal S JS Koudstaal Peter J PJ Krauss Ronald M RM Kuh Diana D Kuusisto Johanna J Kyvik Kirsten O KO Laakso Markku M Lakka Timo A TA Lind Lars L Lindgren Cecilia M CM Martin Nicholas G NG März Winfried W McCarthy Mark I MI McKenzie Colin A CA Meneton Pierre P Metspalu Andres A Moilanen Leena L Morris Andrew D AD Munroe Patricia B PB Njølstad Inger I Pedersen Nancy L NL Power Chris C Pramstaller Peter P PP Price Jackie F JF Psaty Bruce M BM Quertermous Thomas T Rauramaa Rainer R Saleheen Danish D Salomaa Veikko V Sanghera Dharambir K DK Saramies Jouko J Schwarz Peter E H PE Sheu Wayne H-H WH Shuldiner Alan R AR Siegbahn Agneta A Spector Tim D TD Stefansson Kari K Strachan David P DP Tayo Bamidele O BO Tremoli Elena E Tuomilehto Jaakko J Uusitupa Matti M van Duijn Cornelia M CM Vollenweider Peter P Wallentin Lars L Wareham Nicholas J NJ Whitfield John B JB Wolffenbuttel Bruce H R BH Altshuler David D Ordovas Jose M JM Boerwinkle Eric E Palmer Colin N A CN Thorsteinsdottir Unnur U Chasman Daniel I DI Rotter Jerome I JI Franks Paul W PW Ripatti Samuli S Cupples L Adrienne LA Sandhu Manjinder S MS Rich Stephen S SS Boehnke Michael M Deloukas Panos P Mohlke Karen L KL Ingelsson Erik E Abecasis Goncalo R GR Daly Mark J MJ Neale Benjamin M BM Kathiresan Sekar S

Nature genetics 20131006 11

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholester ...[more]

PMID: 24097064

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Project description:BackgroundThe TRIB1 locus has been linked to hepatic triglyceride metabolism in mice and to plasma triglycerides and coronary artery disease in humans. The lipid-associated single nucleotide polymorphisms (SNPs), identified by genome-wide association studies, are located ≈30 kb downstream from TRIB1, suggesting complex regulatory effects on genes or pathways relevant to hepatic triglyceride metabolism. The goal of this study was to investigate the functional relationship between common SNPs at the TRIB1 locus and plasma lipid traits.Methods and resultsCharacterization of the risk locus reveals that it encompasses a gene, TRIB1-associated locus (TRIBAL), composed of a well-conserved promoter region and an alternatively spliced transcript. Bioinformatic analysis and resequencing identified a single SNP, rs2001844, within the promoter region that associates with increased plasma triglycerides and reduced high-density lipoprotein cholesterol and coronary artery disease risk. Further, correction for triglycerides as a covariate indicated that the genome-wide association studies association is largely dependent on triglycerides. In addition, we show that rs2001844 is an expression trait locus (eQTL) for TRIB1 expression in blood and alters TRIBAL promoter activity in a reporter assay model. The TRIBAL transcript has features typical of long noncoding RNAs, including poor sequence conservation. Modulation of TRIBAL expression had limited impact on either TRIB1 or lipid regulatory genes mRNA levels in human hepatocyte models. In contrast, TRIB1 knockdown markedly increased TRIBAL expression in HepG2 cells and primary human hepatocytes.ConclusionsThese studies demonstrate an interplay between a novel locus, TRIBAL, and TRIB1. TRIBAL is located in the genome-wide association studies identified risk locus, responds to altered expression of TRIB1, harbors a risk SNP that is an eQTL for TRIB1 expression, and associates with plasma triglyceride concentrations.

Dataset Information

Common variants associated with plasma triglycerides and risk for coronary artery disease.

Publications

Common variants associated with plasma triglycerides and risk for coronary artery disease.

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