| Literature DB >> 24507774 |
Gina M Peloso1, Paul L Auer2, Joshua C Bis3, Arend Voorman4, Alanna C Morrison5, Nathan O Stitziel6, Jennifer A Brody3, Sumeet A Khetarpal7, Jacy R Crosby8, Myriam Fornage9, Aaron Isaacs10, Johanna Jakobsdottir11, Mary F Feitosa12, Gail Davies13, Jennifer E Huffman14, Ani Manichaikul15, Brian Davis5, Kurt Lohman16, Aron Y Joon17, Albert V Smith18, Megan L Grove5, Paolo Zanoni7, Valeska Redon7, Serkalem Demissie19, Kim Lawson5, Ulrike Peters20, Christopher Carlson20, Rebecca D Jackson21, Kelli K Ryckman22, Rachel H Mackey23, Jennifer G Robinson22, David S Siscovick24, Pamela J Schreiner25, Josyf C Mychaleckyj15, James S Pankow25, Albert Hofman26, Andre G Uitterlinden26, Tamara B Harris27, Kent D Taylor28, Jeanette M Stafford16, Lindsay M Reynolds16, Riccardo E Marioni13, Abbas Dehghan26, Oscar H Franco26, Aniruddh P Patel29, Yingchang Lu30, George Hindy31, Omri Gottesman32, Erwin P Bottinger32, Olle Melander31, Marju Orho-Melander33, Ruth J F Loos34, Stefano Duga35, Piera Angelica Merlini36, Martin Farrall37, Anuj Goel37, Rosanna Asselta35, Domenico Girelli38, Nicola Martinelli38, Svati H Shah39, William E Kraus40, Mingyao Li41, Daniel J Rader7, Muredach P Reilly7, Ruth McPherson42, Hugh Watkins43, Diego Ardissino44, Qunyuan Zhang12, Judy Wang12, Michael Y Tsai45, Herman A Taylor46, Adolfo Correa47, Michael E Griswold47, Leslie A Lange48, John M Starr49, Igor Rudan50, Gudny Eiriksdottir11, Lenore J Launer27, Jose M Ordovas51, Daniel Levy52, Y-D Ida Chen28, Alexander P Reiner53, Caroline Hayward14, Ozren Polasek54, Ian J Deary13, Ingrid B Borecki12, Yongmei Liu16, Vilmundur Gudnason18, James G Wilson55, Cornelia M van Duijn10, Charles Kooperberg20, Stephen S Rich15, Bruce M Psaty56, Jerome I Rotter28, Christopher J O'Donnell57, Kenneth Rice4, Eric Boerwinkle58, Sekar Kathiresan59, L Adrienne Cupples60.
Abstract
Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.Entities:
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Year: 2014 PMID： 24507774 PMCID： PMC3928662 DOI： 10.1016/j.ajhg.2014.01.009
Source DB: PubMed Journal: Am J Hum Genet ISSN： 0002-9297 Impact factor: 11.025