Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks.

Authors:
Gina M Peloso Paul L Auer Joshua C Bis Arend Voorman Alanna C Morrison Nathan O Stitziel Jennifer A Brody Sumeet A Khetarpal Jacy R Crosby Myriam Fornage Aaron Isaacs Johanna Jakobsdottir Mary F Feitosa Gail Davies Jennifer E Huffman Ani Manichaikul Brian Davis Kurt Lohman Aron Y Joon Albert V Smith Megan L Grove Paolo Zanoni Valeska Redon Serkalem Demissie Kim Lawson Ulrike Peters Christopher Carlson Rebecca D Jackson Kelli K Ryckman Rachel H Mackey Jennifer G Robinson David S Siscovick Pamela J Schreiner Josyf C Mychaleckyj James S Pankow Albert Hofman Andre G Uitterlinden Tamara B Harris Kent D Taylor Jeanette M Stafford Lindsay M Reynolds Riccardo E Marioni Abbas Dehghan Oscar H Franco Aniruddh P Patel Yingchang Lu George Hindy Omri Gottesman Erwin P Bottinger Olle Melander Marju Orho-Melander Ruth J F Loos Stefano Duga Piera Angelica Merlini Martin Farrall Anuj Goel Rosanna Asselta Domenico Girelli Nicola Martinelli Svati H Shah William E Kraus Mingyao Li Daniel J Rader Muredach P Reilly Ruth McPherson Hugh Watkins Diego Ardissino Qunyuan Zhang Judy Wang Michael Y Tsai Herman A Taylor Adolfo Correa Michael E Griswold Leslie A Lange John M Starr Igor Rudan Gudny Eiriksdottir Lenore J Launer Jose M Ordovas Daniel Levy Y-D Ida Chen Alexander P Reiner Caroline Hayward Ozren Polasek Ian J Deary Ingrid B Borecki Yongmei Liu Vilmundur Gudnason James G Wilson Cornelia M van Duijn Charles Kooperberg Stephen S Rich Bruce M Psaty Jerome I Rotter Christopher J O'Donnell Kenneth Rice Eric Boerwinkle Sekar Kathiresan L Adrienne Cupples

Am J Hum Genet 2014 Feb;94(2):223-32

Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA; National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, MA 01702, USA. Electronic address:

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.

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http://dx.doi.org/10.1016/j.ajhg.2014.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3928662PMC
February 2014
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