Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks
In: American Journal of Human Genetics, Jg. 94 (2014-02-01), Heft 2
Online
academicJournal
- 223 - 232
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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Association of Low-Frequency and Rare Coding-Sequence Variants with Blood Lipids and Coronary Heart Disease in 56,000 Whites and Blacks
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Autor/in / Beteiligte Person: | Peloso, Gina M ; Auer, Paul L ; Bis, Joshua C ; Voorman, Arend ; Morrison, Alanna C ; Stitziel, Nathan O ; Brody, Jennifer A ; Khetarpal, Sumeet A ; Crosby, Jacy R ; Fornage, Myriam ; Isaacs, Aaron ; Jakobsdottir, Johanna ; Feitosa, Mary F ; Davies, Gail ; Huffman, Jennifer E ; Manichaikul, Ani ; Davis, Brian ; Lohman, Kurt ; Joon, Aron Y ; Smith, Albert V ; Grove, Megan L ; Zanoni, Paolo ; Redon, Valeska ; Demissie, Serkalem ; Lawson, Kim ; Peters, Ulrike ; Carlson, Christopher ; Jackson, Rebecca D ; Ryckman, Kelli K ; Mackey, Rachel H ; Robinson, Jennifer G ; Siscovick, David S ; Schreiner, Pamela J ; Mychaleckyj, Josyf C ; Pankow, James S ; Hofman, Albert ; Uitterlinden, Andre G ; Harris, Tamara B ; Taylor, Kent D ; Stafford, Jeanette M ; Reynolds, Lindsay M ; Marioni, Riccardo E ; Dehghan, Abbas ; Franco, Oscar H ; Patel, Aniruddh P ; Lu, Yingchang ; Hindy, George ; Gottesman, Omri ; Bottinger, Erwin P ; Melander, Olle ; Orho-Melander, Marju ; Loos, Ruth JF ; Duga, Stefano ; Merlini, Piera Angelica ; Farrall, Martin ; Goel, Anuj ; Asselta, Rosanna ; Girelli, Domenico ; Martinelli, Nicola ; Shah, Svati H ; Kraus, William E ; Li, Mingyao ; Rader, Daniel J ; Reilly, Muredach P ; McPherson, Ruth ; Watkins, Hugh ; Ardissino, Diego ; Project, NHLBI GO Exome Sequencing ; Zhang, Qunyuan ; Wang, Judy ; Tsai, Michael Y ; Taylor, Herman A ; Correa, Adolfo ; Griswold, Michael E ; Lange, Leslie A ; Starr, John M ; Rudan, Igor ; Eiriksdottir, Gudny ; Launer, Lenore J ; Ordovas, Jose M ; Levy, Daniel ; Chen, Y-D Ida ; Reiner, Alexander P ; Hayward, Caroline ; Polasek, Ozren ; Deary, Ian J ; Borecki, Ingrid B ; Liu, Yongmei ; Gudnason, Vilmundur ; Wilson, James G ; van Duijn, Cornelia M ; Kooperberg, Charles ; Rich, Stephen S ; Psaty, Bruce M ; Rotter, Jerome I ; O’Donnell, Christopher J ; Rice, Kenneth ; Boerwinkle, Eric ; Kathiresan, Sekar ; Cupples, L Adrienne |
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Zeitschrift: | American Journal of Human Genetics, Jg. 94 (2014-02-01), Heft 2 |
Veröffentlichung: | eScholarship, University of California, 2014 |
Medientyp: | academicJournal |
Umfang: | 223 - 232 |
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