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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.

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 and Fornage, Myriam, et al. (2014) In American Journal of Human Genetics 94(2). p.223-232
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... (More)
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. (Less)
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American Journal of Human Genetics
volume
94
issue
2
pages
223 - 232
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Cell Press
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  • pmid:24507774
  • wos:000331419500006
  • scopus:84893756641
ISSN
0002-9297
DOI
10.1016/j.ajhg.2014.01.009
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English
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5867df04-a8e1-436a-ac9a-3428a708efe4 (old id 4335257)
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http://www.ncbi.nlm.nih.gov/pubmed/24507774?dopt=Abstract
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2014-03-06 14:25:12
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@article{5867df04-a8e1-436a-ac9a-3428a708efe4,
  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.},
  author       = {Peloso, Gina M and Auer, Paul L and Bis, Joshua C and Voorman, Arend and Morrison, Alanna C and Stitziel, Nathan O and Brody, Jennifer A and Khetarpal, Sumeet A and Crosby, Jacy R and Fornage, Myriam and Isaacs, Aaron and Jakobsdottir, Johanna and Feitosa, Mary F and Davies, Gail and Huffman, Jennifer E and Manichaikul, Ani and Davis, Brian and Lohman, Kurt and Joon, Aron Y and Smith, Albert V and Grove, Megan L and Zanoni, Paolo and Redon, Valeska and Demissie, Serkalem and Lawson, Kim and Peters, Ulrike and Carlson, Christopher and Jackson, Rebecca D and Ryckman, Kelli K and Mackey, Rachel H and Robinson, Jennifer G and Siscovick, David S and Schreiner, Pamela J and Mychaleckyj, Josyf C and Pankow, James S and Hofman, Albert and Uitterlinden, Andre G and Harris, Tamara B and Taylor, Kent D and Stafford, Jeanette M and Reynolds, Lindsay M and Marioni, Riccardo E and Dehghan, Abbas and Franco, Oscar H and Patel, Aniruddh P and Lu, Yingchang and Hindy, George and Gottesman, Omri and Bottinger, Erwin P and Melander, Olle and Orho-Melander, Marju and Loos, Ruth J F and Duga, Stefano and Merlini, Piera Angelica and Farrall, Martin and Goel, Anuj and Asselta, Rosanna and Girelli, Domenico and Martinelli, Nicola and Shah, Svati H and Kraus, William E and Li, Mingyao and Rader, Daniel J and Reilly, Muredach P and McPherson, Ruth and Watkins, Hugh and Ardissino, Diego and Zhang, Qunyuan and Wang, Judy and Tsai, Michael Y and Taylor, Herman A and Correa, Adolfo and Griswold, Michael E and Lange, Leslie A and Starr, John M and Rudan, Igor and Eiriksdottir, Gudny and Launer, Lenore J and Ordovas, Jose M and Levy, Daniel and Chen, Y-D Ida and Reiner, Alexander P and Hayward, Caroline and Polasek, Ozren and Deary, Ian J and Borecki, Ingrid B and Liu, Yongmei and Gudnason, Vilmundur and Wilson, James G and van Duijn, Cornelia M and Kooperberg, Charles and Rich, Stephen S and Psaty, Bruce M and Rotter, Jerome I and O'Donnell, Christopher J and Rice, Kenneth and Boerwinkle, Eric and Kathiresan, Sekar and Cupples, L Adrienne},
  issn         = {0002-9297},
  language     = {eng},
  number       = {2},
  pages        = {223--232},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks.},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2014.01.009},
  volume       = {94},
  year         = {2014},
}