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Title: Association of low-frequency and rare coding-sequence variants with blood lipids and Coronary Heart Disease in 56,000 whites and blacks

Author
item PELOSO, GINA - Massachusetts General Hospital
item AUER, PAUL - University Of Wisconsin
item BIS, JOSHUA - University Of Washington
item VOORMAN, AREND - University Of Washington
item MORRISON, ALANNA - University Of Texas
item STITZIEL, NATHAN - Washington University
item BRODY, JENNIFER - University Of Washington
item KHETARPAL, SUMEET - University Of Pennsylvania
item CROSBY, JACY - University Of Texas
item FORNAGE, MYRIAM - University Of Texas
item ISAACS, AARON - Erasmus Medical Center
item JAKOBSDOTTIR, JOHANNA - Icelandic Heart Association
item FEITOSA, MARY - Washington University
item DAVIES, GAIL - University Of Edinburgh
item HUFFMAN, JENNIFER - University Of Edinburgh
item MANICHAIKUL, ANI - University Of Virginia
item DAVIS, BRIAN - University Of Texas
item LOHMAN, KURT - Wake Forest University
item JOON, ARON - University Of Texas
item SMITH, ALBERT - University Of Iceland
item GROVE, MEGAN - University Of Texas
item ZANONI, PAOLO - University Of Pennsylvania
item REDON, VALESKA - University Of Pennsylvania
item DEMISSIE, SERKALEM - Boston University
item LAWSON, KIM - University Of Texas
item PETERS, ULRIKE - Fred Hutchinson Cancer Research Center
item CARLSON, CHRISTOPHER - Fred Hutchinson Cancer Research Center
item JACKSON, REBECCA - The Ohio State University
item RYCKMAN, KELLI - University Of Iowa
item MACKEY, RACHEL - University Of Pittsburgh
item ROBINSON, JENNIFER - University Of Iowa
item SISCOVICK, DAVID - University Of Washington
item SCHREINER, PAMELA - University Of Minnesota
item MYCHALECKYJ, JOSYF - University Of Virginia
item PANKOW, JAMES - University Of Minnesota
item HOFMAN, ALBERT - Erasmus Medical Center
item UITTERLINDEN, ANDRE - Erasmus Medical Center
item HARRIS, TAMARA - National Institutes Of Health (NIH)
item TAYLOR, KENT - Los Angeles Biomedical Research Institute
item STAFFORD, JEANETTE - Wake Forest University
item REYNOLDS, LINDSAY - Wake Forest University
item MARIONI, RICCARDO - University Of Edinburgh
item DEHGHAN, ABBAS - Erasmus Medical Center
item FRANCO, OSCAR - Erasmus Medical Center
item PATEL, ANIRUDDH - Massachusetts General Hospital
item LU, YINGCHANG - The Icahn School Of Medicine At Mount Sinai
item HINDY, GEORGE - Lund University
item GOTTESMAN, OMRI - The Icahn School Of Medicine At Mount Sinai
item BOTTINGER, ERWIN - The Icahn School Of Medicine At Mount Sinai
item MELANDER, OLLE - Lund University
item ORHO-MELANDER, MARJU - Lund University
item LOOS, RUTH J F - The Icahn School Of Medicine At Mount Sinai
item DUGA, STEFANO - Universita Degli Studi Di Salerno
item MERLINI, PIERA ANGELICA - Ospedale Niguarda
item FARRALL, MARTIN - University Of Oxford
item GOEL, ANJUL - University Of Oxford
item ASSELTA, ROSANNA - Universita Degli Studi Di Salerno
item GIRELLI, DOMINICO - University Of Verona
item MARTINELLI, NICOLA - University Of Verona
item SHAH, SVATI - Duke University
item KRAUS, WILLIAM - Duke University
item LI, MINGYAO - University Of Pennsylvania
item RADER, DANIEL - University Of Pennsylvania
item REILLY, MUREDACH - University Of Pennsylvania
item MCPHERSON, RUTH - University Of Ottawa
item WATKINS, HUGH - Merck Research Laboratories
item ARDISSINO, DIEGO - Hospital Of Parma
item ZHANG, QUNYUAN - Washington University
item WANG, JUDY - Washington University
item TSAI, MICHAEL - University Of Minnesota
item TAYLOR, HERMAN - University Of Mississippi
item CORREA, ADOLFO - University Of Mississippi
item GRISWOLD, MICHAEL - University Of Mississippi
item LANGE, LESLIE - University Of Edinburgh
item STARR, JOHN - University Of Edinburgh
item RUDAN, IGOR - University Of Edinburgh
item EIRIKSDOTTIR, GUDNY - Icelandic Heart Association
item LAUNER, LENORE - National Institutes Of Health (NIH)
item ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item LEVY, DANIEL - National Heart, Lung And Blood Institute(NHLBI, NIH)
item CHEN, Y D IDA - Los Angeles Biomedical Research Institute
item REINER, ALEXANDER - Fred Hutchinson Cancer Research Center
item HAYWARD, CAROLINE - University Of Edinburgh
item POLASEK, OZREN - University Of Split
item DEARY, IAN - University Of Edinburgh
item BORECKI, INGRID - Washington University
item LIU, YONGMEI - Wake Forest University
item GUDNASON, VILMUNDUR - Icelandic Heart Association
item WILSON, JAMES - University Of Mississippi
item VAN DUIJN, CORNELIA - Erasmus Medical Center
item KOOPERBERG, CHARLES - Fred Hutchinson Cancer Research Center
item RICH, STEPHEN - University Of Virginia

Submitted to: The American Journal of Human Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/9/2014
Publication Date: 2/6/2014
Citation: Peloso, G.M., Auer, P.L., Bis, J.C., Voorman, A., Morrison, A.C., Stitziel, N.O., Brody, J.A., Khetarpal, S.A., Crosby, J.R., Fornage, M., Isaacs, A., Jakobsdottir, J., Feitosa, M.F., Davies, G., Huffman, J.E., Manichaikul, A., Davis, B., Lohman, K., Joon, A.Y., Smith, A.V., Grove, M.L., Zanoni, P., Redon, V., Demissie, S., Lawson, K., Peters, U., Carlson, C., Jackson, R.D., Ryckman, K.K., Mackey, R.H., Robinson, J.G., Siscovick, D.S., Schreiner, P.J., Mychaleckyj, J.C., Pankow, J.S., Hofman, A., Uitterlinden, A.G., Harris, T.B., Taylor, K.D., Stafford, J.M., Reynolds, L.M., Marioni, R.E., Dehghan, A., Franco, O.H., Patel, A.P., Lu, Y., Hindy, G., Gottesman, O., Bottinger, E.P., Melander, O., Orho-Melander, M., Loos, R., Duga, S., Merlini, P., Farrall, M., Goel, A., Asselta, R., Girelli, D., Martinelli, N., Shah, S.H., Kraus, W.E., Li, M., Rader, D.J., Reilly, M.P., Mcpherson, R., Watkins, H., Ardissino, D., Zhang, Q., Wang, J., Tsai, M.Y., Taylor, H.A., Correa, A., Griswold, M.E., Lange, L.A., Starr, J.M., Rudan, I., Eiriksdottir, G., Launer, L.J., Ordovas, J.M., Levy, D., Chen, Y., Reiner, A.P., Hayward, C., Polasek, O., Deary, I.J., Borecki, I.B., Liu, Y., Gudnason, V., Wilson, J., Van Duijn, C.M., Kooperberg, C., Rich, S.S. 2014. Association of low-frequency and rare coding-sequence variants with blood lipids and Coronary Heart Disease in 56,000 whites and blacks. The American Journal of Human Genetics. 94:223-232.

Interpretive Summary: Blood lipid levels are known cardiovascular risk factors and their levels are defined by a combination of genetic and environmental factors. There is a heated controversy among those who defend the significance of the common genetic variants and those who think that the most important role is played by rare mutations. In this regard, low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) have been found to 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. However, it is uncertain whether this PCSK9 example represents a paradigm or an isolated exception. Therefore, we genotyped >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 low-density lipoprotein cholesterol (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 rare mutations in the ANGPTL8 (rs145464906), PAFAH1B2 (rs186808413), COL18A1 (rs114139997) and PCSK7 (rs142953140) genes with large effects on HDL-C and/or triglycerides. However, 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.

Technical 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.