Genetic variants influencing circulating lipid levels and risk of coronary artery disease

Dawn M. Waterworth; Sally L. Ricketts; Kijoung Song; Li Chen; Jing Hua Zhao; Samuli Ripatti; Yurii S. Aulchenko; Weihua Zhang; Xin Yuan; Noha Lim; Jian'An Luan; Sofie Ashford; Eleanor Wheeler; Elizabeth H. Young; David Hadley; John R. Thompson; Peter S. Braund; Toby Johnson; Maksim Struchalin; Ida Surakka; Robert Luben; Kay Tee Khaw; Sheila A. Rodwell; Ruth J F Loos; S. Matthijs Boekholdt; Michael Inouye; Panagiotis Deloukas; Paul Elliott; David Schlessinger; Serena Sanna; Angelo Scuteri; Anne Jackson; Karen L. Mohlke; Jaako Tuomilehto; Robert Roberts; Alexandre Stewart; Y. Antero Kesäniemi; Robert W. Mahley; Scott M Grundy; Wendy McArdle; Lon Cardon; Gérard Waeber; Peter Vollenweider; John C. Chambers; Michael Boehnke; Gonçalo R. Abecasis; Veikko Salomaa; Marjo Riitta Järvelin; Aimo Ruokonen; Inês Barroso; Stephen E. Epstein; Hakon H. Hakonarson; Daniel J. Rader; Muredach P. Reilly; Jacqueline C M Witteman; Alistair S. Hall; Nilesh J. Samani; David P. Strachan; Philip Barter; Cornelia M. Van Duijn; Jaspal S. Kooner; Leena Peltonen; Nicholas J. Wareham; Ruth McPherson; Vincent Mooser; Manjinder S. Sandhu

doi:10.1161/ATVBAHA.109.201020

Genetic variants influencing circulating lipid levels and risk of coronary artery disease

Dawn M. Waterworth, Sally L. Ricketts, Kijoung Song, Li Chen, Jing Hua Zhao, Samuli Ripatti, Yurii S. Aulchenko, Weihua Zhang, Xin Yuan, Noha Lim, Jian'An Luan, Sofie Ashford, Eleanor Wheeler, Elizabeth H. Young, David Hadley, John R. Thompson, Peter S. Braund, Toby Johnson, Maksim Struchalin, Ida SurakkaRobert Luben, Kay Tee Khaw, Sheila A. Rodwell, Ruth J F Loos, S. Matthijs Boekholdt, Michael Inouye, Panagiotis Deloukas, Paul Elliott, David Schlessinger, Serena Sanna, Angelo Scuteri, Anne Jackson, Karen L. Mohlke, Jaako Tuomilehto, Robert Roberts, Alexandre Stewart, Y. Antero Kesäniemi, Robert W. Mahley, Scott M Grundy, Wendy McArdle, Lon Cardon, Gérard Waeber, Peter Vollenweider, John C. Chambers, Michael Boehnke, Gonçalo R. Abecasis, Veikko Salomaa, Marjo Riitta Järvelin, Aimo Ruokonen, Inês Barroso, Stephen E. Epstein, Hakon H. Hakonarson, Daniel J. Rader, Muredach P. Reilly, Jacqueline C M Witteman, Alistair S. Hall, Nilesh J. Samani, David P. Strachan, Philip Barter, Cornelia M. Van Duijn, Jaspal S. Kooner, Leena Peltonen, Nicholas J. Wareham, Ruth McPherson, Vincent Mooser, Manjinder S. Sandhu

Research output: Contribution to journal › Article › peer-review

345 Scopus citations

Abstract

OBJECTIVE-: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. METHODS AND RESULTS-: We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10^-8 to 3.1×10^-10). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10^-3 to 1.2×10^-9). CONCLUSION-: We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.

Original language	English (US)
Pages (from-to)	2264-2276
Number of pages	13
Journal	Arteriosclerosis, thrombosis, and vascular biology
Volume	30
Issue number	11
DOIs	https://doi.org/10.1161/ATVBAHA.109.201020
State	Published - Nov 2010

Keywords

coronary artery disease
epidemiology
genetics
lipids

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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10.1161/ATVBAHA.109.201020

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Waterworth, D. M., Ricketts, S. L., Song, K., Chen, L., Zhao, J. H., Ripatti, S., Aulchenko, Y. S., Zhang, W., Yuan, X., Lim, N., Luan, JA., Ashford, S., Wheeler, E., Young, E. H., Hadley, D., Thompson, J. R., Braund, P. S., Johnson, T., Struchalin, M., ... Sandhu, M. S. (2010). Genetic variants influencing circulating lipid levels and risk of coronary artery disease. Arteriosclerosis, thrombosis, and vascular biology, 30(11), 2264-2276. https://doi.org/10.1161/ATVBAHA.109.201020

Waterworth, DM, Ricketts, SL, Song, K, Chen, L, Zhao, JH, Ripatti, S, Aulchenko, YS, Zhang, W, Yuan, X, Lim, N, Luan, JA, Ashford, S, Wheeler, E, Young, EH, Hadley, D, Thompson, JR, Braund, PS, Johnson, T, Struchalin, M, Surakka, I, Luben, R, Khaw, KT, Rodwell, SA, Loos, RJF, Boekholdt, SM, Inouye, M, Deloukas, P, Elliott, P, Schlessinger, D, Sanna, S, Scuteri, A, Jackson, A, Mohlke, KL, Tuomilehto, J, Roberts, R, Stewart, A, Kesäniemi, YA, Mahley, RW, Grundy, SM, McArdle, W, Cardon, L, Waeber, G, Vollenweider, P, Chambers, JC, Boehnke, M, Abecasis, GR, Salomaa, V, Järvelin, MR, Ruokonen, A, Barroso, I, Epstein, SE, Hakonarson, HH, Rader, DJ, Reilly, MP, Witteman, JCM, Hall, AS, Samani, NJ, Strachan, DP, Barter, P, Van Duijn, CM, Kooner, JS, Peltonen, L, Wareham, NJ, McPherson, R, Mooser, V & Sandhu, MS 2010, 'Genetic variants influencing circulating lipid levels and risk of coronary artery disease', Arteriosclerosis, thrombosis, and vascular biology, vol. 30, no. 11, pp. 2264-2276. https://doi.org/10.1161/ATVBAHA.109.201020

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title = "Genetic variants influencing circulating lipid levels and risk of coronary artery disease",

abstract = "OBJECTIVE-: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. METHODS AND RESULTS-: We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10-8 to 3.1×10-10). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10-3 to 1.2×10-9). CONCLUSION-: We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.",

keywords = "coronary artery disease, epidemiology, genetics, lipids",

author = "Waterworth, {Dawn M.} and Ricketts, {Sally L.} and Kijoung Song and Li Chen and Zhao, {Jing Hua} and Samuli Ripatti and Aulchenko, {Yurii S.} and Weihua Zhang and Xin Yuan and Noha Lim and Jian'An Luan and Sofie Ashford and Eleanor Wheeler and Young, {Elizabeth H.} and David Hadley and Thompson, {John R.} and Braund, {Peter S.} and Toby Johnson and Maksim Struchalin and Ida Surakka and Robert Luben and Khaw, {Kay Tee} and Rodwell, {Sheila A.} and Loos, {Ruth J F} and Boekholdt, {S. Matthijs} and Michael Inouye and Panagiotis Deloukas and Paul Elliott and David Schlessinger and Serena Sanna and Angelo Scuteri and Anne Jackson and Mohlke, {Karen L.} and Jaako Tuomilehto and Robert Roberts and Alexandre Stewart and Kes{\"a}niemi, {Y. Antero} and Mahley, {Robert W.} and Grundy, {Scott M} and Wendy McArdle and Lon Cardon and G{\'e}rard Waeber and Peter Vollenweider and Chambers, {John C.} and Michael Boehnke and Abecasis, {Gon{\c c}alo R.} and Veikko Salomaa and J{\"a}rvelin, {Marjo Riitta} and Aimo Ruokonen and In{\^e}s Barroso and Epstein, {Stephen E.} and Hakonarson, {Hakon H.} and Rader, {Daniel J.} and Reilly, {Muredach P.} and Witteman, {Jacqueline C M} and Hall, {Alistair S.} and Samani, {Nilesh J.} and Strachan, {David P.} and Philip Barter and {Van Duijn}, {Cornelia M.} and Kooner, {Jaspal S.} and Leena Peltonen and Wareham, {Nicholas J.} and Ruth McPherson and Vincent Mooser and Sandhu, {Manjinder S.}",

year = "2010",

month = nov,

doi = "10.1161/ATVBAHA.109.201020",

language = "English (US)",

volume = "30",

pages = "2264--2276",

journal = "Arteriosclerosis, thrombosis, and vascular biology",

issn = "1079-5642",

publisher = "Lippincott Williams and Wilkins",

number = "11",

}

TY - JOUR

T1 - Genetic variants influencing circulating lipid levels and risk of coronary artery disease

AU - Waterworth, Dawn M.

AU - Ricketts, Sally L.

AU - Song, Kijoung

AU - Chen, Li

AU - Zhao, Jing Hua

AU - Ripatti, Samuli

AU - Aulchenko, Yurii S.

AU - Zhang, Weihua

AU - Yuan, Xin

AU - Lim, Noha

AU - Luan, Jian'An

AU - Ashford, Sofie

AU - Wheeler, Eleanor

AU - Young, Elizabeth H.

AU - Hadley, David

AU - Thompson, John R.

AU - Braund, Peter S.

AU - Johnson, Toby

AU - Struchalin, Maksim

AU - Surakka, Ida

AU - Luben, Robert

AU - Khaw, Kay Tee

AU - Rodwell, Sheila A.

AU - Loos, Ruth J F

AU - Boekholdt, S. Matthijs

AU - Inouye, Michael

AU - Deloukas, Panagiotis

AU - Elliott, Paul

AU - Schlessinger, David

AU - Sanna, Serena

AU - Scuteri, Angelo

AU - Jackson, Anne

AU - Mohlke, Karen L.

AU - Tuomilehto, Jaako

AU - Roberts, Robert

AU - Stewart, Alexandre

AU - Kesäniemi, Y. Antero

AU - Mahley, Robert W.

AU - Grundy, Scott M

AU - McArdle, Wendy

AU - Cardon, Lon

AU - Waeber, Gérard

AU - Vollenweider, Peter

AU - Chambers, John C.

AU - Boehnke, Michael

AU - Abecasis, Gonçalo R.

AU - Salomaa, Veikko

AU - Järvelin, Marjo Riitta

AU - Ruokonen, Aimo

AU - Barroso, Inês

AU - Epstein, Stephen E.

AU - Hakonarson, Hakon H.

AU - Rader, Daniel J.

AU - Reilly, Muredach P.

AU - Witteman, Jacqueline C M

AU - Hall, Alistair S.

AU - Samani, Nilesh J.

AU - Strachan, David P.

AU - Barter, Philip

AU - Van Duijn, Cornelia M.

AU - Kooner, Jaspal S.

AU - Peltonen, Leena

AU - Wareham, Nicholas J.

AU - McPherson, Ruth

AU - Mooser, Vincent

AU - Sandhu, Manjinder S.

PY - 2010/11

Y1 - 2010/11

N2 - OBJECTIVE-: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. METHODS AND RESULTS-: We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10-8 to 3.1×10-10). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10-3 to 1.2×10-9). CONCLUSION-: We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.

AB - OBJECTIVE-: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. METHODS AND RESULTS-: We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10-8 to 3.1×10-10). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10-3 to 1.2×10-9). CONCLUSION-: We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.

KW - coronary artery disease

KW - epidemiology

KW - genetics

KW - lipids

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U2 - 10.1161/ATVBAHA.109.201020

DO - 10.1161/ATVBAHA.109.201020

M3 - Article

C2 - 20864672

AN - SCOPUS:78149245489

SN - 1079-5642

VL - 30

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EP - 2276

JO - Arteriosclerosis, thrombosis, and vascular biology

JF - Arteriosclerosis, thrombosis, and vascular biology

IS - 11

ER -

Genetic variants influencing circulating lipid levels and risk of coronary artery disease

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