Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease

DM Waterworth; SL Ricketts; KJ Song; L Chen; JH Zhao; S Ripatti; YS Aulchenko; WH Zhang; X Yuan; N Lim; JA Luan; S Ashford; E Wheeler; EH Young; D Hadley; JR Thompson; PS Braund; T Johnson; Maksim Struchalin; I Surakka; R Luben; KT Khaw; SA Rodwell; RJF Loos; SM Boekholdt; M Inouye; P Deloukas; P Elliott; D Schlessinger; S Sanna; A Scuteri; A Jackson; KL Mohlke; J Tuomilehto; R Roberts; A Stewart; YA Kesaniemi; RW Mahley; SM Grundy; W McArdle; L Cardon; G Waeber; P Vollenweider; JC Chambers; M Boehnke; GR Abecasis; V Salomaa; MR Jarvelin; A Ruokonen; I Barroso; SE Epstein; HH Hakonarson; DJ Rader; MP Reilly; JCM Witteman; AS Hall; NJ Samani; DP Strachan; P Barter; Cornelia Duijn; JS Kooner; L Peltonen; NJ Wareham; R McPherson; V Mooser; MS Sandhu

doi:10.1161/ATVBAHA.109.201020

Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease

DM Waterworth, SL Ricketts, KJ Song, L Chen, JH Zhao, S Ripatti, YS Aulchenko, WH Zhang, X Yuan, N Lim, JA Luan, S Ashford, E Wheeler, EH Young, D Hadley, JR Thompson, PS Braund, T Johnson, Maksim Struchalin, I SurakkaR Luben, KT Khaw, SA Rodwell, RJF Loos, SM Boekholdt, M Inouye, P Deloukas, P Elliott, D Schlessinger, S Sanna, A Scuteri, A Jackson, KL Mohlke, J Tuomilehto, R Roberts, A Stewart, YA Kesaniemi, RW Mahley, SM Grundy, W McArdle, L Cardon, G Waeber, P Vollenweider, JC Chambers, M Boehnke, GR Abecasis, V Salomaa, MR Jarvelin, A Ruokonen, I Barroso, SE Epstein, HH Hakonarson, DJ Rader, MP Reilly, JCM Witteman, AS Hall, NJ Samani, DP Strachan, P Barter, Cornelia Duijn, JS Kooner, L Peltonen, NJ Wareham, R McPherson, V Mooser, MS Sandhu

Epidemiology

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

352 Citations (Scopus)

Abstract

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, 1.6X10(-8) to 3.1X10(-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, 1.1X10(-3) to 1.2X10(-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. (Arterioscler Thromb Vasc Biol. 2010;30:2264-2276.)

Original language	Undefined/Unknown
Pages (from-to)	2264-U566
Journal	Arteriosclerosis Thrombosis & Vascular Biology
Volume	30
Issue number	11
DOIs	https://doi.org/10.1161/ATVBAHA.109.201020
Publication status	Published - 2010

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EMC NIHES-01-64-01

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10.1161/ATVBAHA.109.201020

http://hdl.handle.net/1765/28251

Cite this

Waterworth, DM., Ricketts, SL., Song, KJ., Chen, L., Zhao, JH., Ripatti, S., Aulchenko, YS., Zhang, WH., Yuan, X., Lim, N., Luan, JA., Ashford, S., Wheeler, E., Young, EH., Hadley, D., Thompson, JR., Braund, PS., Johnson, T., Struchalin, M., ... Sandhu, MS. (2010). Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease. Arteriosclerosis Thrombosis & Vascular Biology, 30(11), 2264-U566. https://doi.org/10.1161/ATVBAHA.109.201020

@article{e88bc0fec2f34f59919134f014db55bf,

title = "Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease",

abstract = "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, 1.6X10(-8) to 3.1X10(-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, 1.1X10(-3) to 1.2X10(-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. (Arterioscler Thromb Vasc Biol. 2010;30:2264-2276.)",

author = "DM Waterworth and SL Ricketts and KJ Song and L Chen and JH Zhao and S Ripatti and YS Aulchenko and WH Zhang and X Yuan and N Lim and JA Luan and S Ashford and E Wheeler and EH Young and D Hadley and JR Thompson and PS Braund and T Johnson and Maksim Struchalin and I Surakka and R Luben and KT Khaw and SA Rodwell and RJF Loos and SM Boekholdt and M Inouye and P Deloukas and P Elliott and D Schlessinger and S Sanna and A Scuteri and A Jackson and KL Mohlke and J Tuomilehto and R Roberts and A Stewart and YA Kesaniemi and RW Mahley and SM Grundy and W McArdle and L Cardon and G Waeber and P Vollenweider and JC Chambers and M Boehnke and GR Abecasis and V Salomaa and MR Jarvelin and A Ruokonen and I Barroso and SE Epstein and HH Hakonarson and DJ Rader and MP Reilly and JCM Witteman and AS Hall and NJ Samani and DP Strachan and P Barter and Cornelia Duijn and JS Kooner and L Peltonen and NJ Wareham and R McPherson and V Mooser and MS Sandhu",

year = "2010",

doi = "10.1161/ATVBAHA.109.201020",

language = "Undefined/Unknown",

volume = "30",

pages = "2264--U566",

journal = "Arteriosclerosis Thrombosis & Vascular Biology",

issn = "1079-5642",

publisher = "Lippincott Williams & Wilkins",

number = "11",

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Waterworth, DM, Ricketts, SL, Song, KJ, Chen, L, Zhao, JH, Ripatti, S, Aulchenko, YS, Zhang, WH, 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, Kesaniemi, YA, Mahley, RW, Grundy, SM, McArdle, W, Cardon, L, Waeber, G, Vollenweider, P, Chambers, JC, Boehnke, M, Abecasis, GR, Salomaa, V, Jarvelin, MR, Ruokonen, A, Barroso, I, Epstein, SE, Hakonarson, HH, Rader, DJ, Reilly, MP, Witteman, JCM, Hall, AS, Samani, NJ, Strachan, DP, Barter, P, Duijn, C, 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 & Vascular Biology, vol. 30, no. 11, pp. 2264-U566. https://doi.org/10.1161/ATVBAHA.109.201020

TY - JOUR

T1 - Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease

AU - Waterworth, DM

AU - Ricketts, SL

AU - Song, KJ

AU - Chen, L

AU - Zhao, JH

AU - Ripatti, S

AU - Aulchenko, YS

AU - Zhang, WH

AU - Yuan, X

AU - Lim, N

AU - Luan, JA

AU - Ashford, S

AU - Wheeler, E

AU - Young, EH

AU - Hadley, D

AU - Thompson, JR

AU - Braund, PS

AU - Johnson, T

AU - Struchalin, Maksim

AU - Surakka, I

AU - Luben, R

AU - Khaw, KT

AU - Rodwell, SA

AU - Loos, RJF

AU - Boekholdt, SM

AU - Inouye, M

AU - Deloukas, P

AU - Elliott, P

AU - Schlessinger, D

AU - Sanna, S

AU - Scuteri, A

AU - Jackson, A

AU - Mohlke, KL

AU - Tuomilehto, J

AU - Roberts, R

AU - Stewart, A

AU - Kesaniemi, YA

AU - Mahley, RW

AU - Grundy, SM

AU - McArdle, W

AU - Cardon, L

AU - Waeber, G

AU - Vollenweider, P

AU - Chambers, JC

AU - Boehnke, M

AU - Abecasis, GR

AU - Salomaa, V

AU - Jarvelin, MR

AU - Ruokonen, A

AU - Barroso, I

AU - Epstein, SE

AU - Hakonarson, HH

AU - Rader, DJ

AU - Reilly, MP

AU - Witteman, JCM

AU - Hall, AS

AU - Samani, NJ

AU - Strachan, DP

AU - Barter, P

AU - Duijn, Cornelia

AU - Kooner, JS

AU - Peltonen, L

AU - Wareham, NJ

AU - McPherson, R

AU - Mooser, V

AU - Sandhu, MS

PY - 2010

Y1 - 2010

N2 - 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, 1.6X10(-8) to 3.1X10(-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, 1.1X10(-3) to 1.2X10(-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. (Arterioscler Thromb Vasc Biol. 2010;30:2264-2276.)

AB - 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, 1.6X10(-8) to 3.1X10(-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, 1.1X10(-3) to 1.2X10(-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. (Arterioscler Thromb Vasc Biol. 2010;30:2264-2276.)

U2 - 10.1161/ATVBAHA.109.201020

DO - 10.1161/ATVBAHA.109.201020

M3 - Article

C2 - 20864672

SN - 1079-5642

VL - 30

SP - 2264-U566

JO - Arteriosclerosis Thrombosis & Vascular Biology

JF - Arteriosclerosis Thrombosis & Vascular Biology

IS - 11

ER -