Comparative analysis of genome-wide association studies signals for lipids, diabetes, and coronary heart disease: Cardiovascular Biomarker Genetics Collaboration

Aspasia Angelakopoulou; Tina Shah; Reecha Sofat; Sonia Shah; Diane J. Berry; Jackie Cooper; Jutta Palmen; Ioanna Tzoulaki; Andrew Wong; Barbara J. Jefferis; Nikolas Maniatis; Fotios Drenos; Bruna Gigante; Rebecca Hardy; Ross C. Laxton; Karin Leander; Anna Motterle; Iain A. Simpson; Liam Smeeth; Andy Thomson; Claudio Verzilli; Diana Kuh; Helen Ireland; John Deanfield; Mark Caulfield; Chris Wallace; Nilesh Samani; Patricia B. Munroe; Mark Lathrop; F. Gerry R Fowkes; Michael Marmot; Peter H. Whincup; John C. Whittaker; Ulf De Faire; Mika Kivimaki; Meena Kumari; Elina Hypponen; Chris Power; Steve E. Humphries; Philippa J. Talmud; Jackie Price; Richard W. Morris; Shu Ye; Juan P. Casas; Aroon D. Hingorani

doi:10.1093/eurheartj/ehr225

Comparative analysis of genome-wide association studies signals for lipids, diabetes, and coronary heart disease: Cardiovascular Biomarker Genetics Collaboration

Aspasia Angelakopoulou, Tina Shah, Reecha Sofat, Sonia Shah, Diane J. Berry, Jackie Cooper, Jutta Palmen, Ioanna Tzoulaki, Andrew Wong, Barbara J. Jefferis, Nikolas Maniatis, Fotios Drenos, Bruna Gigante, Rebecca Hardy, Ross C. Laxton, Karin Leander, Anna Motterle, Iain A. Simpson, Liam Smeeth, Andy ThomsonClaudio Verzilli, Diana Kuh, Helen Ireland, John Deanfield, Mark Caulfield, Chris Wallace, Nilesh Samani, Patricia B. Munroe, Mark Lathrop, F. Gerry R Fowkes, Michael Marmot, Peter H. Whincup, John C. Whittaker, Ulf De Faire, Mika Kivimaki, Meena Kumari, Elina Hypponen, Chris Power, Steve E. Humphries, Philippa J. Talmud, Jackie Price, Richard W. Morris, Shu Ye, Juan P. Casas, Aroon D. Hingorani

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

95 Citations (Scopus)

Abstract

AimsTo evaluate the associations of emergent genome-wide-association study-derived coronary heart disease (CHD)-associated single nucleotide polymorphisms (SNPs) with established and emerging risk factors, and the association of genome-wide-association study-derived lipid-associated SNPs with other risk factors and CHD events.Methods and resultsUsing two casecontrol studies, three cross-sectional, and seven prospective studies with up to 25 000 individuals and 5794 CHD events we evaluated associations of 34 genome-wide-association study-identified SNPs with CHD risk and 16 CHD-associated risk factors or biomarkers. The Ch9p21 SNPs rs1333049 (OR 1.17; 95 confidence limits 1.111.24) and rs10757274 (OR 1.17; 1.091.26), MIA3 rs17465637 (OR 1.10; 1.041.15), Ch2q36 rs2943634 (OR 1.08; 1.031.14), APC rs383830 (OR 1.10; 1.02, 1.18), MTHFD1L rs6922269 (OR 1.10; 1.03, 1.16), CXCL12 rs501120 (OR 1.12; 1.04, 1.20), and SMAD3 rs17228212 (OR 1.11; 1.05, 1.17) were all associated with CHD risk, but not with the CHD biomarkers and risk factors measured. Among the 20 blood lipid-related SNPs, LPL rs17411031 was associated with a lower risk of CHD (OR 0.91; 0.840.97), an increase in Apolipoprotein AI and HDL-cholesterol, and reduced triglycerides. SORT1 rs599839 was associated with CHD risk (OR 1.20; 1.151.26) as well as total-and LDL-cholesterol, and apolipoprotein B. ANGPTL3 rs12042319 was associated with CHD risk (OR 1.11; 1.03, 1.19), total-and LDL-cholesterol, triglycerides, and interleukin-6. ConclusionSeveral SNPs predicting CHD events appear to involve pathways not currently indexed by the established or emerging risk factors; others involved changes in blood lipids including triglycerides or HDL-cholesterol as well as LDL-cholesterol. The overlapping association of SNPs with multiple risk factors and biomarkers supports the existence of shared points of regulation for these phenotypes.

Original language	English
Pages (from-to)	393-407
Number of pages	15
Journal	European heart journal
Volume	33
Issue number	3
DOIs	https://doi.org/10.1093/eurheartj/ehr225
Publication status	Published or Issued - Feb 2012

Keywords

Coronary disease
Genes
Lipids
Risk factors

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

Access to Document

10.1093/eurheartj/ehr225

Cite this

Angelakopoulou, A., Shah, T., Sofat, R., Shah, S., Berry, D. J., Cooper, J., Palmen, J., Tzoulaki, I., Wong, A., Jefferis, B. J., Maniatis, N., Drenos, F., Gigante, B., Hardy, R., Laxton, R. C., Leander, K., Motterle, A., Simpson, I. A., Smeeth, L., ... Hingorani, A. D. (2012). Comparative analysis of genome-wide association studies signals for lipids, diabetes, and coronary heart disease: Cardiovascular Biomarker Genetics Collaboration. European heart journal, 33(3), 393-407. https://doi.org/10.1093/eurheartj/ehr225

@article{0a2c4aac23d34dbf92017bb621da26ad,

title = "Comparative analysis of genome-wide association studies signals for lipids, diabetes, and coronary heart disease: Cardiovascular Biomarker Genetics Collaboration",

abstract = "AimsTo evaluate the associations of emergent genome-wide-association study-derived coronary heart disease (CHD)-associated single nucleotide polymorphisms (SNPs) with established and emerging risk factors, and the association of genome-wide-association study-derived lipid-associated SNPs with other risk factors and CHD events.Methods and resultsUsing two casecontrol studies, three cross-sectional, and seven prospective studies with up to 25 000 individuals and 5794 CHD events we evaluated associations of 34 genome-wide-association study-identified SNPs with CHD risk and 16 CHD-associated risk factors or biomarkers. The Ch9p21 SNPs rs1333049 (OR 1.17; 95 confidence limits 1.111.24) and rs10757274 (OR 1.17; 1.091.26), MIA3 rs17465637 (OR 1.10; 1.041.15), Ch2q36 rs2943634 (OR 1.08; 1.031.14), APC rs383830 (OR 1.10; 1.02, 1.18), MTHFD1L rs6922269 (OR 1.10; 1.03, 1.16), CXCL12 rs501120 (OR 1.12; 1.04, 1.20), and SMAD3 rs17228212 (OR 1.11; 1.05, 1.17) were all associated with CHD risk, but not with the CHD biomarkers and risk factors measured. Among the 20 blood lipid-related SNPs, LPL rs17411031 was associated with a lower risk of CHD (OR 0.91; 0.840.97), an increase in Apolipoprotein AI and HDL-cholesterol, and reduced triglycerides. SORT1 rs599839 was associated with CHD risk (OR 1.20; 1.151.26) as well as total-and LDL-cholesterol, and apolipoprotein B. ANGPTL3 rs12042319 was associated with CHD risk (OR 1.11; 1.03, 1.19), total-and LDL-cholesterol, triglycerides, and interleukin-6. ConclusionSeveral SNPs predicting CHD events appear to involve pathways not currently indexed by the established or emerging risk factors; others involved changes in blood lipids including triglycerides or HDL-cholesterol as well as LDL-cholesterol. The overlapping association of SNPs with multiple risk factors and biomarkers supports the existence of shared points of regulation for these phenotypes.",

keywords = "Coronary disease, Genes, Lipids, Risk factors",

author = "Aspasia Angelakopoulou and Tina Shah and Reecha Sofat and Sonia Shah and Berry, {Diane J.} and Jackie Cooper and Jutta Palmen and Ioanna Tzoulaki and Andrew Wong and Jefferis, {Barbara J.} and Nikolas Maniatis and Fotios Drenos and Bruna Gigante and Rebecca Hardy and Laxton, {Ross C.} and Karin Leander and Anna Motterle and Simpson, {Iain A.} and Liam Smeeth and Andy Thomson and Claudio Verzilli and Diana Kuh and Helen Ireland and John Deanfield and Mark Caulfield and Chris Wallace and Nilesh Samani and Munroe, {Patricia B.} and Mark Lathrop and Fowkes, {F. Gerry R} and Michael Marmot and Whincup, {Peter H.} and Whittaker, {John C.} and {De Faire}, Ulf and Mika Kivimaki and Meena Kumari and Elina Hypponen and Chris Power and Humphries, {Steve E.} and Talmud, {Philippa J.} and Jackie Price and Morris, {Richard W.} and Shu Ye and Casas, {Juan P.} and Hingorani, {Aroon D.}",

note = "Funding Information: NPHS II was supported by the British Medical Research Council, the US National Institute of Health (grant NHLBI 33014) and Du Pont Pharma, Wilmington, USA. The British Regional Heart Study is a British Heart Foundation Research Group and is supported by British Heart Foundation (RG/04/003). The views expressed in this publication are those of the authors and not necessarily those of the funding bodies. Samples from the English Longitudinal Study of Ageing (ELSA) DNA Repository (EDNAR), received support under a grant (AG1764406S1) awarded by the National Institute on Ageing (NIA). ELSA was developed by a team of researchers based at the National Centre for Social Research, University College London and the Institute of Fiscal Studies. The data were collected by the National Centre for Social Research. The developers and funders of ELSA and the Archive do not bear any responsibility for the analyses or interpretations presented here. The Edinburgh Artery Study (EAS) was funded by the British Heart Foundation. The Whitehall II study has been supported by grants from the Medical Research Council; Economic and Social Research Council; British Heart Foundation; Health and Safety Executive; Department of Health; National Heart Lung and Blood Institute (HL36310), US, NIH: National Institute on Aging (AG13196), US, NIH; Agency for Health Care Policy Research (HS06516); and the John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health. Analyses of the 1958 birth cohort data were funded by the Medical Research Council (G0601653) and undertaken at GOSH/UCL Institute of Child Health, which received a proportion of funding from the Department of Health{\textquoteright}s NIHR Biomedical Research Centres funding scheme. DNA collection was funded by MRC grant G0000934 and genotyping was funded by Wellcome Trust grant 068545/Z/02. The 1946 British birth cohort is funded by the UK Medical Research Council. The Southampton Atherosclerosis Study (SAS) was funded by the British Heart Foundation PG/ 98183. This work was facilitated by the Barts and The London National Institute for Health Research Cardiovascular Biomedical Research Unit. The Stockholm Heart Epidemiology Program Study (SHEEP) was supported by grants from the Research Council of Sweden (09533), the Swedish Heart and Lung Foundation and Stockholm County Council (ALF). The BRIGHT study is supported by the Medical Research Council (G9521010D) and the British Heart Foundation (PG/02/128). The Barts and The London Charity funded the Barts and The London Genome Centre. This work forms part of the research themes contributing to the translational research portfolio of Barts and the London Cardiovascular Biomedical Research Unit which is supported and funded by the National Institute of Health Research. The BRIGHT study is also extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. The Wellcome Trust Case Control Consortium was funded by the Wellcome Trust (grant number; 076113/B/04/Z). A.D.H. holds a British Heart Foundation Senior Fellowship (FS 05/125). L.S. holds a Wellcome Trust Senior Research Fellowship. R.S. is supported by a British Heart Foundation (Schillingford) Clinical Training Fellowship (FS/07/011). S.E.H. holds a British Heart Foundation Chair in Cardiovascular Genetics, he, P.J.T., J.C. and J.P. are supported by British Heart Foundation RG08/014. E.H. is funded by a Department of Health (UK) Public Health Career Scientist Award. S.Y. is supported by the British Heart Foundation FS/07/021. D.K., R.H. and A.W. are funded by the MRC. C.W. was supported by a British Heart Foundation Intermediate Fellowship (FS/05/061/19501). J.D. holds a British Heart Foundation Chair in Cardiology. M.K. and M.K. are supported by the National Heart, Lung, and Blood Institute, NIH, USA (R01HL036310). M.C. and P.B.M. are funded by the Barts and The London National Institute for Health Research Cardiovascular Biomedical Research Unit and the MRC Programme grant G9521010. Funding to pay the Open Access publication charges for this article will be provided by the British Heart Foundation.",

year = "2012",

month = feb,

doi = "10.1093/eurheartj/ehr225",

language = "English",

volume = "33",

pages = "393--407",

journal = "European heart journal",

issn = "0195-668X",

publisher = "Oxford University Press",

number = "3",

}

Angelakopoulou, A, Shah, T, Sofat, R, Shah, S, Berry, DJ, Cooper, J, Palmen, J, Tzoulaki, I, Wong, A, Jefferis, BJ, Maniatis, N, Drenos, F, Gigante, B, Hardy, R, Laxton, RC, Leander, K, Motterle, A, Simpson, IA, Smeeth, L, Thomson, A, Verzilli, C, Kuh, D, Ireland, H, Deanfield, J, Caulfield, M, Wallace, C, Samani, N, Munroe, PB, Lathrop, M, Fowkes, FGR, Marmot, M, Whincup, PH, Whittaker, JC, De Faire, U, Kivimaki, M, Kumari, M, Hypponen, E, Power, C, Humphries, SE, Talmud, PJ, Price, J, Morris, RW, Ye, S, Casas, JP & Hingorani, AD 2012, 'Comparative analysis of genome-wide association studies signals for lipids, diabetes, and coronary heart disease: Cardiovascular Biomarker Genetics Collaboration', European heart journal, vol. 33, no. 3, pp. 393-407. https://doi.org/10.1093/eurheartj/ehr225

TY - JOUR

T1 - Comparative analysis of genome-wide association studies signals for lipids, diabetes, and coronary heart disease

T2 - Cardiovascular Biomarker Genetics Collaboration

AU - Angelakopoulou, Aspasia

AU - Shah, Tina

AU - Sofat, Reecha

AU - Shah, Sonia

AU - Berry, Diane J.

AU - Cooper, Jackie

AU - Palmen, Jutta

AU - Tzoulaki, Ioanna

AU - Wong, Andrew

AU - Jefferis, Barbara J.

AU - Maniatis, Nikolas

AU - Drenos, Fotios

AU - Gigante, Bruna

AU - Hardy, Rebecca

AU - Laxton, Ross C.

AU - Leander, Karin

AU - Motterle, Anna

AU - Simpson, Iain A.

AU - Smeeth, Liam

AU - Thomson, Andy

AU - Verzilli, Claudio

AU - Kuh, Diana

AU - Ireland, Helen

AU - Deanfield, John

AU - Caulfield, Mark

AU - Wallace, Chris

AU - Samani, Nilesh

AU - Munroe, Patricia B.

AU - Lathrop, Mark

AU - Fowkes, F. Gerry R

AU - Marmot, Michael

AU - Whincup, Peter H.

AU - Whittaker, John C.

AU - De Faire, Ulf

AU - Kivimaki, Mika

AU - Kumari, Meena

AU - Hypponen, Elina

AU - Power, Chris

AU - Humphries, Steve E.

AU - Talmud, Philippa J.

AU - Price, Jackie

AU - Morris, Richard W.

AU - Ye, Shu

AU - Casas, Juan P.

AU - Hingorani, Aroon D.

N1 - Funding Information: NPHS II was supported by the British Medical Research Council, the US National Institute of Health (grant NHLBI 33014) and Du Pont Pharma, Wilmington, USA. The British Regional Heart Study is a British Heart Foundation Research Group and is supported by British Heart Foundation (RG/04/003). The views expressed in this publication are those of the authors and not necessarily those of the funding bodies. Samples from the English Longitudinal Study of Ageing (ELSA) DNA Repository (EDNAR), received support under a grant (AG1764406S1) awarded by the National Institute on Ageing (NIA). ELSA was developed by a team of researchers based at the National Centre for Social Research, University College London and the Institute of Fiscal Studies. The data were collected by the National Centre for Social Research. The developers and funders of ELSA and the Archive do not bear any responsibility for the analyses or interpretations presented here. The Edinburgh Artery Study (EAS) was funded by the British Heart Foundation. The Whitehall II study has been supported by grants from the Medical Research Council; Economic and Social Research Council; British Heart Foundation; Health and Safety Executive; Department of Health; National Heart Lung and Blood Institute (HL36310), US, NIH: National Institute on Aging (AG13196), US, NIH; Agency for Health Care Policy Research (HS06516); and the John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health. Analyses of the 1958 birth cohort data were funded by the Medical Research Council (G0601653) and undertaken at GOSH/UCL Institute of Child Health, which received a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres funding scheme. DNA collection was funded by MRC grant G0000934 and genotyping was funded by Wellcome Trust grant 068545/Z/02. The 1946 British birth cohort is funded by the UK Medical Research Council. The Southampton Atherosclerosis Study (SAS) was funded by the British Heart Foundation PG/ 98183. This work was facilitated by the Barts and The London National Institute for Health Research Cardiovascular Biomedical Research Unit. The Stockholm Heart Epidemiology Program Study (SHEEP) was supported by grants from the Research Council of Sweden (09533), the Swedish Heart and Lung Foundation and Stockholm County Council (ALF). The BRIGHT study is supported by the Medical Research Council (G9521010D) and the British Heart Foundation (PG/02/128). The Barts and The London Charity funded the Barts and The London Genome Centre. This work forms part of the research themes contributing to the translational research portfolio of Barts and the London Cardiovascular Biomedical Research Unit which is supported and funded by the National Institute of Health Research. The BRIGHT study is also extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. The Wellcome Trust Case Control Consortium was funded by the Wellcome Trust (grant number; 076113/B/04/Z). A.D.H. holds a British Heart Foundation Senior Fellowship (FS 05/125). L.S. holds a Wellcome Trust Senior Research Fellowship. R.S. is supported by a British Heart Foundation (Schillingford) Clinical Training Fellowship (FS/07/011). S.E.H. holds a British Heart Foundation Chair in Cardiovascular Genetics, he, P.J.T., J.C. and J.P. are supported by British Heart Foundation RG08/014. E.H. is funded by a Department of Health (UK) Public Health Career Scientist Award. S.Y. is supported by the British Heart Foundation FS/07/021. D.K., R.H. and A.W. are funded by the MRC. C.W. was supported by a British Heart Foundation Intermediate Fellowship (FS/05/061/19501). J.D. holds a British Heart Foundation Chair in Cardiology. M.K. and M.K. are supported by the National Heart, Lung, and Blood Institute, NIH, USA (R01HL036310). M.C. and P.B.M. are funded by the Barts and The London National Institute for Health Research Cardiovascular Biomedical Research Unit and the MRC Programme grant G9521010. Funding to pay the Open Access publication charges for this article will be provided by the British Heart Foundation.

PY - 2012/2

Y1 - 2012/2

N2 - AimsTo evaluate the associations of emergent genome-wide-association study-derived coronary heart disease (CHD)-associated single nucleotide polymorphisms (SNPs) with established and emerging risk factors, and the association of genome-wide-association study-derived lipid-associated SNPs with other risk factors and CHD events.Methods and resultsUsing two casecontrol studies, three cross-sectional, and seven prospective studies with up to 25 000 individuals and 5794 CHD events we evaluated associations of 34 genome-wide-association study-identified SNPs with CHD risk and 16 CHD-associated risk factors or biomarkers. The Ch9p21 SNPs rs1333049 (OR 1.17; 95 confidence limits 1.111.24) and rs10757274 (OR 1.17; 1.091.26), MIA3 rs17465637 (OR 1.10; 1.041.15), Ch2q36 rs2943634 (OR 1.08; 1.031.14), APC rs383830 (OR 1.10; 1.02, 1.18), MTHFD1L rs6922269 (OR 1.10; 1.03, 1.16), CXCL12 rs501120 (OR 1.12; 1.04, 1.20), and SMAD3 rs17228212 (OR 1.11; 1.05, 1.17) were all associated with CHD risk, but not with the CHD biomarkers and risk factors measured. Among the 20 blood lipid-related SNPs, LPL rs17411031 was associated with a lower risk of CHD (OR 0.91; 0.840.97), an increase in Apolipoprotein AI and HDL-cholesterol, and reduced triglycerides. SORT1 rs599839 was associated with CHD risk (OR 1.20; 1.151.26) as well as total-and LDL-cholesterol, and apolipoprotein B. ANGPTL3 rs12042319 was associated with CHD risk (OR 1.11; 1.03, 1.19), total-and LDL-cholesterol, triglycerides, and interleukin-6. ConclusionSeveral SNPs predicting CHD events appear to involve pathways not currently indexed by the established or emerging risk factors; others involved changes in blood lipids including triglycerides or HDL-cholesterol as well as LDL-cholesterol. The overlapping association of SNPs with multiple risk factors and biomarkers supports the existence of shared points of regulation for these phenotypes.

AB - AimsTo evaluate the associations of emergent genome-wide-association study-derived coronary heart disease (CHD)-associated single nucleotide polymorphisms (SNPs) with established and emerging risk factors, and the association of genome-wide-association study-derived lipid-associated SNPs with other risk factors and CHD events.Methods and resultsUsing two casecontrol studies, three cross-sectional, and seven prospective studies with up to 25 000 individuals and 5794 CHD events we evaluated associations of 34 genome-wide-association study-identified SNPs with CHD risk and 16 CHD-associated risk factors or biomarkers. The Ch9p21 SNPs rs1333049 (OR 1.17; 95 confidence limits 1.111.24) and rs10757274 (OR 1.17; 1.091.26), MIA3 rs17465637 (OR 1.10; 1.041.15), Ch2q36 rs2943634 (OR 1.08; 1.031.14), APC rs383830 (OR 1.10; 1.02, 1.18), MTHFD1L rs6922269 (OR 1.10; 1.03, 1.16), CXCL12 rs501120 (OR 1.12; 1.04, 1.20), and SMAD3 rs17228212 (OR 1.11; 1.05, 1.17) were all associated with CHD risk, but not with the CHD biomarkers and risk factors measured. Among the 20 blood lipid-related SNPs, LPL rs17411031 was associated with a lower risk of CHD (OR 0.91; 0.840.97), an increase in Apolipoprotein AI and HDL-cholesterol, and reduced triglycerides. SORT1 rs599839 was associated with CHD risk (OR 1.20; 1.151.26) as well as total-and LDL-cholesterol, and apolipoprotein B. ANGPTL3 rs12042319 was associated with CHD risk (OR 1.11; 1.03, 1.19), total-and LDL-cholesterol, triglycerides, and interleukin-6. ConclusionSeveral SNPs predicting CHD events appear to involve pathways not currently indexed by the established or emerging risk factors; others involved changes in blood lipids including triglycerides or HDL-cholesterol as well as LDL-cholesterol. The overlapping association of SNPs with multiple risk factors and biomarkers supports the existence of shared points of regulation for these phenotypes.

KW - Coronary disease

KW - Genes

KW - Lipids

KW - Risk factors

UR - http://www.scopus.com/inward/record.url?scp=84856747078&partnerID=8YFLogxK

U2 - 10.1093/eurheartj/ehr225

DO - 10.1093/eurheartj/ehr225

M3 - Article

C2 - 21804106

AN - SCOPUS:84856747078

SN - 0195-668X

VL - 33

SP - 393

EP - 407

JO - European heart journal

JF - European heart journal

IS - 3

ER -

Comparative analysis of genome-wide association studies signals for lipids, diabetes, and coronary heart disease: Cardiovascular Biomarker Genetics Collaboration

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