Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies

Nadeem Sarwar; Manjinder S Sandhu; Sally L Ricketts; Adam S Butterworth; Emanuele Di Angelantonio; S Matthijs Boekholdt; Willem Ouwehand; Hugh Watkins; Nilesh J Samani; Danish Saleheen; Debbie Lawlor; Muredach P Reilly; Aroon D Hingorani; Philippa J Talmud; John Danesh; Torben Jørgensen; Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration; Anne Tybjærg-Hansen; Ruth Frikke-Schmidt; Børge G. Nordestgaard

doi:10.1016/S0140-6736(10)60545-4

Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies

Nadeem Sarwar, Manjinder S Sandhu, Sally L Ricketts, Adam S Butterworth, Emanuele Di Angelantonio, S Matthijs Boekholdt, Willem Ouwehand, Hugh Watkins, Nilesh J Samani, Danish Saleheen, Debbie Lawlor, Muredach P Reilly, Aroon D Hingorani, Philippa J Talmud, John Danesh, Torben Jørgensen, Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration, Anne Tybjærg-Hansen, Ruth Frikke-Schmidt, Børge G. Nordestgaard

491 Citations (Scopus)

Abstract

Summary Background Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality. Methods We assessed the –1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20 842 patients with coronary heart disease, 35 206 controls) with that recorded for equivalent diff erences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12 785 incident cases of coronary heart disease during 2・79 million person-years at risk). We analysed –1131T>C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy. Findings The minor allele frequency of –1131T>C was 8% (95% CI 7–9). –1131T>C was not signifi cantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean diff erence per C allele 3・5% [95% CI 2・6–4・6]; 0・053 mmol/L [0・039–0・068]), lower apolipoprotein AI (1・3% [0・3–2・3]; 0・023 g/L [0・005–0・041]), and higher apolipoprotein B (3・2% [1・3–5・1]; 0・027 g/L [0・011–0・043]). By contrast, for every C allele inherited, mean triglyceride concentration was 16・0% (95% CI 12・9–18・7), or 0・25 mmol/L (0・20–0・29), higher (p=4・4×10–²⁴). The odds ratio for coronary heart disease was 1・18 (95% CI 1・11–1・26; p=2・6×10–⁷) per C allele, which was concordant with the hazard ratio of 1・10 (95% CI 1・08–1・12) per 16% higher triglyceride concentration recorded in prospective studies. –1131T>C was signifi cantly associated with higher VLDL particle concentration (mean diff erence per C allele 12・2 nmol/L [95% CI 7・7–16・7]; p=9・3×10–⁸) and smaller HDL particle size (0・14 nm [0・08–0・20]; p=7・0×10–⁵), factors that could mediate the eff ects of triglyceride. Interpretation These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease. Funding British Heart Foundation, UK Medical Research Council, Novartis.

Original language	English
Journal	Lancet
Volume	375
Issue number	9726
Pages (from-to)	1634-9
Number of pages	6
ISSN	0140-6736
DOIs	https://doi.org/10.1016/S0140-6736(10)60545-4
Publication status	Published - 1 Nov 2010

Keywords

Apolipoproteins
Apolipoproteins A
Coronary Disease
Gene Frequency
Genotype
Humans
Lipids
Lipoproteins, HDL
Lipoproteins, LDL
Lipoproteins, VLDL
Mendelian Randomization Analysis
Particle Size
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Risk Factors
Triglycerides

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/S0140-6736(10)60545-4

Cite this

Sarwar, N., Sandhu, M. S., Ricketts, S. L., Butterworth, A. S., Di Angelantonio, E., Boekholdt, S. M., Ouwehand, W., Watkins, H., Samani, N. J., Saleheen, D., Lawlor, D., Reilly, M. P., Hingorani, A. D., Talmud, P. J., Danesh, J., Jørgensen, T., Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration, Tybjærg-Hansen, A., Frikke-Schmidt, R., & Nordestgaard, B. G. (2010). Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet, 375(9726), 1634-9. https://doi.org/10.1016/S0140-6736(10)60545-4

Sarwar, N, Sandhu, MS, Ricketts, SL, Butterworth, AS, Di Angelantonio, E, Boekholdt, SM, Ouwehand, W, Watkins, H, Samani, NJ, Saleheen, D, Lawlor, D, Reilly, MP, Hingorani, AD, Talmud, PJ, Danesh, J, Jørgensen, T, Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration, Tybjærg-Hansen, A, Frikke-Schmidt, R & Nordestgaard, BG 2010, 'Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies', Lancet, vol. 375, no. 9726, pp. 1634-9. https://doi.org/10.1016/S0140-6736(10)60545-4

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title = "Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies",

abstract = "Summary Background Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality. Methods We assessed the –1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20 842 patients with coronary heart disease, 35 206 controls) with that recorded for equivalent diff erences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12 785 incident cases of coronary heart disease during 2・79 million person-years at risk). We analysed –1131T>C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy. Findings The minor allele frequency of –1131T>C was 8% (95% CI 7–9). –1131T>C was not signifi cantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean diff erence per C allele 3・5% [95% CI 2・6–4・6]; 0・053 mmol/L [0・039–0・068]), lower apolipoprotein AI (1・3% [0・3–2・3]; 0・023 g/L [0・005–0・041]), and higher apolipoprotein B (3・2% [1・3–5・1]; 0・027 g/L [0・011–0・043]). By contrast, for every C allele inherited, mean triglyceride concentration was 16・0% (95% CI 12・9–18・7), or 0・25 mmol/L (0・20–0・29), higher (p=4・4×10–2⁴). The odds ratio for coronary heart disease was 1・18 (95% CI 1・11–1・26; p=2・6×10–⁷) per C allele, which was concordant with the hazard ratio of 1・10 (95% CI 1・08–1・12) per 16% higher triglyceride concentration recorded in prospective studies. –1131T>C was signifi cantly associated with higher VLDL particle concentration (mean diff erence per C allele 12・2 nmol/L [95% CI 7・7–16・7]; p=9・3×10–⁸) and smaller HDL particle size (0・14 nm [0・08–0・20]; p=7・0×10–⁵), factors that could mediate the eff ects of triglyceride. Interpretation These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease. Funding British Heart Foundation, UK Medical Research Council, Novartis.",

keywords = "Apolipoproteins, Apolipoproteins A, Coronary Disease, Gene Frequency, Genotype, Humans, Lipids, Lipoproteins, HDL, Lipoproteins, LDL, Lipoproteins, VLDL, Mendelian Randomization Analysis, Particle Size, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Risk Factors, Triglycerides",

author = "Nadeem Sarwar and Sandhu, {Manjinder S} and Ricketts, {Sally L} and Butterworth, {Adam S} and {Di Angelantonio}, Emanuele and Boekholdt, {S Matthijs} and Willem Ouwehand and Hugh Watkins and Samani, {Nilesh J} and Danish Saleheen and Debbie Lawlor and Reilly, {Muredach P} and Hingorani, {Aroon D} and Talmud, {Philippa J} and John Danesh and Torben J{\o}rgensen and Anne Tybj{\ae}rg-Hansen and Anne Tybj{\ae}rg-Hansen and Ruth Frikke-Schmidt and Nordestgaard, {B{\o}rge G.}",

year = "2010",

month = nov,

day = "1",

doi = "10.1016/S0140-6736(10)60545-4",

language = "English",

volume = "375",

pages = "1634--9",

journal = "Lancet",

issn = "0140-6736",

publisher = "TheLancet Publishing Group",

number = "9726",

}

TY - JOUR

T1 - Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies

AU - Sarwar, Nadeem

AU - Sandhu, Manjinder S

AU - Ricketts, Sally L

AU - Butterworth, Adam S

AU - Di Angelantonio, Emanuele

AU - Boekholdt, S Matthijs

AU - Ouwehand, Willem

AU - Watkins, Hugh

AU - Samani, Nilesh J

AU - Saleheen, Danish

AU - Lawlor, Debbie

AU - Reilly, Muredach P

AU - Hingorani, Aroon D

AU - Talmud, Philippa J

AU - Danesh, John

AU - Jørgensen, Torben

AU - Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration

AU - Tybjærg-Hansen, Anne

AU - Frikke-Schmidt, Ruth

AU - Nordestgaard, Børge G.

PY - 2010/11/1

Y1 - 2010/11/1

N2 - Summary Background Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality. Methods We assessed the –1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20 842 patients with coronary heart disease, 35 206 controls) with that recorded for equivalent diff erences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12 785 incident cases of coronary heart disease during 2・79 million person-years at risk). We analysed –1131T>C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy. Findings The minor allele frequency of –1131T>C was 8% (95% CI 7–9). –1131T>C was not signifi cantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean diff erence per C allele 3・5% [95% CI 2・6–4・6]; 0・053 mmol/L [0・039–0・068]), lower apolipoprotein AI (1・3% [0・3–2・3]; 0・023 g/L [0・005–0・041]), and higher apolipoprotein B (3・2% [1・3–5・1]; 0・027 g/L [0・011–0・043]). By contrast, for every C allele inherited, mean triglyceride concentration was 16・0% (95% CI 12・9–18・7), or 0・25 mmol/L (0・20–0・29), higher (p=4・4×10–2⁴). The odds ratio for coronary heart disease was 1・18 (95% CI 1・11–1・26; p=2・6×10–⁷) per C allele, which was concordant with the hazard ratio of 1・10 (95% CI 1・08–1・12) per 16% higher triglyceride concentration recorded in prospective studies. –1131T>C was signifi cantly associated with higher VLDL particle concentration (mean diff erence per C allele 12・2 nmol/L [95% CI 7・7–16・7]; p=9・3×10–⁸) and smaller HDL particle size (0・14 nm [0・08–0・20]; p=7・0×10–⁵), factors that could mediate the eff ects of triglyceride. Interpretation These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease. Funding British Heart Foundation, UK Medical Research Council, Novartis.

AB - Summary Background Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality. Methods We assessed the –1131T>C (rs662799) promoter polymorphism of the apolipoprotein A5 (APOA5) gene in relation to triglyceride concentration, several other risk factors, and risk of coronary heart disease. We compared disease risk for genetically-raised triglyceride concentration (20 842 patients with coronary heart disease, 35 206 controls) with that recorded for equivalent diff erences in circulating triglyceride concentration in prospective studies (302 430 participants with no history of cardiovascular disease; 12 785 incident cases of coronary heart disease during 2・79 million person-years at risk). We analysed –1131T>C in 1795 people without a history of cardiovascular disease who had information about lipoprotein concentration and diameter obtained by nuclear magnetic resonance spectroscopy. Findings The minor allele frequency of –1131T>C was 8% (95% CI 7–9). –1131T>C was not signifi cantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean diff erence per C allele 3・5% [95% CI 2・6–4・6]; 0・053 mmol/L [0・039–0・068]), lower apolipoprotein AI (1・3% [0・3–2・3]; 0・023 g/L [0・005–0・041]), and higher apolipoprotein B (3・2% [1・3–5・1]; 0・027 g/L [0・011–0・043]). By contrast, for every C allele inherited, mean triglyceride concentration was 16・0% (95% CI 12・9–18・7), or 0・25 mmol/L (0・20–0・29), higher (p=4・4×10–2⁴). The odds ratio for coronary heart disease was 1・18 (95% CI 1・11–1・26; p=2・6×10–⁷) per C allele, which was concordant with the hazard ratio of 1・10 (95% CI 1・08–1・12) per 16% higher triglyceride concentration recorded in prospective studies. –1131T>C was signifi cantly associated with higher VLDL particle concentration (mean diff erence per C allele 12・2 nmol/L [95% CI 7・7–16・7]; p=9・3×10–⁸) and smaller HDL particle size (0・14 nm [0・08–0・20]; p=7・0×10–⁵), factors that could mediate the eff ects of triglyceride. Interpretation These data are consistent with a causal association between triglyceride-mediated pathways and coronary heart disease. Funding British Heart Foundation, UK Medical Research Council, Novartis.

KW - Apolipoproteins

KW - Apolipoproteins A

KW - Coronary Disease

KW - Gene Frequency

KW - Genotype

KW - Humans

KW - Lipids

KW - Lipoproteins, HDL

KW - Lipoproteins, LDL

KW - Lipoproteins, VLDL

KW - Mendelian Randomization Analysis

KW - Particle Size

KW - Polymorphism, Single Nucleotide

KW - Promoter Regions, Genetic

KW - Risk Factors

KW - Triglycerides

U2 - 10.1016/S0140-6736(10)60545-4

DO - 10.1016/S0140-6736(10)60545-4

M3 - Journal article

C2 - 20452521

SN - 0140-6736

VL - 375

SP - 1634

EP - 1639

JO - Lancet

JF - Lancet

IS - 9726

ER -

Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies

Abstract

Keywords

UN SDGs

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