Triglyceride-mediated pathways and coronary disease: Statistical methods for the time-to-event analysis of individual participant data from multiple epidemiological 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, George Davey Smith, Muredach P Reilly, Aroon D Hingorani, Philippa J Talmud, John Danesh, Triglyceride Coronary Disease Genetics Consortium, Emerging Risk Factors Collaboration, Richard W Morris

Research output: Contribution to journalArticle (Academic Journal)peer-review

485 Citations (Scopus)

Abstract

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 differences 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 significantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean difference 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=4.4x10(-24)). The odds ratio for coronary heart disease was 1.18 (95% CI 1.11-1.26; p=2.6x10(-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 significantly associated with higher VLDL particle concentration (mean difference per C allele 12.2 nmol/L [95% CI 7.7-16.7]; p=9.3x10(-8)) and smaller HDL particle size (0.14 nm [0.08-0.20]; p=7.0x10(-5)), factors that could mediate the effects 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.

Translated title of the contributionTriglyceride-mediated pathways and coronary disease: Statistical methods for the time-to-event analysis of individual participant data from multiple epidemiological studies
Original languageEnglish
Pages (from-to)1634 - 1639
Number of pages5
JournalLancet
Volume375
Issue number9726
DOIs
Publication statusPublished - 8 May 2010

Bibliographical note

Copyright 2010 Elsevier Ltd. All rights reserved.

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

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