Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies
By N. Sarwar, M. Sandhu, S. Ricketts, Adam S. Butterworth, E. di Angelantonio, S. Boekholdt, Willem H. Ouwehand, H. Watkins, N. Samani, D. Saleheen and 5 more. The Lancet, 2010
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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 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=4·4×10−24). 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 significantly associated with higher VLDL particle concentration (mean difference 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 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.
Subfields: Cardiology and Cardiovascular Medicine, Endocrinology, Diabetes and Metabolism, Surgery
View Paper: https://www.semanticscholar.org/paper/180ca0455694d76e1a1d59cf5a2b27fbe4811fe1
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Citations in the corpus
- National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2. (2015, background): “The magnitude of the differences observed with genetically induced differences in VLDL-C are at least as large as those associated with differences in LDL-C for a given mg/dL difference.(9,14) For example, in the Copenhagen Heart Studies, each 38.”
- Triglyceride-Rich Lipoproteins and Atherosclerotic Cardiovascular Disease: New Insights From Epidemiology, Genetics, and Biology. (2016, neutral): “in another large Mendelian randomization study using a single APOA5 genetic variant.(70) Finally, for APOA5 2 versus 0 triglyceride-reducing alleles, a reduction in nonfasting triglycerides of 35% caused an ASCVD reduction of 24%.”