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.