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

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.

Figure 1

APOA5 −1131T>C genotypes and circulating lipid concentration Size of data markers is proportional to the inverse of the variance of the weighted mean difference (the reference group is represented by a square with an arbitrary fixed size) and the vertical lines represent 95% CIs. To enable comparison of associations across lipids and apolipoproteins, associations are presented as percentage differences (calculated in reference to the weighted mean of each marker in common homozygotes). *Reference group.

Figure 2

Association of APOA5 −1131T>C with circulating lipid concentration per C allele Size of data markers is proportional to the inverse of the variance of the weighted mean difference, and the horizontal lines represent 95% CIs. To enable comparison of associations across lipids and apolipoproteins, associations are presented as percentage differences (calculated in reference to the weighted mean of each marker in common homozygotes).

Figure 3

Association of APOA5 −1131T>C genotypes and equivalent differences in circulating triglyceride concentration with risk of coronary heart disease Non-lipid factors adjusted for included smoking status, systolic blood pressure, body-mass index, and history of diabetes (webappendix p 5). Size of data markers is proportional to the inverse of the variance of the weighted mean difference (the reference group is represented by a square with an arbitrary fixed size) and the vertical lines represent 95% CIs. *Reference group. †Odds ratio for coronary heart disease associated with APOA5 −1131T>C. ‡Hazard ratio for coronary heart disease in prospective studies for differences in usual triglyceride concentration equal to those recorded with APOA5 −1131T>C (as reported in figure 1).