Triglyceride (TG)-lowering LPL variants in combination with genetic
LDL-C-lowering variants are associated with reduced risk of
coronary artery disease (CAD). Genetic variation in the APOA5 gene encoding
apolipoprotein A-V also strongly affects TG levels, but the potential clinical impact and underlying mechanisms are yet to be resolved. Here, we aimed to study the effects of APOA5 genetic variation on CAD risk and plasma
lipoproteins through factorial genetic association analyses. Using data from 309,780 European-ancestry participants from the UK Biobank, we evaluated the effects of lower TG levels as a result of genetic variation in APOA5 and/or LPL on CAD risk with or without a background of reduced
LDL-C. Next, we compared lower TG levels via APOA5 and LPL variation with over 100
lipoprotein measurements in a combined sample from the Netherlands Epidemiology of
Obesity study (N = 4,838) and the Oxford Biobank (N = 6,999). We found that lower TG levels due to combined APOA5 and LPL variation and genetically-influenced lower
LDL-C levels afforded the largest reduction in CAD risk (odds ratio: 0.78 (0.73-0.82)). Compared to patients with genetically-influenced lower TG via LPL, genetically-influenced lower TG via APOA5 had similar and independent, but notably larger, effects on the
lipoprotein profile. Our results suggest that lower TG levels as a result of APOA5 variation have strong beneficial effects on CAD risk and the
lipoprotein profile, which suggest
apo A-V may be a potential novel therapeutic target for CAD prevention.