Apolipoprotein A-V is a potential target for treating coronary artery disease: evidence from genetic and metabolomic analyses

Abstract

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.

Keywords: LDL; cardiovascular disease; clinical data; factorial analysis; genetic variation; hyperlipidemia; lipid-lowering therapy; lipoprotein lipase; lipoproteins; triglycerides.

Fig. 1

Associations of genotype group with Coronary Artery Disease in the UK Biobank cohort. Values are mean (SD) for LDL-C levels and median (IQR) for TG levels. GRS unit is in SD. CI, Confidence interval; OR, odds ratio; GRS, genetic risk scores.

Fig. 2

Associations of the group with genetically-influenced lower TG levels via LPL with 145 NMR-based metabolomic measures in 2 × 2 factorial analyses, in the Netherlands Epidemiology of Obesity (NEO) study (n = 4,838) and in the Oxford Biobank (OBB) cohort (n=6,999). Group with genetically-influenced lower TG levels via LPL compared with the reference group (genetically-influenced higher TG levels via both LPL and APOA5). Bar heights represent the magnitude of the beta coefficient from linear regression, which is expressed in SD units. Red bars indicate positive betas and blue bars indicate negative betas. The transparency of the bars indicates the level of statistical significance. A p <1.35 × 10⁻³ is regarded statistical significant, as represented by the black dots.

Fig. 3

Associations of the group with genetically-influenced lower TG levels via APOA5 with 145 NMR-based metabolomic measures in 2 × 2 factorial analyses, in the Netherlands Epidemiology of Obesity (NEO) study (n = 4,838) and in the Oxford Biobank (OBB) cohort (n=6,999). Group with genetically-influenced lower TG levels via APOA5 compared with the reference group (genetically-influenced higher TG levels via both LPL and APOA5). Bar heights represent the magnitude of the beta coefficient from linear regression, which is expressed in SD units. Red bars indicate positive betas and blue bars indicate negative betas. The transparency of the bars indicates the level of statistical significance. A p <1.35 × 10⁻³ is regarded statistical significant, as represented by the black dots.

Fig. 4

Associations of the group with genetically-influenced lower TG levels via both LPL and APOA5 with 145 NMR-based metabolomic measures in 2 × 2 factorial analyses, in the Netherlands Epidemiology of Obesity (NEO) study (n = 4,838) and in the Oxford Biobank (OBB) cohort (n=6,999). Group with genetically-influenced lower TG levels via both LPL and APOA5 compared with the reference group (genetically-influenced higher TG levels via both LPL and APOA5). Bar heights represent the magnitude of the beta coefficient from linear regression, which is expressed in SD units. Red bars indicate positive betas and blue bars indicate negative betas. The transparency of the bars indicates the level of statistical significance. A p <1.35 × 10⁻³ is regarded statistical significant, as represented by the black dots.