Genetic variation in apolipoprotein A-I concentrations and risk of coronary artery disease

Abstract

Rationale: Apolipoprotein A-I (apoA-I) infusions represent a potential novel therapeutic approach for the prevention of coronary artery disease (CAD) with phase III cardiovascular outcome trials currently underway. Although circulating apoA-I levels inversely associate with risk of CAD, the evidence base of this representing a causal relationship is lacking.Objective: To assess the causal role of apoA-I in CAD using human genetics. Methods and Results:We identified a variant (rs12225230) in APOA1 locus that associated with circulating apoA-I concentrations at GWAS significance (P<5x10 -8 ) in 20,370 Finnish participants and meta-analyzed our data with a previous genome-wide association study of apoA-I. We obtained genetic estimates of CAD from UK Biobank and CARDIoGRAMplusC4D (totaling 122,733 CAD cases) and conducted a two-sample Mendelian randomization analysis. We compared our genetic findings to observational associations of apoA-I with risk of CAD in 918 incident CAD cases among 11,535 individuals from population-based prospective cohorts. We also summarized the available evidence from randomized controlled trials (RCTs) of apoA-I infusion therapies reporting CAD events. ApoA-I was associated with a lower risk of CAD in observational analyses (HR 0.81; 95%CI: 0.75, 0.88; per 1-SD higher apoA-I), with the association showing a dose-response relationship. Rs12225230 associated with apoA-I concentrations (per-C allele beta 0.076 SD; SE: 0.013; P=1.5x10 -9 ) but not with potential confounders. In Mendelian randomization analyses, apoA-I was not related to risk of CAD (OR 1.13; 95%CI: 0.98, 1.30 per 1-SD higher apoA-I), which was different to the observational association (P-het<0.001). RCTs of apoA-I infusions did not show an effect on the risk of CAD.

High-density lipoprotein characteristics and coronary heart disease: a Mendelian randomization study

“…Recent studies suggest that HDL functions and quality characteristics, rather than HDL-C concentration, are the main determinants of HDL anti-atherogenic properties 5 . Our data are consistent with previous evidence, and reflect that HDL-C and ApoA-I levels in the bloodstream are not causally related to CAD 3,11 . However, we observed a decrease in CAD risk when HDL-C was mainly transported in smaller HDLs, but an increase in CAD risk when HDL-C was carried by larger HDL particles (in both main and validation analyses, there is a gradient towards greater CAD risk as more cholesterol is transported in larger HDLs).…”

“…These studies assess the association between the genetically determined lifelong values of a biomarker and the development of a clinical outcome. MR studies have already raised serious doubts on the causal role of quantitative HDL characteristics, such as HDL-C and apolipoprotein A-I (ApoA-I) levels, in CAD 3,11 . However, to date, the association between qualitative HDL characteristics and CAD has not been tested using a MR approach.…”

Association of LpPLA2 with coronary artery disease a hospital-based case control study

“…ApoA-I has the ability to reverse cholesterol transport (RCT), to bind lipids, and to activate lecithin cholesterol acyltransferase (LCAT) to form mature HDL. [12][13][14][15] Apolipoprotein B exists in two forms, apo B-48 and apo B-100. Apo B-48 is synthesized in the intestine, where it is complexes with dietary triglycerides and free cholesterol absorbed from the gut lumen to form chylomicron particles.…”