Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

BACKGROUND AND AIMS: Apolipoprotein A-I (apoA-I) infusions represent a potential novel therapeutic approach for the prevention of coronary artery disease (CAD). Although circulating apoA-I concentrations inversely associate with risk of CAD, the evidence base of this representing a causal relationship is lacking. The aim was to assess the causal role of apoA-I using human genetics. METHODS: We identified a variant (rs12225230) in APOA1 locus that associated with circulating apoA-I concentrations (p < 5 × 10-8) in 20,370 Finnish participants, and meta-analyzed our data with a previous GWAS 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. RESULTS: 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 = 1.5 × 10-9) but not with 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 from the observational association. Similar findings were observed using an independent ABCA1 variant in sensitivity analysis. CONCLUSIONS: Genetic evidence fails to support a cardioprotective role for apoA-I. This is in line with the cumulative evidence showing that HDL-related phenotypes are unlikely to have a protective role in CAD.

Original publication

DOI

10.1016/j.atherosclerosis.2020.02.002

Type

Journal article

Journal

Atherosclerosis

Publication Date

14/02/2020

Keywords

Apolipoprotein, Heart disease, Lipids, Mendelian randomization