Apolipoprotein A-I concentrations and risk of coronary artery disease: A Mendelian randomization study

Atherosclerosis. 2020 Apr:299:56-63. doi: 10.1016/j.atherosclerosis.2020.02.002. Epub 2020 Feb 14.

Abstract

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.

Keywords: Apolipoprotein; Heart disease; Lipids; Mendelian randomization.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apolipoprotein A-I* / blood
  • Apolipoprotein A-I* / genetics
  • Apolipoprotein A-I* / therapeutic use
  • Biomarkers / blood
  • Coronary Artery Disease* / blood
  • Coronary Artery Disease* / epidemiology
  • Coronary Artery Disease* / genetics
  • Coronary Artery Disease* / prevention & control
  • Finland / epidemiology
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Incidence
  • Mendelian Randomization Analysis
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Prognosis
  • Protective Factors
  • Risk Assessment
  • Risk Factors

Substances

  • APOA1 protein, human
  • Apolipoprotein A-I
  • Biomarkers