A1 Refereed original research article in a scientific journal
Apolipoprotein A-I concentrations and risk of coronary artery disease: A Mendelian randomization study
Authors: Minna K. Karjalainen, Michael V. Holmes, Qin Wang, Olga Anufrieva, Mika Kähönen, Terho Lehtimäki, Aki S. Havulinna, Kati Kristiansson, Veikko Salomaa, Markus Perola, Jorma S. Viikari, Olli T. Raitakari, Marjo-Riitta Järvelin, Mika Ala-Korpela, Johannes Kettunen
Publisher: Elsevier
Publication year: 2020
Journal: Atherosclerosis
Journal name in source: Atherosclerosis
Journal acronym: Atherosclerosis
Volume: 299
First page : 56
Last page: 63
Number of pages: 8
ISSN: 0021-9150
eISSN: 1879-1484
DOI: https://doi.org/10.1016/j.atherosclerosis.2020.02.002
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/46736406
Background and aimsApolipoprotein 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.MethodsWe 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.ResultsApoA-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.ConclusionsGenetic 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.
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