Apolipoprotein A-I concentrations and risk of coronary artery disease: A Mendelian randomization study
Markus Perola; Kati Kristiansson; Olli T. Raitakari; Qin Wang; Minna K. Karjalainen; Marjo-Riitta Järvelin; Olga Anufrieva; Michael V. Holmes; Jorma S. Viikari; Veikko Salomaa; Mika Kähönen; Johannes Kettunen; Terho Lehtimäki; Mika Ala-Korpela; Aki S. Havulinna
Apolipoprotein A-I concentrations and risk of coronary artery disease: A Mendelian randomization study
Markus Perola
Kati Kristiansson
Olli T. Raitakari
Qin Wang
Minna K. Karjalainen
Marjo-Riitta Järvelin
Olga Anufrieva
Michael V. Holmes
Jorma S. Viikari
Veikko Salomaa
Mika Kähönen
Johannes Kettunen
Terho Lehtimäki
Mika Ala-Korpela
Aki S. Havulinna
Elsevier
Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021042824853
https://urn.fi/URN:NBN:fi-fe2021042824853
Tiivistelmä
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.
Kokoelmat
- Rinnakkaistallenteet [19207]