| Title: |
Apolipoprotein A-I concentrations and risk of coronary artery disease: A Mendelian randomization study |
| Authors: |
Karjalainen, MK; Holmes, MV; Wang, Q; Anufrieva, O; Kähönen, M; Lehtimäki, T; Havulinna, AS; Kristiansson, K; Salomaa, V; Perola, M; Viikari, JS; Raitakari, OT; Järvelin, M-R; Ala-Korpela, M; Kettunen, J |
| Publisher Information: |
Elsevier |
| Publication Year: |
2020 |
| Collection: |
Oxford University Research Archive (ORA) |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://doi.org/10.1016/j.atherosclerosis.2020.02.002 |
| DOI: |
10.1016/j.atherosclerosis.2020.02.002 |
| Availability: |
https://doi.org/10.1016/j.atherosclerosis.2020.02.002; https://ora.ox.ac.uk/objects/uuid:9c7e8eac-542b-4e52-a324-90a20ad6c2bd |
| Rights: |
info:eu-repo/semantics/openAccess ; CC Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND) |
| Accession Number: |
edsbas.FE77756A |
| Database: |
BASE |