Genetic variation in apolipoprotein A-I concentrations and risk of coronary artery disease
Minna K Karjalainen,
Michael V Holmes,
Aki S Havulinna,
Jorma S Viikari,
Olli T. Raitakari,
Posted 15 Mar 2019
bioRxiv DOI: 10.1101/576504
Posted 15 Mar 2019
Rationale: Apolipoprotein A-I (apoA-I) infusions represent a potential novel therapeutic approach for the prevention of coronary artery disease (CAD) with phase III cardiovascular outcome trials currently underway. Although circulating apoA-I levels inversely associate with risk of CAD, the evidence base of this representing a causal relationship is lacking. Objective: To assess the causal role of apoA-I in CAD using human genetics. Methods and Results: We identified a variant (rs12225230) in APOA1 locus that associated with circulating apoA-I concentrations at GWAS significance (P<5x10-8) in 20,370 Finnish participants and meta-analyzed our data with a previous genome-wide association study 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. We also summarized the available evidence from randomized controlled trials (RCTs) of apoA-I infusion therapies reporting CAD events. 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=1.5x10-9) but not with potential 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 to the observational association (P-het<0.001). RCTs of apoA-I infusions did not show an effect on the risk of CAD. Conclusions: Genetic evidence fails to support a cardioprotective role for apoA-I. This casts doubt on the likely benefit of apoA-I infusion therapy in the ongoing phase III cardiovascular outcome trial.
- Downloaded 313 times
- Download rankings, all-time:
- Site-wide: 74,320
- In epidemiology: 3,023
- Year to date:
- Site-wide: 74,577
- Since beginning of last month:
- Site-wide: 118,331
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!