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bioRxiv · 10.1101/576504

Genetic variation in apolipoprotein A-I concentrations and risk of coronary artery disease

Karjalainen, M. K.·Holmes, M. V.·Wang, Q.·Anufrieva, O.·Kahonen, M.·Lehtimaki, T.·Havulinna, A. S.·Kristiansson, K.·Salomaa, V.·Perola, M.·Viikari, J. S.·Raitakari, O. T.·Jarvelin, M.-R.·Ala-Korpela, M.·Kettunen, J.
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Abstract

RationaleApolipoprotein 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.\n\nObjectiveTo assess the causal role of apoA-I in CAD using human genetics.\n\nMethods and ResultsWe 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.\n\nConclusionsGenetic 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.

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Karjalainen, M. K., Holmes, M. V., Wang, Q., Anufrieva, O., Kahonen, M., Lehtimaki, T., Havulinna, A. S., Kristiansson, K., Salomaa, V., Perola, M., Viikari, J. S., Raitakari, O. T., Jarvelin, M.-R., Ala-Korpela, M., Kettunen, J.. 2019-03-15. Genetic variation in apolipoprotein A-I concentrations and risk of coronary artery disease. https://doi.org/10.1101/576504

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