University of Oulu

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, Apolipoprotein A-I concentrations and risk of coronary artery disease: A Mendelian randomization study, Atherosclerosis, Volume 299, 2020, Pages 56-63, ISSN 0021-9150,

Apolipoprotein A-I concentrations and risk of coronary artery disease : a Mendelian randomization study

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Author: Karjalainen, Minna K.1,2,3; Holmes, Michael V.4,5,6,7; Wang, Qin1,2,3,8;
Organizations: 1Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland
2Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
3Biocenter Oulu, University of Oulu, Oulu, Finland
4Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK
5Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
6National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK
7Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
8Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
9Department of Clinical Physiology, Tampere University Hospital, and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
10Department of Clinical Chemistry, Fimlab Laboratoriesand Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
11National Institute for Health and Welfare, Helsinki, Finland
12Institute for Molecular Medicine Finland (FIMM-HiLIFE), Helsinki, Finland
13Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland
14Estonian Genome Center, University of Tartu, Tartu, Estonia
15Department of Medicine, University of Turku, Turku, Finland
16Division of Medicine, Turku University Hospital, Turku, Finland
17Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
18Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
19Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
20Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland
21Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK
22Department of Life Sciences, College of Health and Life Sciences, Brunel University London, UK
23NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
24Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, The Alfred Hospital, Monash University, Melbourne, VIC, Australia
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.4 MB)
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Language: English
Published: Elsevier, 2020
Publish Date: 2020-06-01


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.

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Series: Atherosclerosis
ISSN: 0021-9150
ISSN-E: 1879-1484
ISSN-L: 0021-9150
Volume: 299
Pages: 56 - 63
DOI: 10.1016/j.atherosclerosis.2020.02.002
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
Funding: MAK and JK are supported by a research grant from the Sigrid Juselius Foundation, Finland. JK is supported through funds from the Academy of Finland (grant numbers 297338 and 307247) and the Novo Nordisk Foundation (grant number NNF17OC0026062). MVH works in a unit that receives funding from the UK Medical Research Council and is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre. QW is supported by a Postdoctoral Fellowship from the Novo Nordisk Foundation (NNF17OC0027034). VS is supported by the Finnish Foundation for Cardiovascular Research. KK is supported by the Academy of Finland (grant number 250207). The Young Finns Study has been financially supported by the Academy of Finland: grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; EU Horizon 2020 (grant 755320 for TAXINOMISIS); European Research Council (grant 742927 for MULTIEPIGEN project); and Tampere University Hospital Supporting Foundation. NFBC66 received financial support from University of Oulu Grant no. 65354; Oulu University Hospital Grant no. 2/97, 8/97; Ministry of Health and Social Affairs Grant no. 23/251/97, 160/97, 190/97; National Institute for Health and Welfare, Helsinki Grant no. 54121; and Regional Institute of Occupational Health, Oulu, Finland Grant no. 50621, 54231. NFBC86 was supported by the following grants: EU QLG1- CT-2000-01643 (EUROBLCS) Grant no. E51560; NorFA Grants no. 731, 20056, 30167; and USA/NIHH 2000 G DF682 Grant no. 50945. The Baker Institute is supported in part by the Victorian Government's Operational Infrastructure Support Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Academy of Finland Grant Number: 297338
Detailed Information: 297338 (Academy of Finland Funding decision)
307247 (Academy of Finland Funding decision)
Copyright information: © 2020 The Authors. Published by Elsevier B.V. This manuscript version is made available under the CC-BY-NC-ND 4.0 license