Genetic variation in apolipoprotein A-I concentrations and risk of coronary artery disease
Genetic variation in apolipoprotein A-I concentrations and risk of coronary artery disease
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. ObjectiveTo assess the causal role of apoA-I in CAD using human genetics. Methods and ResultsWe identified a variant (rs12225230) in APOA1 locus that associated with circulating apoA-I concentrations at GWAS significance (P<5×10?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=1.5×10?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. ConclusionsGenetic 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.
Havulinna Aki S.、Kristiansson Kati、Perola Markus、Kettunen Johannes、Salomaa Veikko、Karjalainen Minna K.、Anufrieva Olga、Viikari Jorma S.、Lehtim?ki Terho、Raitakari Olli T.、J?rvelin Marjo-Riitta、Holmes Michael V.、Wang Qin、Ala-Korpela Mika、K?h?nen Mika
National Institute for Health and Welfare||Institute for Molecular Medicine Finland (FIMM-HiLIFE)National Institute for Health and WelfareNational Institute for Health and Welfare||Diabetes and Obesity Research Program, University of Helsinki||Estonian Genome Center, University of TartuComputational Medicine, Faculty of Medicine, University of Oulu||Center for Life Course Health Research, Faculty of Medicine, University of Oulu||Biocenter Oulu, University of Oulu||National Institute for Health and WelfareNational Institute for Health and WelfareComputational Medicine, Faculty of Medicine, University of Oulu||Center for Life Course Health Research, Faculty of Medicine, University of Oulu||Biocenter Oulu, University of OuluComputational Medicine, Faculty of Medicine, University of Oulu||Center for Life Course Health Research, Faculty of Medicine, University of Oulu||Biocenter Oulu, University of OuluDepartment of Medicine, University of Turku||Division of Medicine, Turku University HospitalDepartment of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere UniversityResearch Centre of Applied and Preventive Cardiovascular Medicine, University of Turku||Department of Clinical Physiology and Nuclear Medicine, Turku University HospitalCenter for Life Course Health Research, Faculty of Medicine, University of Oulu||Biocenter Oulu, University of Oulu||Unit of Primary Health Care, Oulu University Hospital||Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London||Department of Life Sciences, College of Health and Life Sciences, Brunel University LondonMedical Research Council Population Health Research Unit, University of Oxford||Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford||National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospital||Medical Research Council Integrative Epidemiology Unit at the University of BristolComputational Medicine, Faculty of Medicine, University of Oulu||Center for Life Course Health Research, Faculty of Medicine, University of Oulu||Biocenter Oulu, University of Oulu||Systems Epidemiology, Baker Heart and Diabetes InstituteComputational Medicine, Faculty of Medicine, University of Oulu||Center for Life Course Health Research, Faculty of Medicine, University of Oulu||Biocenter Oulu, University of Oulu||Medical Research Council Integrative Epidemiology Unit at the University of Bristol||Systems Epidemiology, Baker Heart and Diabetes Institute||Population Health Science, Bristol Medical School, University of Bristol||NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland||Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, The Alfred Hospital, Monash UniversityDepartment of Clinical Physiology, Tampere University Hospital, and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University
医药卫生理论医学研究方法基础医学
Coronary artery diseaseApolipoprotein A-IMendelian randomization
Havulinna Aki S.,Kristiansson Kati,Perola Markus,Kettunen Johannes,Salomaa Veikko,Karjalainen Minna K.,Anufrieva Olga,Viikari Jorma S.,Lehtim?ki Terho,Raitakari Olli T.,J?rvelin Marjo-Riitta,Holmes Michael V.,Wang Qin,Ala-Korpela Mika,K?h?nen Mika.Genetic variation in apolipoprotein A-I concentrations and risk of coronary artery disease[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/576504.点此复制
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