Minna K Karjalainen1, Michael V Holmes2, Qin Wang3, Olga Anufrieva4, Mika Kähönen5, Terho Lehtimäki6, Aki S Havulinna7, Kati Kristiansson8, Veikko Salomaa8, Markus Perola9, Jorma S Viikari10, Olli T Raitakari11, Marjo-Riitta Järvelin12, Mika Ala-Korpela13, Johannes Kettunen14. 1. Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland; Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland. Electronic address: minna.k.karjalainen@oulu.fi. 2. Medical Research Council Population Health Research Unit, University of Oxford, Oxford, UK; Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK; National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK; Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK. Electronic address: michael.holmes@ndph.ox.ac.uk. 3. Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland; Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland; Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia. 4. Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland; Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland. 5. Department of Clinical Physiology, Tampere University Hospital, and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland. 6. Department of Clinical Chemistry, Fimlab Laboratoriesand Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland. 7. National Institute for Health and Welfare, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM-HiLIFE), Helsinki, Finland. 8. National Institute for Health and Welfare, Helsinki, Finland. 9. National Institute for Health and Welfare, Helsinki, Finland; Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland; Estonian Genome Center, University of Tartu, Tartu, Estonia. 10. Department of Medicine, University of Turku, Turku, Finland; Division of Medicine, Turku University Hospital, Turku, Finland. 11. Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland. 12. Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland; Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland; Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK; Department of Life Sciences, College of Health and Life Sciences, Brunel University London, UK. 13. Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland; Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, 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 University, Melbourne, VIC, Australia. Electronic address: mika.ala-korpela@oulu.fi. 14. Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland; Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland; Biocenter Oulu, University of Oulu, Oulu, Finland; National Institute for Health and Welfare, Helsinki, Finland. Electronic address: johannes.kettunen@oulu.fi.
Abstract
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.
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.
Authors: Yiming Li; Jaro Karppinen; Kathryn S E Cheah; Danny Chan; Pak C Sham; Dino Samartzis Journal: Eur Spine J Date: 2021-09-25 Impact factor: 3.134
Authors: Tom G Richardson; Juha Mykkänen; Katja Pahkala; Mika Ala-Korpela; Joshua A Bell; Kurt Taylor; Jorma Viikari; Terho Lehtimäki; Olli Raitakari; George Davey Smith Journal: Int J Epidemiol Date: 2021-11-10 Impact factor: 7.196
Authors: Paola León-Mimila; Hugo Villamil-Ramírez; Luis R Macías-Kauffer; Leonor Jacobo-Albavera; Blanca E López-Contreras; Rosalinda Posadas-Sánchez; Carlos Posadas-Romero; Sandra Romero-Hidalgo; Sofía Morán-Ramos; Mayra Domínguez-Pérez; Marisol Olivares-Arevalo; Priscilla López-Montoya; Roberto Nieto-Guerra; Víctor Acuña-Alonzo; Gastón Macín-Pérez; Rodrigo Barquera-Lozano; Blanca E Del-Río-Navarro; Israel González-González; Francisco Campos-Pérez; Francisco Gómez-Pérez; Victor J Valdés; Alicia Sampieri; Juan G Reyes-García; Miriam Del C Carrasco-Portugal; Francisco J Flores-Murrieta; Carlos A Aguilar-Salinas; Gilberto Vargas-Alarcón; Diana Shih; Peter J Meikle; Anna C Calkin; Brian G Drew; Luis Vaca; Aldons J Lusis; Adriana Huertas-Vazquez; Teresa Villarreal-Molina; Samuel Canizales-Quinteros Journal: Arterioscler Thromb Vasc Biol Date: 2021-07-08 Impact factor: 10.514
Authors: John T Wilkins; Henrique S Seckler; Jonathan Rink; Philip D Compton; Luca Fornelli; C Shad Thaxton; Rich LeDuc; David Jacobs; Peter F Doubleday; Allan Sniderman; Donald M Lloyd-Jones; Neil L Kelleher Journal: J Am Heart Assoc Date: 2021-09-02 Impact factor: 5.501
Authors: Diego Aguilar-Ramirez; Jesus Alegre-Díaz; William G Herrington; Natalie Staplin; Raúl Ramirez-Reyes; Louisa Gnatiuc; Michael Hill; Frederik Romer; Jason Torres; Eirini Trichia; Rachel Wade; Rory Collins; Jonathan R Emberson; Pablo Kuri-Morales; Roberto Tapia-Conyer Journal: J Clin Endocrinol Metab Date: 2021-09-27 Impact factor: 5.958