Importance: Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets. Objective: To identify novel genetic loci and pathways associated with AS. Design, Setting, and Participants: This genome-wide association study used a case-control design to evaluate 44703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019. Exposures: Genetic variants (615643 variants) and polyunsaturated fatty acids (ω-6 and ω-3) measured in blood samples. Main Outcomes and Measures: Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography. Results: The mean (SD) age of the 44703 GERA participants was 69.7 (8.4) years, and 22019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P = 3.0 × 10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P = 2.5 × 10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P =.03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P = 6.6 × 10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associated with AS (OR per unit of normalized expression, 1.31 [95% CI, 1.17-1.48; P = 7.4 × 10-6]; OR per 5-percentage point increase in arachidonic acid for AVC, 1.23 [95% CI, 1.01-1.49; P =.04]; OR per 5-percentage point increase in arachidonic acid for AS, 1.08 [95% CI, 1.04-1.13; P = 4.1 × 10-4]). Conclusions and Relevance: Variation at the FADS1/2 locus was associated with AS and AVC. Findings from biomarker measurements and mendelian randomization appear to link ω-6 fatty acid biosynthesis to AS, which may represent a therapeutic target.
Bibliographical noteFunding Information:
grant R01 HL128550 from the NHLBI of the NIH (Dr Thanassoulis); the Ellison Medical Foundation, Robert Wood Johnson Foundation, Wayne and Gladys Valley Foundation, Kaiser Permanente Northern California, and the Kaiser Permanente National and Regional Community Benefit Programs (The Kaiser Permanente Research Program on Genes, Environment and Health); a grant from the NIH (The Genetic Epidemiology Research on Adult Health and Aging cohort); a strategic partnership between the MRC and the University of Oxford (University of Oxford MRC Population Health Research Unit); application 24281 from the UK Biobank Resource; contracts NO1-HC-25195 and HHSN268201500001I, R01 HL 089590, and the SHARe project from the NHLBI (Framingham Heart Study); the NHLBI in collaboration with Multi-Ethnic Study of Atherosclerosis (MESA) investigators (MESA and the MESA SHARe project); contracts HHSN268201500003I from the NIH, contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the NHLBI,
Funding/Support: This study was supported by
grants from Ionis Pharmaceuticals and Pfizer, Inc, and personal fees from Novartis International AG outside the submitted work. Dr Mathieu reported holding a Fonds de Recherche du Québec-Santé Research Chair on the Pathobiology of Calcific Aortic Valve Disease. Dr Rotter reported receiving grants from the NIH during the conduct of the study. Dr Post reported receiving grants from the NIH during the conduct of the study. Dr Söderberg reported receiving personal fees from Actelion Ltd outside the submitted work and support from the Swedish Heart–Lung Foundation (grant numbers 20140799, 20120631 and 20100635), the County Council of Västerbotten (ALF, VLL-548791), Umeå University, and the Heart Foundation of Northern Sweden. Dr Smith reported receiving grants from the Swedish Heart-Lung Foundation (2016-0134 and 2016-0315), the Swedish Research Council (2017-02554), the European Research Council (ERC-STG-2015-679242), the Crafoord Foundation, Skåne University Hospital, Scania County, governmental funding of clinical research within the Swedish National Health Service, the Knut and Alice Wallenberg Foundation to the Wallenberg Center for Molecular Medicine in Lund, and funding from the Swedish Research Council (Linnaeus grant 349-2006-237, Strategic Research Area Exodiab 2009-1039), and Swedish Foundation for Strategic Research (IRC15-0067) to the Lund University Diabetes Center. Dr Rader reported receiving personal fees from Alnylam Pharmaceuticals, Inc, Novartis International AG, Pfizer, Inc, Verve Therapeutics, and AstraZeneca plc outside the submitted work. Dr Thanassoulis reported receiving grants from the Canadian Institutes of Health Research, the National Heart, Lung, and Blood Institute (NHLBI) of the NIH, Heart and Stroke Foundation of Canada, Fonds de Recherche Québec-Santé, Doggone Foundation, Courtois Foundation, and the Ingram Family Foundation during the conduct of the study; participating on the advisory boards of Amgen, Inc, and Regeneron/ Sanofi, personal fees from HLS Therapeutics, Inc, grants and personal fees from Servier Laboratories, and consulting fees from Ionis Pharmaceuticals outside the submitted work. No other disclosures were reported.
receiving grants from McGill University Faculty of Medicine and McGill University Health Centre Foundation during the conduct of the study. Dr Cairns reported receiving grants from the Medical Research Council (MRC) UK during the conduct of the study. Dr Thériault reported receiving grants from Fonds de Recherche du Québec-Santé (FRQS) during the conduct of the study. Dr Budoff reported receiving grants from General Electric outside the submitted work. Dr Vasan reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study and support from the Evans Medical Foundation and the Jay and Louis Coffman Endowment from the Department of Medicine, Boston University School of Medicine. Dr Damrauer reported receiving grants from RenalytixAI plc and the US Department of Veterans Affairs outside the submitted work. Dr Stark reported receiving salary support from the Canada Research Chairs program for a Chair in Nutritional Lipidomics. Dr Pibarot reported receiving grants from Edwards Lifesciences and Medtronic plc outside the submitted work. Dr Arsenault reported receiving
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