Title: | Association of FADS1/2 Locus Variants and Polyunsaturated Fatty Acids With Aortic Stenosis |
Author: |
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Date: | 2020-06-01 |
Language: | English |
Scope: | 694 |
University/Institute: | Háskóli Íslands University of Iceland |
School: | Heilbrigðisvísindasvið (HÍ) School of Health Sciences (UI) |
Department: | Læknadeild (HÍ) Faculty of Medicine (UI) |
Series: | JAMA Cardiology;5(6) |
ISSN: | 2380-6583 |
DOI: | 10.1001/jamacardio.2020.0246 |
Subject: | Genetic analysis; FADS1/2; Aortic stenosis; Erfðagreining; Gen; Æðasjúkdómar |
URI: | https://hdl.handle.net/20.500.11815/2422 |
Citation:Chen HY, Cairns BJ, Small AM, et al. Association of FADS1/2 Locus Variants and Polyunsaturated Fatty Acids With Aortic Stenosis. JAMA Cardiol. 2020;5(6):694–702. doi:10.1001/jamacardio.2020.0246
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Abstract: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.
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Description:Publisher's version (útgefin grein)
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Rights:This is an open access article distributed under the terms of the CC-BY License. © 2020 Chen HY et al. JAMA Cardiology.
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