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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
Can genetic analysis identify additional causes of aortic stenosis?
In this genome-wide association study of 44 703 participants, each copy of a FADS1/2 (fatty acid desaturase) genetic variant was associated with a 13% decrease in the odds of aortic stenosis. Results of a meta-analysis with 7 replication cohorts showed genome-wide significance, with biomarker and mendelian randomization analyses implicating elevated ω-6 fatty acid levels as having a potentially causal association with aortic valve calcium and aortic stenosis.
These findings demonstrate that the FADS1/2 locus and fatty acid biosynthesis are associated with aortic stenosis and should be examined further for their potential as therapeutic targets.
Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets.
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 44 703 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 256 926 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.
Genetic variants (615 643 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.
The mean (SD) age of the 44 703 GERA participants was 69.7 (8.4) years, and 22 019 (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 312 118 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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