Association of FADS1/2 Locus Variants and Polyunsaturated Fatty Acids With Aortic Stenosis

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 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. EXPOSURES 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. RESULTS 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,

Omega-3 Polyunsaturated Fatty Acids and the Resolution of Inflammation: Novel Therapeutic Opportunities for Aortic Valve Stenosis?

“…Since this variant genotype has been shown to alter both omega-3 and omega-6 PUFA metabolism and to lower AA generation from linoleic acid ( Sasaki et al, 2019 ; Chen et al, 2020 ), those findings provide a potential link between PUFA and AVS. This is further reinforced by the finding that higher systemic levels of AA furthermore are associated with aortic valve calcification ( Chen et al, 2020 ). However, the local valve levels rather than systemic levels of PUFA may be decisive for their availabilities as substrates for the biosynthesis of lipid mediators.…”

“…Genome-wide association and Mendelian randomization studies have identified a genetic variant in the FADS1/2 loci associated with AVS ( Yuan et al, 2019 ), where each copy of the minor-C allele reduced more than 10% the odds of the disease ( Chen et al, 2020 ). Since this variant genotype has been shown to alter both omega-3 and omega-6 PUFA metabolism and to lower AA generation from linoleic acid ( Sasaki et al, 2019 ; Chen et al, 2020 ), those findings provide a potential link between PUFA and AVS. This is further reinforced by the finding that higher systemic levels of AA furthermore are associated with aortic valve calcification ( Chen et al, 2020 ).…”

Fatty acids and aortic valve stenosis

“…To our knowledge, associations of PUFAs in phospholipids extracted from plasma and AVS specifically only come from one genome wide association studies (GWAS) study [10]. In pooled results from two previous studies, LA and ALA were inversely associated with aortic valve calcium (AVC), a predecessor of AVS.…”

“…The importance of the latter as causal factor for AVS is illustrated by results from Mendelian Randomization (MR), in which body mass and fat mass indexes exhibit stronger associations with AVS compared with other cardiovascular diseases [8]. The genetic variants located in proximity to LPA and FADS1 have genome-wide association with AVS [9,10] and coronary artery disease [11] and acting through affecting levels of lipoprotein (a) (Lp(a)) and fatty acids, respectively. Interestingly, MR studies have shown a stronger association of these genetically determined risk factors with AVS compared with other cardiovascular diseases [12,13].…”

The Evolving Story in the Genetic Analysis for Heart Failure

“…IHD and AF have been reported to have more than 100 disease susceptibility loci as already described (2,3), where IHD has been suggested to be strongly associated with lipids, hypertension, diabetes, inflammation, and other atherosclerosis-related traits, while AF has been suggested to have mechanisms strongly related to HF, such as cardiac development and myocardial contractility, apart from electrophysiological traits. As for valvular disease, Chen et al (20) have recently identified nine disease-susceptibility loci in aortic stenosis, suggesting the involvement of lipids and the immune system. In addition, there are a few reports on mitral valve prolapse syndrome (21,22) in which mitral valve repair and cardiac development are reported to be involved in the pathogenesis.…”