Introduction: Aortic stenosis (AS) is the most prevalent valvular heart disease in developed countries. Currently, the LPA locus is the only genome-wide significant susceptibility locus for AS. The identification of additional genetic loci could inform drug development for AS, a disease without effective medical therapy.
Methods: We conducted a genome-wide association study for AS in the Genetic Epidemiology on Adult Health and Aging (GERA) cohort (44,703 individuals; 3,469 cases), adjusted for age, age2, and sex. A locus which demonstrated suggestive evidence of association in GERA (p < 1 х 10-6) was examined in PennCATH (5,938 individuals; 1,252 cases), UK Biobank (111,560 individuals; 535 cases), Malmö Diet and Cancer Study (16,168 individuals; 521 cases), and Umeå University (839 individuals; 218 cases). Results were combined by inverse variance-weighted fixed effects meta-analysis. Further validation was performed in the CHARGE Consortium using aortic valve calcium (AVC) (6,942 individuals; 2,245 with AVC), a subclinical phenotype that precedes AS.
Results: In the GERA cohort, we confirmed the LPA locus at genome-wide significance (p = 5.7 х 10-10) and also identified a variant in the fatty acid desaturase (FADS) locus demonstrating strong evidence of association with AS (odds ratio per minor allele [OR] 0.87; 95% confidence interval [CI] 0.83-0.92; p = 9.7 х 10-7). Among the replication cohorts, the pooled OR was 0.92 (95% CI 0.86-0.99; p = 0.019). For the discovery and replication cohorts, the pooled OR was 0.89 (95% CI 0.86-0.93; p = 1.3 х 10-7). No heterogeneity was observed across cohorts (I2 = 0%; 95% CI 0-68%; p = 0.63). The lead variant was also significantly associated with AVC in the CHARGE Consortium, and demonstrated consistent effect size and direction (OR 0.91; 95% CI 0.83-0.99; p = 0.026).
Conclusions: A common variant in the FADS locus is associated with both clinical AS and AVC. This discovery implicates fatty acid metabolism in the development of AS, which may represent a novel therapeutic target.