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

Hao Yu Chen, Benjamin J. Cairns, Aeron M. Small, Hannah A. Burr, Athithan Ambikkumar, Andreas Martinsson, Sébastien Thériault, Hans Markus Munter, Brian Steffen, Richard Zhang, Rebecca T. Levinson, Christian M. Shaffer, Jian Rong, Emily Sonestedt, Line Dufresne, Johan Ljungberg, Ulf Näslund, Bengt Johansson, Dilrini K. Ranatunga, Rachel A. WhitmerMatthew J. Budoff, Albert Nguyen, Ramachandran S. Vasan, Martin G. Larson, William S. Harris, Scott M. Damrauer, Ken D. Stark, S. Matthijs Boekholdt, Nicholas J. Wareham, Philippe Pibarot, Benoit J. Arsenault, Patrick Mathieu, Vilmundur Gudnason, Christopher J. O'Donnell, Jerome I. Rotter, Michael Y. Tsai, Wendy S. Post, Robert Clarke, Stefan Söderberg, Yohan Bossé, Quinn S. Wells, J. Gustav Smith, Daniel J. Rader, Mark Lathrop, James C. Engert, George Thanassoulis

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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..

Original languageEnglish (US)
Article number0246
JournalJAMA cardiology
DOIs
StateAccepted/In press - Jan 1 2020

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    Chen, H. Y., Cairns, B. J., Small, A. M., Burr, H. A., Ambikkumar, A., Martinsson, A., Thériault, S., Munter, H. M., Steffen, B., Zhang, R., Levinson, R. T., Shaffer, C. M., Rong, J., Sonestedt, E., Dufresne, L., Ljungberg, J., Näslund, U., Johansson, B., Ranatunga, D. K., ... Thanassoulis, G. (Accepted/In press). Association of FADS1/2 Locus Variants and Polyunsaturated Fatty Acids with Aortic Stenosis. JAMA cardiology, [0246]. https://doi.org/10.1001/jamacardio.2020.0246