Association of FADS1/2 Locus Variants and Polyunsaturated Fatty Acids With Aortic Stenosis | Valvular Heart Disease | JAMA Cardiology | JAMA Network
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Original Investigation
March 18, 2020

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

Author Affiliations
  • 1Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
  • 2Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, Quebec, Canada
  • 3MRC (Medical Research Council) Population Health Research Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
  • 4Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
  • 5Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
  • 6Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 7Department of Cardiology, Clinical Sciences, Lund University, Lund, Sweden
  • 8Department of Cardiology, Skåne University Hospital, Lund, Sweden
  • 9Quebec Heart and Lung Institute, Laval University, Quebec City, Quebec, Canada
  • 10McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada
  • 11Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
  • 12Vanderbilt Translational and Clinical Cardiovascular Research Center, Vanderbilt University Medical Center, Nashville, Tennessee
  • 13National Heart, Lung, and Blood Institute, Bethesda, Maryland
  • 14Boston University’s Framingham Heart Study, Boston, Massachusetts
  • 15Nutritional Epidemiology, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
  • 16Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
  • 17Division of Research, Kaiser Permanente of Northern California, Oakland
  • 18Department of Public Health Sciences, University of California, Davis
  • 19Los Angeles Biomedical Research Institute, Torrance, California
  • 20Departments of Pediatrics and Medicine at Harbor-UCLA (University of California, Los Angeles) Medical Center, Torrance
  • 21Department of Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls, South Dakota
  • 22OmegaQuant Analytics LLC, Sioux Falls, South Dakota
  • 23Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 24Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada
  • 25Department of Cardiology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
  • 26MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom
  • 27Faculty of Medicine, University of Iceland, Reykjavík
  • 28Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 29Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
  • 30Lund University Diabetes Center, Lund University, Lund, Sweden
  • 31Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 32Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 33Department of Human Genetics, McGill University, Montreal, Quebec, Canada
JAMA Cardiol. 2020;5(6):694-702. doi:10.1001/jamacardio.2020.0246
Key Points

Question  Can genetic analysis identify additional causes of aortic stenosis?

Findings  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.

Meaning  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.

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, 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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