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  • Chen, Hao YuMcGill University Health Center,McGill University (author)

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

  • Article/chapterEnglish2020

Publisher, publication year, extent ...

  • American Medical Association (AMA),2020
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:umu-170494
  • https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-170494URI
  • https://doi.org/10.1001/jamacardio.2020.0246DOI
  • https://lup.lub.lu.se/record/2dfa9178-9252-42bb-9b80-f98b68c8b76aURI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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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  • Cairns, Benjamin J.University of Oxford (author)
  • Small, Aeron M.Cochin Hospital (author)
  • Burr, Hannah A.McGill University Health Center,McGill University (author)
  • Ambikkumar, AthithanUniversity of California, Davis (author)
  • Martinsson, AndreasLund University,Lunds universitet,Kardiologi,Sektion II,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Molecular Epidemiology and Cardiology,Forskargrupper vid Lunds universitet,Cardiology,Section II,Department of Clinical Sciences, Lund,Faculty of Medicine,Lund University Research Groups,Skåne University Hospital(Swepub:lu)med-asm (author)
  • Thériault, SébastienInstitut universitaire de cardiologie et de pneumologie de Québec (author)
  • Munter, Hans MarkusMcGill University (author)
  • Steffen, BrianUniversity of Minnesota (author)
  • Zhang, RichardMcGill University Health Center (author)
  • Levinson, Rebecca T.Vanderbilt University (author)
  • Shaffer, Christian M.Vanderbilt University (author)
  • Rong, JianBoston University,National Heart Lung and Blood Institute (author)
  • Sonestedt, EmilyLund University,Lunds universitet,Nutritionsepidemiologi,Forskargrupper vid Lunds universitet,Nutrition Epidemiology,Lund University Research Groups(Swepub:lu)medf-eso (author)
  • Dufresne, LineMcGill University Health Center (author)
  • Ljungberg, JohanUmeå University,Umeå universitet,Kardiologi(Swepub:umu)jonljg02 (author)
  • Näslund, UlfUmeå University,Umeå universitet,Kardiologi(Swepub:umu)ulna0002 (author)
  • Johansson, BengtUmeå University,Umeå universitet,Kardiologi,Institut universitaire de cardiologie et de pneumologie de Québec(Swepub:umu)bejo0003 (author)
  • Ranatunga, Dilrini K.Kaiser Permanente (author)
  • Whitmer, Rachel A. (author)
  • Budoff, Matthew J.University of California, Los Angeles (author)
  • Nguyen, AlbertMcGill University Health Center (author)
  • Vasan, Ramachandran S.Umeå University (author)
  • Larson, Martin G.National Heart Lung and Blood Institute,Boston University (author)
  • Harris, William S. (author)
  • Damrauer, Scott M.Cochin Hospital (author)
  • Stark, Ken D.University of Waterloo (author)
  • Boekholdt, S. MatthijsAcademic Medical Center of University of Amsterdam (AMC) (author)
  • Wareham, Nicholas J.University of Cambridge (author)
  • Pibarot, PhilippeInstitut universitaire de cardiologie et de pneumologie de Québec (author)
  • Arsenault, Benoit J. (author)
  • Mathieu, PatrickInstitut universitaire de cardiologie et de pneumologie de Québec (author)
  • Gudnason, VilmundurUniversity of Iceland (author)
  • O'Donnell, Christopher J.National Heart Lung and Blood Institute,Boston University (author)
  • Rotter, Jerome I.University of California, Los Angeles (author)
  • Tsai, Michael Y.University of Minnesota (author)
  • Post, Wendy S.Johns Hopkins University (author)
  • Clarke, RobertUniversity of Oxford (author)
  • Söderberg, StefanUmeå universitet,Kardiologi,Vanderbilt University(Swepub:umu)stso0001 (author)
  • Bossé, YohanInstitut universitaire de cardiologie et de pneumologie de Québec (author)
  • Wells, Quinn S. (author)
  • Smith, J. GustavLund University,Lunds universitet,Molecular Epidemiology and Cardiology,Forskargrupper vid Lunds universitet,WCMM- Wallenberg center för molekylär medicinsk forskning,Medicinska fakulteten,Lund University Research Groups,WCMM-Wallenberg Centre for Molecular Medicine,Faculty of Medicine,Skåne University Hospital(Swepub:lu)med-gvs (author)
  • Rader, Daniel J.Cochin Hospital (author)
  • Lathrop, MarkMcGill University (author)
  • Engert, James C.McGill University Health Center,McGill University (author)
  • Thanassoulis, GeorgeMcGill University,McGill University Health Center (author)
  • McGill University Health CenterMcGill University (creator_code:org_t)

Related titles

  • In:JAMA cardiology: American Medical Association (AMA)5:6, s. 694-7022380-65832380-6591

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