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

Chen, Hao Yu ; Cairns, Benjamin J. ; Small, Aeron M. ; Burr, Hannah A. ; Ambikkumar, Athithan ; Martinsson, Andreas LU ; Thériault, Sébastien ; Munter, Hans Markus ; Steffen, Brian and Zhang, Richard , et al. (2020) In JAMA Cardiology 5(6). p.694-702
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... (More)

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.

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published
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JAMA Cardiology
volume
5
issue
6
pages
9 pages
publisher
American Medical Association
external identifiers
  • scopus:85082412919
  • pmid:32186652
ISSN
2380-6583
DOI
10.1001/jamacardio.2020.0246
language
English
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yes
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2dfa9178-9252-42bb-9b80-f98b68c8b76a
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2021-01-12 10:08:16
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2021-04-06 03:29:04
@article{2dfa9178-9252-42bb-9b80-f98b68c8b76a,
  abstract     = {<p>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<sup>-6</sup>), 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<sup>-8</sup>). 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<sup>-5</sup>). 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<sup>-6</sup>]; 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<sup>-4</sup>]). 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.</p>},
  author       = {Chen, Hao Yu and Cairns, Benjamin J. and Small, Aeron M. and Burr, Hannah A. and Ambikkumar, Athithan and Martinsson, Andreas and Thériault, Sébastien and Munter, Hans Markus and Steffen, Brian and Zhang, Richard and Levinson, Rebecca T. and Shaffer, Christian M. and Rong, Jian and Sonestedt, Emily and Dufresne, Line and Ljungberg, Johan and Näslund, Ulf and Johansson, Bengt and Ranatunga, Dilrini K. and Whitmer, Rachel A. and Budoff, Matthew J. and Nguyen, Albert and Vasan, Ramachandran S. and Larson, Martin G. and Harris, William S. and Damrauer, Scott M. and Stark, Ken D. and Boekholdt, S. Matthijs and Wareham, Nicholas J. and Pibarot, Philippe and Arsenault, Benoit J. and Mathieu, Patrick and Gudnason, Vilmundur and O'Donnell, Christopher J. and Rotter, Jerome I. and Tsai, Michael Y. and Post, Wendy S. and Clarke, Robert and Söderberg, Stefan and Bossé, Yohan and Wells, Quinn S. and Smith, J. Gustav and Rader, Daniel J. and Lathrop, Mark and Engert, James C. and Thanassoulis, George},
  issn         = {2380-6583},
  language     = {eng},
  number       = {6},
  pages        = {694--702},
  publisher    = {American Medical Association},
  series       = {JAMA Cardiology},
  title        = {Association of FADS1/2 Locus Variants and Polyunsaturated Fatty Acids with Aortic Stenosis},
  url          = {http://dx.doi.org/10.1001/jamacardio.2020.0246},
  doi          = {10.1001/jamacardio.2020.0246},
  volume       = {5},
  year         = {2020},
}