Hannah A Burr

AIMS: Although highly heritable, the genetic etiology of calcific aortic stenosis (AS) remains incompletely understood. The aim of this study was to discover novel genetic contributors to AS and to integrate functional, expression, and cross-phenotype data to identify mechanisms of AS. METHODS AND RESULTS: A genome-wide meta-analysis of 11.6 million variants in 10 cohorts involving 653 867 European ancestry participants (13 765 cases) was performed. Seventeen loci were associated with AS at P ≤ 5 × 10-8, of which 15 replicated in an independent cohort of 90 828 participants (7111 cases), including CELSR2-SORT1, NLRP6, and SMC2. A genetic risk score comprised of the index variants was associated with AS [odds ratio (OR) per standard deviation, 1.31; 95% confidence interval (CI), 1.26-1.35; P = 2.7 × 10-51] and aortic valve calcium (OR per standard deviation, 1.22; 95% CI, 1.08-1.37; P = 1.4 × 10-3), after adjustment for known risk factors. A phenome-wide association study indicated multiple associations with coronary artery disease, apolipoprotein B, and triglycerides. Mendelian randomization supported a causal role for apolipoprotein B-containing lipoprotein particles in AS (OR per g/L of apolipoprotein B, 3.85; 95% CI, 2.90-5.12; P = 2.1 × 10-20) and replicated previous findings of causality for lipoprotein(a) (OR per natural logarithm, 1.20; 95% CI, 1.17-1.23; P = 4.8 × 10-73) and body mass index (OR per kg/m2, 1.07; 95% CI, 1.05-1.9; P = 1.9 × 10-12). Colocalization analyses using the GTEx database identified a role for differential expression of the genes LPA, SORT1, ACTR2, NOTCH4, IL6R, and FADS. CONCLUSION: Dyslipidemia, inflammation, calcification, and adiposity play important roles in the etiology of AS, implicating novel treatments and prevention strategies.

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.

Abstract Tissues are active materials where epithelial turnover, immune surveillance, and remodeling of stromal cells such as macrophages all regulate form and function. Scattering modalities such as Brillouin microscopy (BM) can non-invasively access mechanical signatures at GHz. However, our traditional understanding of tissue material properties is derived mainly from modalities which probe mechanical properties at different frequencies. Thus, reconciling measurements amongst these modalities remains an active area. Here, we compare optical tweezer active microrheology (OT-AMR) and Brillouin microscopy (BM) to longitudinally map brain development in the larval zebrafish. We determine that each measurement is able to detect a mechanical signature linked to functional units of the brain. We demonstrate that the corrected BM-Longitudinal modulus using a density factor correlates well with OT-AMR storage modulus at lower frequencies. We also show that the brain tissue mechanical properties are dependent on both the neuronal architecture and the presence of macrophages. Moreover, the BM technique is able to delineate the contributions to mechanical properties of the macrophage from that due to colony stimulating factor 1 receptor (CSF1R) mediated stromal remodeling. Here, our data suggest that macrophage remodeling is instrumental in the maintenance of tissue mechanical homeostasis during development. Moreover, the strong agreement between the OT-AM and BM further demonstrates that scattering-based technique is sensitive to both large and minute structural modification in vivo .

GWAS Summary Statistics for a Global Meta-Analysis of Aortic Stenosis in the TARGET Consortium 10.5281/zenodo.7630002 This dataset contains the genome-wide association summary statistics for a Global Meta-Analysis of Aortic Stenosis. For the analysis description and included cohorts, please see Chen et al., the European Heart Journal (2023). The data are provided on an "AS-IS" basis, without warranty of any type, expressed or implied, including but not limited to any warranty as to their performance, merchantability, or fitness for any particular purpose. If investigators use these data, any and all consequences are entirely their responsibility. By downloading and using these data, you agree that you will cite the appropriate publication in any communications or publications arising directly or indirectly from these data. <strong>When using this data, please cite the paper and this repository:</strong> Chen et al., GWAS Summary Statistics for a Global Meta-Analysis of Aortic Stenosis, the European Heart Journal (2023). Zenodo. 10.5281/zenodo.7630002 <strong>Column headers:</strong> CHR: Chromosome code. Not present with 'no-map' modifier. BP: Base-pair coordinate. Not present with 'no-map' modifier. SNP: Variant identifier A1: Effect Allele A2: Other Allele N_cohort: Number of valid studies for variant P: Fixed-effects meta-analysis p-value P.R.: Random-effects meta-analysis p-value OR: Fixed-effects BETA/OR estimate OR.R.: Random-effects BETA/OR estimate Q: p-value for Cochran's Q statistic I: I2 heterogeneity index (0-100 scale) N_ind: Number of individuals <strong>Fundings:</strong> Fundings for this study were obtained from the following (listed in alphabetical order): ALFEDIAM Ardix Medical Assistance Publique - Hôpitaux de Paris Association Diabète Risque Vasculaire Bayer Diagnostics Becton Dickinson British Heart Foundation British Heart Foundation Oxford Centre Canadian Institutes for Health Research Capital Regions Research Council Cardionics, Merck Santé, Novo Nordisk CNAMTS, Lilly, Novartis Pharma Cohortes Santé TGIR County Council of Västerbotten Crafoord Foundation Ellison Medical Foundation European Research Council Fédération Française de Cardiologie Fédération Française de Cardiologie, a Fondation Coeur et Recherche Fonds de Recherche du Québec - Santé. French Regional Council of Pays-de-la-Loire (VaCaRMe program) Heart and Stroke Foundation of Canada Heart Foundation of Northern Sweden. Kaiser Permanente Knut and Alice Wallenberg foundation to the Wallenberg Center La Fondation de France Medical Research Council and the University of Oxford National Center for Advancing Translational Sciences (CTSI) National Heart, Lung, and Blood Institute (NHLBI) National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) National Institutes of Health Novo Nordisk Foundation ONIVINS Robert Wood Johnson Foundation Sanofi-Aventis; by INSERM (Réseaux en Santé Publique, Interactions entre les déterminants de la santé) Skåne University Hospital Société francophone du diabète Swedish Foundation for Strategic Research Swedish Heart–Lung Foundation Swedish National Health Service Swedish Research Council The Innovation Fund Denmark Umeå University U.S. Department of Veteran Affairs Vanderbilt University Medical Center’s institutional funding Wayne and Gladys Valley Foundation

Background: Elevated lipoprotein(a) levels are a causal factor for aortic stenosis (AS). However, large-scale replication of associations between LPA polymorphisms and AS, their interactions with a...