Genetics of Pulmonary Pressure and Right Ventricle Stress Identify Diabetes as a Causal Risk Factor

Author:

Bagheri Minoo12ORCID,Agrawal Vineet1ORCID,Annis Jeffrey1ORCID,Shi Mingjian2ORCID,Ferguson Jane F.12ORCID,Freiberg Matthew S.1ORCID,Mosley Jonathan D.32ORCID,Brittain Evan L.1ORCID

Affiliation:

1. Division of Cardiovascular Medicine, Department of Medicine Vanderbilt University Medical Center Nashville TN USA

2. Department of Biomedical Informatics Vanderbilt University Medical Center Nashville TN USA

3. Division of Clinical Pharmacology, Department of Medicine Vanderbilt University Medical Center Nashville TN USA

Abstract

Background Epidemiologic studies have identified risk factors associated with pulmonary hypertension and right heart failure, but causative drivers of pulmonary hypertension and right heart adaptation are not well known. We sought to leverage unbiased genetic approaches to determine clinical conditions that share genetic architecture with pulmonary pressure and right ventricular dysfunction. Methods and Results We leveraged Vanderbilt University's deidentified electronic health records and DNA biobank to identify 14 861 subjects of European ancestry who underwent at least 1 echocardiogram with available estimates of pulmonary pressure and right ventricular function. Analyses of the study were performed between 2020 and 2022. The final analytical sample included 14 861 participants (mean [SD] age, 63 [15] years and mean [SD] body mass index, 29 [7] kg/m 2 ). An unbiased phenome‐wide association study identified diabetes as the most statistically significant clinical International Classifications of Diseases , Ninth Revision ( ICD‐9 ) code associated with polygenic risk for increased pulmonary pressure. We validated this finding further by finding significant associations between genetic risk for diabetes and a related condition, obesity, with pulmonary pressure estimate. We then used 2‐sample univariable Mendelian randomization and multivariable Mendelian randomization to show that diabetes, but not obesity, was independently associated with genetic risk for increased pulmonary pressure and decreased right ventricle load stress. Conclusions Our findings show that genetic risk for diabetes is the only significant independent causative driver of genetic risk for increased pulmonary pressure and decreased right ventricle load stress. These findings suggest that therapies targeting genetic risk for diabetes may also potentially be beneficial in treating pulmonary hypertension and right heart dysfunction.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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