Abstract 13097: Diabetes and Obesity Are Causally Associated With Pulmonary Hypertension and Right Ventricular Function

Abstract

Background: Observational studies have shown overlap between pulmonary pressure, right ventricular (RV) function, and metabolic function, but causality has not been established. We used genetic variants associated with metabolic phenotypes to test for causality between metabolic function, pulmonary pressure, and RV function. Methods: We included all European ancestry subjects in Vanderbilt University’s de-identified DNA biobank (BioVU) with an echo reporting pulmonary pressure (RVSP) and RV function (TAPSE). To investigate causal relationships, two-sample univariate and multivariate Mendelian Randomization (MR) analyses were conducted using genetic variants associated with phenotypes and echo measures. Significant phenotypes by univariate MR were included in multivariable MR models. We also tested echo measures for associations with polygenic risk scores (PRS) for metabolic phenotypes [score threshold: 5x10 -8 ]. Results: We identified 17,221 men and women (mean age: 62yr) with RVSP and 6,209 men and women (mean age: 61yr) with TAPSE. Diabetes genetic risk was associated with higher RVSP (β=0.015, p=0.016) [Figure 1A] and lower TAPSE (β=-0.028, p<0.05) [Figure 1C]. BMI genetic risk was positively associated with RVSP (β=0.06, p=7.18 x 10 -6 ) [Figure 1C] but not TAPSE. In multivariable MR models, genetic risk for diabetes and BMI remained directly associated with RVSP (p<0.05) and only diabetes genetic risk was inversely associated with TAPSE (β=-0.031, p=0.005). PRS for diabetes and BMI were associated with higher RVSP (β=0.01, p=0.001 for diabetes and β=0.01, p=2.04x10 -5 for BMI) but only PRS for diabetes was linked to lower TAPSE (β=-0.015, p=0.057). Conclusions: Genetic determinants of BMI and diabetes are causally associated with pulmonary pressure and RV function in a large, unselected population referred for echocardiography. These may be modifiable risk factors in the treatment and prevention of pulmonary hypertension and RV dysfunction.