Genetically Predicted Body Mass Index and Mortality in Chronic Obstructive Pulmonary Disease

Rationale: Body mass index (BMI) is associated with chronic obstructive pulmonary disease (COPD) mortality, but the underlying mechanisms are unclear. The effect of genetic variants aggregated into a polygenic score may elucidate the causal mechanisms and predict risk. Objectives: To examine the associations of genetically predicted BMI with all-cause and cause-specific mortality in COPD. Methods: We developed a polygenic score (PGS) for BMI (PGS_BMI) and tested for associations of the PGS_BMI with all-cause, respiratory, and cardiovascular mortality in participants with COPD from the COPDGene (Genetic Epidemiology of COPD), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), and Framingham Heart studies. We calculated the difference between measured BMI and PGS-predicted BMI (BMI_diff) and categorized participants into groups of discordantly low (BMI_diff <20th percentile), concordant (BMI_diff between the 20th and 80th percentiles), and discordantly high (BMI_diff >80th percentile) BMI. We applied Cox models, examined potential nonlinear associations of the PGS_BMI and BMI_diff with mortality, and summarized results with meta-analysis. Measurements and Main Results: We observed significant nonlinear associations of measured BMI and BMI_diff, but not PGS_BMI, with all-cause mortality. In meta-analyses, a one-standard deviation increase in the PGS_BMI was associated with an increased hazard for cardiovascular mortality (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.12-1.49), but not for respiratory or all-cause mortality. Compared with participants with concordant measured and genetically predicted BMI, those with discordantly low BMI had higher risks for all-cause mortality (HR, 1.57; 95% CI, 1.41-1.74) and respiratory death (HR, 2.01; 95% CI, 1.61-2.51). Conclusions: In people with COPD, a higher genetically predicted BMI is associated with higher cardiovascular mortality but not respiratory mortality. Individuals with a discordantly low BMI have higher all-cause and respiratory mortality rates than those with a concordant BMI.