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

Abstract

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.

Keywords: BMI; COPD; cardiovascular mortality; respiratory mortality; weight loss.

Figure 1.

Plots of partial residuals of measured body mass index and body mass index polygenic score in Cox models with penalized splines for all-cause, respiratory, and cardiovascular mortality. Solid lines represent fitted values of partial residuals; dashed lines represent standard errors of fitted values. Respiratory death was not captured in the Framingham Heart Study. AA = African American; BMI = body mass index; COPDGene = Genetic Epidemiology of COPD study; ECLIPSE = Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints [study]; FHS = Framingham Heart Study; NHW = non-Hispanic White; PGS = polygenic score.

Figure 2.

Associations of the body mass index polygenic score with all-cause, respiratory, and cardiovascular mortality. AA = African American; BMI = body mass index; COPDGene = Genetic Epidemiology of COPD study; ECLIPSE = Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints [study]; FHS = Framingham Heart Study; HR = hazard ratio; NHW = non-Hispanic White; PGS = polygenic score; SD = standard deviation.

Figure 3.

Plots of partial residuals of the difference between measured and polygenic score–predicted BMI (in kg/m²) in Cox models with penalized splines for all-cause mortality. Solid lines represent fitted values of partial residuals; dashed lines represent standard errors of fitted values. BMI_diff = difference between measured and polygenic score–predicted BMI; COPDGene = Genetic Epidemiology of COPD study; ECLIPSE = Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints [study]; FHS = Framingham Heart Study; NHW = non-Hispanic White.

Figure 4.

Survival probability for all-cause mortality and scatter plots of participants among groups based on the concordance between measured and polygenic score–predicted body mass index (BMI). Participants with a discordantly low BMI (difference between measured and PGS-predicted BMI [BMI_diff] <20th percentile) are shown in red; those with a concordant BMI (BMI_diff within 20th to 80th percentiles) are shown in blue, and those with a discordantly high BMI (BMI_diff >80th percentile) are shown in yellow. BMI = body mass index; COPDGene = Genetic Epidemiology of COPD study; ECLIPSE = Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints [study]; FHS = Framingham Heart Study; NHW = non-Hispanic White; PGS = polygenic score.

Figure 5.

Associations of body mass index (BMI) concordance group with all-cause, respiratory, and cardiovascular mortality. A discordantly low BMI indicates a difference between measured and polygenic score–predicted BMI (BMI_diff) lower than the 20th percentile, a concordant BMI indicates a BMI_diff within the 20th to the 80th percentile, and a discordantly high BMI indicates a BMI_diff higher than the 80th percentile. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study was not included in the analysis comparing cardiovascular mortality risk between participants of discordantly low BMI versus concordant BMI because of the limited number of events (n = 1) in those with a discordantly low BMI. CI = confidence interval; COPDGene = Genetic Epidemiology of COPD study; ECLIPSE = Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints [study]; FHS = Framingham Heart Study; HR = hazard ratio; NHW = non-Hispanic White.