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

Area of Science:

• Genetics and Epidemiology
• Pulmonary Medicine
• Cardiovascular Health

Background:

• Body mass index (BMI) is a known factor in chronic obstructive pulmonary disease (COPD) mortality.
• The precise mechanisms linking BMI to COPD mortality remain unclear.
• Polygenic scores (PGS) offer a tool to investigate genetic influences on complex traits like BMI and their causal roles.

Purpose of the Study:

• To investigate the association between genetically predicted BMI and mortality in individuals with COPD.
• To differentiate between all-cause, respiratory, and cardiovascular mortality.
• To explore the impact of discordance between measured and genetically predicted BMI on mortality risk.

Main Methods:

• Development of a polygenic score for BMI (PGS_BMI).
• Analysis of PGS_BMI and BMI difference (BMI_diff) in relation to mortality in COPD cohorts (COPDGene, ECLIPSE, Framingham).
• Application of Cox models, meta-analysis, and categorization of participants based on BMI concordance/discordance.

Main Results:

• Genetically predicted BMI was associated with increased cardiovascular mortality (HR, 1.29; 95% CI, 1.12-1.49) but not all-cause or respiratory mortality.
• Measured BMI and BMI_diff showed nonlinear associations with all-cause mortality.
• Individuals with discordantly low BMI exhibited significantly higher risks for all-cause (HR, 1.57; 95% CI, 1.41-1.74) and respiratory mortality (HR, 2.01; 95% CI, 1.61-2.51) compared to concordant individuals.

Conclusions:

• In COPD patients, genetically predicted higher BMI is a risk factor for cardiovascular mortality.
• Discordance between measured and genetically predicted BMI, particularly low measured BMI, is linked to increased all-cause and respiratory mortality.
• These findings highlight the complex interplay of genetics and measured BMI in COPD outcomes.