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Genetically Predicted Body Mass Index and Mortality in COPD.

Jingzhou Zhang,M. Moll,B. Hobbs,P. Bakke,Elizabeth A Regan,Hanfei Xu,J. Dupuis,J. Chiles,Merry-Lynn N. McDonald,M. Divo,Edwin K. Silverman,B. Celli,George T O'Connor,Michael H. Cho

Published 2024 in American Journal of Respiratory and Critical Care Medicine

ABSTRACT

RATIONALE BMI is associated with COPD mortality, but the underlying mechanisms are unclear. The effect of genetic variants aggregated into a polygenic score may elucidate 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 for BMI (PGSBMI) and tested for associations of the PGSBMI with all-cause, respiratory, and cardiovascular mortality in participants with COPD from the COPDGene, ECLIPSE, and Framingham Heart studies. We calculated the difference between measured BMI and PGS-predicted BMI (BMIdiff) and categorized participants into groups of discordantly low (BMIdiff < 20th percentile), concordant (BMIdiff between 20th - 80th percentile), and discordantly high (BMIdiff > 80th percentile) BMI. We applied Cox models, examined potential non-linear associations of the PGSBMI and BMIdiff with mortality, and summarized results with meta-analysis. MEASUREMENTS AND MAIN RESULTS We observed significant non-linear associations of measured BMI and BMIdiff, but not PGSBMI, with all-cause mortality. In meta-analyses, a one standard deviation increase in the PGSBMI was associated with an increased hazard for cardiovascular mortality (HR=1.29, 95% CI=1.12-1.49), but not with respiratory or all-cause mortality. Compared to participants with concordant measured and genetically predicted BMI, those with discordantly low BMI had higher mortality risk for all-cause (HR=1.57, CI=1.41-1.74) and respiratory death (HR=2.01, CI=1.61-2.51). CONCLUSIONS In people with COPD, higher genetically predicted BMI is associated with higher cardiovascular mortality but not respiratory mortality. Individuals with discordantly low BMI have higher all-cause and respiratory mortality compared to those with concordant BMI.

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