TITLE: Dysanapsis Genetic Risk and Chronic Obstructive Pulmonary Disease Mortality

INTRODUCTION: Dysanapsis refers to a developmental mismatch between airway tree and lung size. CT-assessed dysanapsis is associated with prevalent and incident chronic obstructive pulmonary disease (COPD) and with several genetic variants implicated in lung development. This study tested whether dysanapsis genetic risk is associated COPD mortality in a general population sample.

METHODS: We analysed data from the UK Biobank, a cohort that enrolled participants aged 40-69 years from England, Wales and Scotland. Dysanapsis genetic risk score was computed using risk alleles identified in an independent genome-wide association analysis of CT-assessed dysanapsis. COPD mortality was defined by the International Classification of Disease code listed as the primary cause of death. A proportional hazard regression model was used to adjust for participant age, sex, principal components of genetic ancestry, height, weight, cigarette smoking status, pack-years, and PM2.5. Secondary analysis included a quantile analysis to examine potential non-linear relations.

RESULTS: Among 420,187 participants (mean±SD age 76 ±8 years; 54.6% female, 55.3% never smoking), there were 999 COPD deaths over 3,992,500 person-years. Per 1-SD increment in dysanapsis genetic risk, the adjusted hazard ratio for COPD mortality was 1.10 (95%CI: 1.00?1.05; p = 0.008). Quantile analysis suggested a non-linear inflection in COPD mortality at the approximate median of dysanapsis genetic risk (aHR 1.27; 95%CI: 1.05-1.55; p=0.0136).

CONCLUSION: Among community-dwelling adults in the UK, higher dysanapsis genetic risk is associated with COPD mortality.