Associations of genetic risk and smoking with incident COPD

Abstract

Background: Genetic factors and smoking contribute to chronic obstructive pulmonary disease (COPD), but whether a combined polygenic risk score (PRS) is associated with incident COPD and whether it has a synergistic effect on smoking remains unclear. We aimed to investigate the association of the PRS with COPD and explore whether smoking behaviours could modify such association.

Methods: Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals for the association of the PRS and smoking with COPD.

Results: The study included 439 255 participants (mean age 56.5 years; 53.9% female), with a median follow-up of 9.0 years. PRS_lasso containing 2.5 million variants showed better discrimination and a stronger association for incident COPD than PRS₂₇₉ containing 279 genome-wide significance variants. Compared with low genetic risk, the HRs of medium and high genetic risk were 1.39 (95% CI 1.31-1.48) and 2.40 (95% CI 2.24-2.56), respectively. The HR of high genetic risk and current smoking was 11.62 (95% CI 10.31-13.10) times that of low genetic risk and never smoking. There were significant interactions between PRS_lasso and smoking status for incident COPD (p_interaction<0.001). From low genetic risk to high genetic risk, the HRs of current smoking increased from 4.32 (95% CI 3.69-5.06) to 6.89 (95% CI 6.21-7.64) and the population-attributable risks of smoking increased from 42.7% to 61.1%.

Conclusions: The PRS constructed from millions of variants below genome-wide significance showed significant associations with incident COPD. Participants with a high genetic risk may be more susceptible to developing COPD when exposed to smoking.