Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility

Impaired lung function is often caused by cigarette smoking, making it challenging to disentangle its role in lung cancer susceptibility. Investigation of the shared genetic basis of
these phenotypes in the UK Biobank and International Lung Cancer Consortium (29,266
cases, 56,450 controls) shows that lung cancer is genetically correlated with reduced forced
expiratory volume in one second (FEV1: rg = 0.098, p = 2.3 × 10−8) and the ratio of FEV1 to
forced vital capacity (FEV1/FVC: rg = 0.137, p = 2.0 × 10−12). Mendelian randomization
analyses demonstrate that reduced FEV1 increases squamous cell carcinoma risk (odds ratio
(OR) = 1.51, 95% confidence intervals: 1.21–1.88), while reduced FEV1/FVC increases the risk
of adenocarcinoma (OR = 1.17, 1.01–1.35) and lung cancer in never smokers (OR = 1.56,
1.05–2.30). These findings support a causal role of pulmonary impairment in lung cancer
etiology. Integrative analyses reveal that pulmonary function instruments, including 73 novel
variants, influence lung tissue gene expression and implicate immune-related pathways in
mediating the observed effects on lung carcinogenesis.