Association between systemic sclerosis and risk of lung cancer: results from a pool of cohort studies and Mendelian randomization analysis

Background: Population-based cohort studies have indicated that systemic sclerosis (SSc) may be associated with an increased risk of lung cancer. However, there are few studies that comprehensively investigate their correlation and the causal effect remains unknown. Methods: A systematic search of PubMed, Web of Science, Cochrane Library and Embase from the inception dates to December 1, 2019 was carried out. Meta-analysis was performed to calculate odds ratio (OR) and corresponding 95% confidence interval (CI) using random-effects models. Subgroup analyses were performed regarding gender. Two-sample Mendelian randomization (MR) was carried out with summary data from published genome-wide association studies of SSc (Neale Lab, 3871 individuals; UK Biobank, 463,315 individuals) and lung cancer (International Lung Cancer Consortium, 27,209 individuals; UK Biobank, 508,977 individuals). Study-specific estimates were summarized using inverse variance-weighted, weighted median, and MR-Egger method. Results: Through meta-analysis of 10 population-based cohort studies involving 12,218 patients, we observed a significantly increased risk of lung cancer among patients with SSc (OR 2.80, 95% CI 1.55-5.03). In accordance with subgroup analysis, male patients (OR 4.11, 95% CI 1.92-8.79) had a 1.5-fold higher lung cancer risk compared with female patients (OR 2.73, 95% CI 1.41-5.27). However, using a score of 11 SSc-related single nucleotide polymorphisms (p < 5*10(-8)) as instrumental variables, the MR study did not support a causality between SSc and lung cancer (OR 1.001, 95% CI 0.929-1.100, p = 0.800). Specifically, subgroup MR analyses indicated that SSc was not associated with increased risks of non-small-cell lung cancer (OR 1.000, 95% CI 0.999-1.000, p = 0.974), including lung adenocarcinoma (OR 0.996, 95% CI 0.906-1.094, p = 0.927), squamous cell lung carcinoma (OR 1.034, 95% CI 0.937-1.140, p = 0.507), nor small-cell lung cancer (OR 1.000, 95% CI 0.999-1.000, p = 0.837). Conclusions: This study indicated an increased risk of lung cancer among patients with SSc by meta-analysis, whereas the MR study did not support a causality between the two diseases. Further studies are warranted to investigate the factors underlying the attribution of SSc to lung cancer risk.