Xinyan Wang,1,* Xin Chen,2,* Ruizhi Feng,1 Hongli Jiang,1 Wei Liu1 

1Division of Internal Medicine, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Department of Integrated Traditional Chinese and Western Medicine, Zigong First People’s Hospital, Zigong, 643000, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Wei Liu, Division of Internal Medicine, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, People’s Republic of China, Tel/Fax +86 028-85423546, Email liuwei0929@wchscu.cn

Purpose: Diabetes, particularly type 2 diabetes (T2D), is a common comorbidity that occurs at a higher frequency in chronic obstructive pulmonary disease (COPD) patients compared to the general population. The COPD-diabetes association is documented epidemiologically and experimentally. Potential mechanisms, including systemic inflammation and metabolic dysregulation, are discussed as plausible pathways. However, their causal relationship still needs to be confirmed.
Methods: We conducted a comprehensive bidirectional two-sample Mendelian randomization (MR) analysis to evaluate the causal links between COPD and both type 1 diabetes (T1D) and T2D by using genome-wide association study (GWAS) summary statistics in European and Asian populations. By employing MR methods, the causal effect of diabetes on the risk of COPD as well as specific COPD-related clinical outcomes, including COPD with infections (COPD-I), pneumonia or pneumonia-derived septicaemia, chronic opportunistic infections, respiratory insufficiency, hospital admissions, and onset age (early or late) were explored.
Results: Forward MR analysis provided evidence consistent with a causal relationship between T2D and an increased risk of COPD in the European population (IVW odds ratio (OR): 1.002, 95% confidence interval (CI): 1.001– 1.003, P = 0.001). This association appeared consistent with MR Egger analysis, yielding a similar result for European COPD patients (MR Egger OR: 1.108, 95% CI: 1.016 − 1.208, P = 0.021). No statistically conclusive evidence of a causal relationship between diabetes and COPD was found in the Asian population. Besides, genetically determined T1D was identified as a risk factor for the incidence of COPD-I in the European-specific population (IVW OR: 1.017, 95% CI: 1.009– 1.025, P < 0.001). The reverse MR analysis, exploring the effect of COPD on the risk of diabetes, did not achieve consistent results in either the European or Asian populations.
Conclusion: This study suggested a modest but statistically significant causal association between T2D and COPD in individuals of European ancestry. Further explorations are required to better understand the underlying mechanisms linking diabetes to COPD development.

Keywords: chronic obstructive pulmonary disease, type 1 diabetes mellitus, type 2 diabetes mellitus, Mendelian randomization, causal inference