Smoking, Systemic Inflammation, and Airflow Limitation: A Mendelian Randomization Analysis of 98 085 Individuals From the General Population

Abstract

Abstract Introduction Smoking is associated with systemic and local inflammation in the lungs. Furthermore, in chronic obstructive pulmonary disease, which is often caused by smoking, there is often systemic inflammation that is linked to lung function impairment. However, the causal pathways linking smoking, systemic inflammation, and airflow limitation are still unknown. We tested whether higher tobacco consumption is associated with higher systemic inflammation, observationally and genetically and whether genetically higher systemic inflammation is associated with airflow limitation. Methods We included 98 085 individuals aged 20–100 years from the Copenhagen General Population Study; 36589 were former smokers and 16172 were current smokers. CHRNA3 rs1051730 genotype was used as a proxy for higher tobacco consumption and the IL6R rs2228145 genotype was used for higher systemic inflammation. Airflow limitation was defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <70%. Results Difference in plasma level of C-reactive protein was 4.8% (95% CI = 4.4% to 5.2%) per 10 pack-year increase and 1.6% (95% CI = 0.4% to 2.8%) per T allele. Corresponding differences were 1.2% (95% CI = 1.1% to 1.3%) and 0.5% (95% CI = 0.3% to 0.8%) for fibrinogen, 1.2% (95% CI = 1.2% to 1.3%) and 0.7% (95% CI = 0.5% to 1.0%) for α1-antitrypsin, 2.0% (95% CI = 1.8% to 2.1%) and 0.7% (95% CI = 0.4% to 1.1%) for leukocytes, 1.9% (95% CI = 1.8% to 2.1%) and 0.8% (95% CI = 0.4% to 1.2%) for neutrophils, and 0.8% (95% CI = 0.7% to 1.0%) and 0.4% (95% CI = 0.1% to 0.7%) for thrombocytes. The differences in these levels were lower for former smokers compared with current smokers. The IL6R rs2228145 genotype was associated with higher plasma acute-phase reactants but not with airflow limitation. Compared with the C/C genotype, the odds ratio for airflow limitation was 0.95 (95% CI = 0.89 to 1.02) for A/C genotype and 0.94 (95% CI = 0.87 to 1.01) for A/A genotype. Conclusions Higher tobacco consumption is associated with higher systemic inflammation both genetically and observationally, whereas systemic inflammation was not associated with airflow limitation genetically. Implications The association between higher tobacco consumption and higher systemic inflammation may be causal, and the association is stronger among current smokers compared to former smokers, indicating that smoking cessation may reduce the effects of smoking on systemic inflammation. Systemic inflammation does not seem to be a causal driver in development of airflow limitation. These findings can help to understand the pathogenic effects of smoking and the interplay between smoking, systemic inflammation, and airflow limitation and hence development and progression of chronic obstructive pulmonary disease.