Candidate gene association studies of chronic obstructive pulmonary disease and asthma

COPD and asthma are complex diseases characterized by pulmonary inflammation. The roles of single nucleotide polymorphisms (SNPs) in the inflammatory cytokine IL10, IL10RA, CSF2, CSF3 and IL6 in COPD and SNPs in a Th2-polarizing cytokine thymic stromal lymphopoietin (TSLP) in asthma are not clear. Association studies were performed to explore the genetic contribution of these cytokines to COPD or asthma. Housekeeping genes on airway epithelium were also optimized. In the study of COPD in the Lung Health Study (LHS), no association was found for IL10, IL10RA and CSF2; an increase in the number of CSF3 -1719T alleles was associated with protection against low forced expiratory volume in one second (FEV₁), odds ratio (OR) = .73, 95% confidence interval (CI) = .56 - .95, P = .018; three IL6 SNPs were associated with the rate of decline of FEV₁ (.023 ≤ P ≤ .041 in additive models). In the National Emphysema Treatment Trial - Normative Aging Study, IL6_-174G/C and four other highly linked SNPs were associated with COPD (.01 ≤ P ≤ .04 in additive genetic models). Association between IL6 and rate of FEV₁ decline was the most statistically significant observations in all of our studies in LHS, which has examined more than 40 candidate genes. In the study of TSLP association with asthma, the A allele of rs1837253 was associated with protection from asthma, atopic asthma, and airway hyperresponsiveness (AHR), with ORs (95% CI) and corrected P values for each being .79 (.69 - .90) and .0058; .75 (.63 - .88) and .0074; and .76 (.64 – .89) and .0094, respectively. These associations were the most statistically significant observations in our study, which has examined 98 candidate genes. Cyclophilin A was identified as the most suitable normalizer in gene expression studies involving human airway epithelium. In summary, we demonstrate for the first time that IL6 SNPs are associated with rapid decline of FEV₁ and COPD; TSLP SNPs are associated with asthma and AHR. These results will help our understanding of COPD and asthma and lead to more effective and individualized strategies for the management of COPD and asthma.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat