Effects of Lung Function-Related Genes and TSLP on COPD Phenotypes

A weighted genetic risk score (GRS) based on 16 SNPs implicated in reduced lung function in both Japanese and non-Japanese populations was previously associated with the onset of COPD and asthma. We here examine the genetic impact of this lung function GRS on specific COPD phenotypes. A cohort of Japanese COPD patients (N = 270) underwent lung function testing followed by genotyping with allele-specific arrays for 16 SNPs as well as expression quantitative trait loci at TSLP (rs2289276, rs3806933). Lung function GRS scoring and two-step cluster analyses grouped patients into different COPD phenotypes based on gender, age, smoking index, %FEV₁ and lung function GRS. The genetic effect of TSLP on COPD phenotypes was also examined for interactions with the lung function GRS. A total of 270 participants were grouped into 5 clusters. The cluster with the highest levels of lung function GRS was characterized by moderate to severe airflow obstruction and the highest blood eosinophil counts. Regarding TSLP, an increased number of T alleles at both SNPs was found in the cluster characterized by moderate to severe airflow obstruction and heavy smoking (rs2289276, p value = 0.035; rs3806933, p value = 0.047) independent of the lung function GRS. A genetic susceptibility to impaired lung function carries an increased risk of developing COPD characterized by increased eosinophil counts and severe airflow obstruction while individuals with increased TSLP responses to external stimuli have an independent risk of developing severe airflow obstruction in the presence of heavy smoking.