Exome and Sputum Microbiota as Predictive Markers of Frequent Exacerbations in Chronic Obstructive Pulmonary Disease

Frequent acute exacerbations are the leading cause of high rates of hospitalization and mortality in chronic obstructive pulmonary disease (COPD). Despite the enormous worldwide medical burden, reliable molecular markers for effective early diagnosis and prognosis of acute exacerbations are still lacking. Both the host genetics and airway microbiome are known to play potential roles in the pathogenesis of frequent exacerbations. Here, we performed whole exome sequencing (WES) and 16S rRNA gene sequencing to explore the interaction between these two factors and their implications in the pathogenesis of frequent exacerbations. We collected peripheral blood (n = 82), sputum samples (n = 59) and clinical data from 50 frequent-exacerbation phenotype (FE) COPD patients and 32 infrequent-exacerbation phenotype (IE) as controls. Based on filtering the deleterious sites, candidate mutated genes shared only in FE patients and did not occur in the IE group were identified. Microbiota analysis revealed significant differences in bacterial diversity and composition between FE and IE groups. We report the underlying pathogenic gene including, AATF, HTT, CEP350, ADAMTS9, TLL2 genes, etc., and explore their possible genotypic-phenotypic correlations with microbiota dysbiosis. Importantly, we observed that AATF gene mutations were significantly negatively correlated with microbial richness and diversity. Our study indicated several deleterious mutations in candidate genes that might be associated with microbial dysbiosis and the increased risk of frequent acute exacerbations in COPD patients. These results provide novel evidence that exomes and related microbiomes may potentially serve as biomarkers for predicting frequent acute exacerbations in COPD patients.