The effect of MUC5B promoter polymorphism on susceptibility to idiopathic interstitial pneumonias and cell profiles in bronchoalveolar Lavage fluid

Abstract

Background: A polymorphism in the MUC5B gene (rs35705950) is associated with susceptibility to familial interstitial pneumonia (FIP) and idiopathic pulmonary fibrosis (IPF). We hypothesised that the MUC5B risk allele also predisposes to idiopathic nonspecific interstitial pneumonia (iNSIP). Furthermore, we assessed if there were any correlations between MUC5B genotype and bronchoalveolar lavage fluid (BALf) characteristics. Method: IPF (n=117), FIP (n=54), iNSIP (n=34), NSIP secondary to connective tissue disease (NSIP_CTD, n=32) and a healthy subjects cohort (n=249) were genotyped for MUC5B rs35705950. Lungfunction and survival data were collected for IPF and FIP. Result: Case-control analysis showed significant allelic association of rs35705950 with FIP (p=4.3x10 −10 ), IPF (p=1.3x10 −10 ) and iNSIP (p=0.001). Minor allele frequencies (MAF) were 31%, 27% and 22% respectively, compared to 9% in controls. This association was not observed in NSIP_CTD (MAF 8%). FIP subgroup analysis revealed an association with telomerase mutated FIP (p=2.0x10 −4 ) and FIP with unknown genetic cause (p=2.5x10 −9 ), but not with surfactant mutated FIP. FIP survival analysis showed longer survival time for MUC5B minor allele carriers. BALf MUC5B levels were significantly higher in ever smokers than in never smokers in IPF. MUC5B minor allele associated with significantly lower count of neutrophils and eosinophils in BALf of IPF. Conclusion: We show that the MUC5B risk allele predisposes to iNSIP, IPF and FIP and not to NSIP_CTD. IPF BAL cell profiles show that MUC5B minor allele carriers have lower inflammatory cell counts and might therefore be less prone to infections.