Effect of Muc5b promoter polymorphism on disease predisposition and survival in idiopathic interstitial pneumonias

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Background and objective:A common polymorphism in theMUC5Bgene (rs35705950) is associated with susceptibility to idiopathic pulmonary fibrosis (IPF) and familial interstitial pneumonia (FIP). We investigated predisposition of theMUC5Bpolymorphism to fibrotic interstitial pneumonias in Dutch Caucasian patient cohorts. Furthermore, we investigated the correlation betweenMUC5Bgenotype and survival in these cohorts.Methods:Sporadic IPF (spIPF,n= 115), FIP (n= 55), idiopathic non-specific interstitial pneumonia (iNSIP,n= 43), connective tissue disease associated interstitial pneumonia (CTD_IP,n= 35) and a control cohort (n= 249) were genotyped for rs35705950.Results:Rs35705950 minor allele frequency (MAF) in controls was 0.09. Case-control analysis showed significant allelic association with spIPF (MAF = 0.27;P= 5.0 × 10−10), FIP (MAF = 0.30;P= 2.7 × 10−9) and iNSIP (MAF = 0.22;P= 3.4 × 10−4). No association was observed in CTD_IP (MAF = 0.07). FIP subgroup analysis revealed an association betweenMUC5Band telomerase mutated FIP (P= 0.003), and betweenMUC5Band FIP with unknown genetic cause (P= 1.2 × 10−8). In spIPF carriership ofMUC5Bminor allele did not influence survival. In FIPMUC5Bminor allele carriers had better survival (non-carriers 37 vs carriers 53 months,P= 0.01). In iNSIP survival analysis showed an opposite effect. Worse survival was found in iNSIP patients that carried theMUC5Bminor allele (non-carriers 118 vs carriers 46 months,P= 0.027)Conclusion:This study showed thatMUC5Bminor allele predisposes to spIPF, FIP and iNSIP. In spIPF, survival is not influenced byMUC5Balleles. In FIP,MUC5Bminor allele predicts better survival, pointing towards a subgroup of FIP patients with a milder, MUC5B-driven form of pulmonary fibrosis.SUMMARY AT A GLANCEWe investigated the effect of MUC5B polymorphism on disease predisposition and survival in IPF, FIP and iNSIP. The minor allele of MUC5B rs35705950 predisposes to disease in IPF, FIP and iNSIP, and predicts better survival in a subgroup of FIP patients with a milder, MUC5B-driven form of pulmonary fibrosis.

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