A CommonMUC5BPromoter Polymorphism and Pulmonary Fibrosis

Abstract

BACKGROUND The mutations that have been implicated in pulmonary fibrosis account for only a small proportion of the population risk. METHODS Using a genomewide linkage scan, we detected linkage between idiopathic interstitial pneumonia and a 3.4-Mb region of chromosome 11p15 in 82 families. We then evaluated genetic variation in this region in gel-forming mucin genes expressed in the lung among 83 subjects with familial interstitial pneumonia, 492 subjects with idiopathic pulmonary fibrosis, and 322 controls. MUC5B expression was assessed in lung tissue. RESULTS Linkage and fine mapping were used to identify a region of interest on the p-terminus of chromosome 11 that included gel-forming mucin genes. The minor-allele of the single-nucleotide polymorphism (SNP) rs35705950, located 3 kb upstream of the MUC5B transcription start site, was present at a frequency of 34% among subjects with familial interstitial pneumonia, 38% among subjects with idiopathic pulmonary fibrosis, and 9% among controls (allelic association with familial interstitial pneumonia, P = 1.2×10−15; allelic association with idiopathic pulmonary fibrosis, P = 2.5×10−37). The odds ratios for disease among subjects who were heterozygous and those who were homozygous for the minor allele of this SNP were 6.8 (95% confidence interval [CI], 3.9 to 12.0) and 20.8 (95% CI, 3.8 to 113.7), respectively, for familial interstitial pneumonia and 9.0 (95% CI, 6.2 to 13.1) and 21.8 (95% CI, 5.1 to 93.5), respectively, for idiopathic pulmonary fibrosis. MUC5B expression in the lung was 14.1 times as high in subjects who had idiopathic pulmonary fibrosis as in those who did not (P<0.001). The variant allele of rs35705950 was associated with up-regulation in MUC5B expression in the lung in unaffected subjects (expression was 37.4 times as high as in unaffected subjects homozygous for the wild-type allele, P<0.001). MUC5B protein was expressed in lesions of idiopathic pulmonary fibrosis. CONCLUSIONS A common polymorphism in the promoter of MUC5B is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis. Our findings suggest that dys-regulated MUC5B expression in the lung may be involved in the pathogenesis of pulmonary fibrosis. (Funded by the National Heart, Lung, and Blood Institute and others.)

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

“…In a joint statement of the American Thoracic Society and European Respiratory Society, HPS-related pulmonary fibrosis (HPS-PF) and idiopathic pulmonary fibrosis (IPF) are considered similar entities (albeit with distinct causes) because both can show similar histological patterns (30). IPF occurs spontaneously in most patients, but research has uncovered some genetic mutations in surfactant proteins, mucins, and telomerases that are considered relevant (1,(3)(4)(5)(6). In contrast, 100% of patients with HPS-1 develop HPS-PF (29).…”

“…Environmental factors (e.g., asbestos and silica exposure), genetic factors (e.g., surfactant-related proteins and telomerase), and viral factors (herpesvirus) have been associated with the development of lung fibrosis, and other factors are believed to contribute to its progression (e.g., allergens, tobacco). However, pulmonary fibrosis often occurs in subjects where a cause cannot be identified (1)(2)(3)(4)(5)(6).…”

Basal cells of the human airways acquire mesenchymal traits in idiopathic pulmonary fibrosis and in culture

“…46,47 More recently, Schwartz and colleagues have, through several publications, linked a common single-nucleotide polymorphism in the promoter region of the mucin gene MUC5B to idiopathic interstitial pneumonias, including IPF. [48][49][50] The mutations in the surfactant family proteins, SFTPC and SFTPA2, both expressed exclusively by type II alveolar epithelial cells (AECs) in the lungs, suggest that AEC dysfunction is a prominent feature of IPF. Furthermore, accumulating evidence supports endoplasmic reticulum (ER) stress with consequent apoptosis as a prominent feature in IPF.…”

Oxidative and endoplasmic reticulum stress in respiratory disease

“…), one of which is the ER stress pathway. Inappropriate expression of MUC5B in type II pneumocytes, particularly in the honeycomb cysts characteristic of this disease, is a feature of IPF,80, 81 and the MUC5B promoter polymorphism leads to enhanced MUC5B mRNA expression 77. Interestingly, this expression, potentially driven by altered transcription factor binding sites in the promoter, occurs in the absence of expression of SPDEF,80 which is a transcription factor that drives expression of mucin genes and a network of other genes involved in mucin biosynthesis and secretion 82.…”

“…The common variant rs35705950 in the promoter region of MUC5B is carried by 9% of the European population and is the strongest risk factor for developing IPF accounting for 30–35% of the risk and also predicting asymptomatic mild fibrosis 68, 77, 78, 79. There are multiple potential explanations for how this polymorphism could lead to fibrosis (for a discussion, Evans et al 68…”