MUC5B Rs35705950 Research Articles

A meta-analysis examining the association between the MUC5B rs35705950 T/G polymorphism and susceptibility to idiopathic pulmonary fibrosis.

To explore whether the mucin (MUC) 5B rs35705950 T/G polymorphism confers susceptibility to idiopathic pulmonary fibrosis (IPF). A meta-analysis was conducted to determine associations between the MUC5B rs35705950 T/G polymorphism and either IPF or connective tissue disease-associated interstitial lung disease (CTD-ILD). We used the allele contrast, recessive, dominant, and additive models. A total of 12 IPF studies comprising 2859 patients and 6901 controls and four CTD-ILD studies involving 903 patients and 3306 controls were included in the meta-analysis. There was a significant association between the Tallele of the MUC5B rs35705950 polymorphism and IPF in all subjects (OR 3.768, 95 % CI 2.935-4.836, p < 1.0 × 10(-8)). Analysis after stratification by ethnicity indicated that the Tallele was significantly associated with IPF in Europeans and Asians (OR 3.728, 95 % CI 2.858-4.863, p < 1.0 × 10(-8); OR 4.334, 95 % CI 2.186-8.594, p = 2.6 × 10(-6)). However, there was no association between the Tallele and CTD-ILD in all subjects (OR 1.130, 95 % CI 0.937-1.363, p = 0.200), and in Europeans and Asians. Subgroup analysis by CTD type revealed no association between the Tallele and systemic sclerosis-associated ILD (SSc-ILD) and other CTD-ILDs. The MUC5B rs35705950 T/G polymorphism confers susceptibility to IPF in Europeans and Asians, but is not associated with susceptibility to CTD-ILD.

Extensive Phenotyping of Individuals at Risk for Familial Interstitial Pneumonia Reveals Clues to the Pathogenesis of Interstitial Lung Disease

Asymptomatic relatives of patients with familial interstitial pneumonia (FIP), the inherited form of idiopathic interstitial pneumonia, carry increased risk for developing interstitial lung disease. Studying these at-risk individuals provides a unique opportunity to investigate early stages of FIP pathogenesis and develop predictive models of disease onset. Seventy-five asymptomatic first-degree relatives of FIP patients (mean age, 50.8 yr) underwent blood sampling and high-resolution chest computed tomography (HRCT) scanning in an ongoing cohort study; 72 consented to bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsies. Twenty-seven healthy individuals were used as control subjects. Eleven of 75 at-risk subjects (14%) had evidence of interstitial changes by HRCT, whereas 35.2% had abnormalities on transbronchial biopsies. No differences were noted in inflammatory cells in BAL between at-risk individuals and control subjects. At-risk subjects had increased herpesvirus DNA in cell-free BAL and evidence of herpesvirus antigen expression in alveolar epithelial cells (AECs), which correlated with expression of endoplasmic reticulum stress markers in AECs. Peripheral blood mononuclear cell and AEC telomere length were shorter in at-risk individuals than healthy control subjects. The minor allele frequency of the Muc5B rs35705950 promoter polymorphism was increased in at-risk subjects. Levels of several plasma biomarkers differed between at-risk subjects and control subjects, and correlated with abnormal HRCT scans. Evidence of lung parenchymal remodeling and epithelial dysfunction was identified in asymptomatic individuals at risk for FIP. Together, these findings offer new insights into the early pathogenesis of idiopathic interstitial pneumonia and provide an ongoing opportunity to characterize presymptomatic abnormalities that predict progression to clinical disease.

CT Scan Findings of Probable Usual Interstitial Pneumonitis Have a High Predictive Value for Histologic Usual Interstitial Pneumonitis

The current usual interstitial pneumonitis (UIP)/idiopathic pulmonary fibrosis CT scan classification system excludes probable UIP as a diagnostic category. We sought to determine the predictive effect of probable UIP on CT scan on histology and the effect of the promoter polymorphism in MUC5B (rs35705950) on histologic and CT scan UIP diagnosis. The cohort included 201 subjects with pulmonary fibrosis who had lung tissue samples obtained within 1 year of chest CT scan. UIP diagnosis on CT scan was categorized as inconsistent with, indeterminate, probable, or definite UIP by two to three pulmonary radiologists. Tissue slides were scored by two expert pulmonary pathologists. All subjects with available DNA (N = 200) were genotyped for rs35705950. The proportion of CT scan diagnoses were as follows: inconsistent with (69 of 201, 34.3%), indeterminate (72 of 201, 35.8%), probable (34 of 201, 16.9%), and definite (26 of 201, 12.9%) UIP. Subjects with probable UIP on CT scan were more likely to have histologic probable/definite UIP than subjects with indeterminate UIP on CT scan (82.4% [28 of 34] vs 54.2% [39 of 72]; P = .01). CT scan and microscopic honeycombing were not associated with each other (P = .76). The minor (T) allele of the MUC5B polymorphism was associated with concordant CT scan and histologic UIP diagnosis (P = .03). Probable UIP on CT scan is associated with a higher rate of histologic UIP than indeterminate UIP on CT scan suggesting that they are distinct groups and should not be combined into a single CT scan category as currently recommended by guidelines. CT scan and microscopic honeycombing may be dissimilar entities. The T allele at rs35705950 predicts a UIP diagnosis by both chest CT scan and histology.

Abstract 3401: Inter-individual variation in MUC5B allele specific expression in normal bronchial epithelial cells and relationship to lung cancer

Abstract Background: Familial interstitial pneumonia and idiopathic pulmonary fibrosis are associated with increased risk of lung cancer. Seibold et al (NEJM, 2011) recently identified a common variant in the putative promoter of MUC5B (rs35705950) associated with level of MUC5B expression in lung tissue and also with development of these diseases. The goal of this study was to determine whether the MUC5B rs35705950 variant is associated with a) MUC5B allele-specific expression (ASE) or total expression in normal bronchial epithelial cells (NBEC) or b) lung cancer risk. Through funding in part from RC2 CA148572 and HL108016 we collected NBEC samples from over 500 subjects with lung cancer or at risk for lung cancer. Methods: This was a pilot study of 85 subjects (26 cancer cases and 59 non-cancer controls). RNA was extracted from normal bronchial airway brush NBEC specimens of 85 subjects and reverse transcribed. Using next generation sequencing (NGS), allele-specific expression (ASE) was measured as allelic imbalance in each cDNA at three marker SNPs in MUC5B coding region (rs2075859, rs2943510, and rs4963059) selected for common (&amp;gt;0.05) minor allele frequency, using matched peripheral blood cell gDNA as a control. Specifically, each cDNA and matched gDNA sample was subjected to targeted competitive template multiplex PCR amplicon library generation followed by NGS (Blomquist et al, PLOS one, 2013) on Illumina Hiseq platform. This NGS method controlled for inter-target variation in PCR amplification during library preparation by measuring each transcript native template relative to a known number of synthetic competitive template internal standard copies. The genotype at putative cis-regulatory SNP rs35705950 was assessed in gDNA from 95 subjects (31 cancer cases and 64 non-cancer controls) including those assessed for ASE using a TaqMan® SNP assay. Results: There was significant (p&amp;lt;0.001) inter-individual variation in MUB5B allelic imbalance among heterozygotes at all three marker SNP loci and the level of imbalance measured at rs2075859 was greater in NBEC from cancer cases compared with non-cancer controls (P=0.0264). The genotype (i.e., heterozygote vs homozygote) at putative cis-regulatory SNP rs35705950 was not associated with MUC5B allelic imbalance or with lung cancer status. Inter-individual variation in MUC5B total expression was large (&amp;gt;3 log) but not associated with lung cancer. Conclusions: These results support previous observations that there is significant inter-individual variation in cis-regulation of MUC5B in NBEC and suggest that this variation also may contribute to inherited lung cancer risk. Lack of association between rs35705950 genotype and MUC5B ASE may have been due to role of other cis-regulatory factors, and/or environmentally associated transfactors that contributed to large inter-individual variation in total MUC5B expression. Citation Format: Xiaolu Zhang, Jiyoun Yeo, Erin L. Crawford, Thomas M. Blomquist, James C. Willey. Inter-individual variation in MUC5B allele specific expression in normal bronchial epithelial cells and relationship to lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3401. doi:10.1158/1538-7445.AM2014-3401

Genetic risk factors for respiratory diseases of preterm infants

Aims Genetic variants of pulmonary surface glycoproteins like Muc5a and Muc5b are known to affect mucociliary clearance, control of infections and maybe associated with pulmonary fibrosis [1-3]. We tested the hypothesis that Muc5b (rs35705950) is associated with bronchopulmonary dysplasia (BPD) in mechanically ventilated preterm infants. In addition, we aimed to identify common variants associated with the need for surfactant treatment.

Association between MUC5B and TERT polymorphisms and different interstitial lung disease phenotypes

TERT and MUC5B polymorphisms have been associated consistently with idiopathic pulmonary fibrosis (IPF) in recent genomewide genetic studies. However, it remains unclear how both loci contribute to the susceptibility to different entities of sporadic interstitial lung disease (ILD). We sought to test the associations of the 2 polymorphisms with IPF and non-IPF ILD entities in a white population. Associations between 2 polymorphisms in TERT (rs2736100) and MUC5B (rs35705950) and IPF or non-IPF sporadic ILD were tested using 227 patients with ILD and 689 control subjects. Genotypic data were also correlated with pulmonary functions measured in patients with ILD. As a result, rs2736100 and rs35705950 were associated significantly and independently with ILD as a single phenotype (Odds ratio [OR],1.29; 95% confidence interval [CI], 1.04-1.60; P=2×10(-2); and OR, 2.22; 95% CI, 1.69-2.92; P=7×10(-9); respectively). When considering IPF and "other ILD" (non-IPF) separately, rs35705950 had a stronger association with IPF (OR, 3.2; 95% CI, 2.21-4.63; P=1.2×10(-10)) than with other ILD (OR, 1.72; 95% CI, 1.22-2.42; P=1.2×10(-3)). In contrast, rs2736100 was associated with other ILD (OR, 1.43; 95% CI, 1.11-1.85; P=6.2×10(-3)) but not with IPF (OR, 1.08; 95% CI, 0.78-1.49; P>0.05). Rs35705950 correlated significantly with increased pulmonary function (P<0.05). It was also associated with ILD without airflow obstruction in both the IPF and other ILD groups (P<0.01 for both), and conferred the highest risk for IPF without airflow obstruction (OR, 4.46; 95% CI, 2.60-7.66; P=4.5×10(-9)). Our study suggests that although both loci confer independent risks for ILD, rs35705950 may, in particular, contribute differentially to IPF and other ILD entities. Our study further highlights the genetic and phenotypic heterogeneity of ILD.

The Pulmonary Fibrosis-Associated MUC5B Promoter Polymorphism Does Not Influence the Development of Interstitial Pneumonia in Systemic Sclerosis

More than 80% of patients with systemic sclerosis (SSc) develop lung involvement, most commonly interstitial pneumonia (IP). We recently identified a common variant in the promoter region of MUC5B (rs35705950) that has a significant effect on the risk of developing both familial and sporadic forms of IP. We hypothesized that this MUC5B promoter polymorphism is also associated with IP in subjects with SSc. We examined the minor allele frequency of the MUC5B polymorphism among 231 subjects with SSc, 109 with IP, and 122 without IP. IP diagnosis was confirmed by HRCT imaging and defined as the presence of reticular infiltrates and/or honeycomb cysts. FVC and diffusing capacity of the lung for carbon monoxide (Dlco) were also assessed. We found no association between IP and the MUC5B polymorphism among subjects with SSc (OR = 1.1, P = .80). The frequencies of the MUC5B polymorphism among subjects with SSc with IP (10.6%) and without IP (9.4%) were similar to the frequency observed in a population of unaffected control subjects (9.0%). In secondary analyses, we found the MUC5B polymorphism was not significantly associated with either FVC (P = .42) or Dlco (P = .06). No association with SSc-associated IP was found even when we used a more conservative definition of IP (FVC ≤ 70% and evidence of reticulations or honeycombing vs SSc FVC &gt; 70% and no evidence of reticulation or honeycombing). Although SSc-associated IP is clinically, radiologically, and histologically similar to other forms of IP, it appears to have distinct genetic risk factors. This study highlights the genetic and phenotypic heterogeneity of IP in general.