Mucin 5B Promoter Polymorphism Is Associated with Susceptibility to Interstitial Lung Diseases in Chinese Males

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Abstract

The variation of G>T in the MUC5B promoter (rs35705950) has been associated with idiopathic pulmonary fibrosis (IPF) and familial interstitial pneumonia (FIP) in Caucasians, but no information is available regarding this variant in the Chinese population. We recruited 405 patients with interstitial lung diseases (ILD), including 165 IPF patients and 2043 healthy controls, for genotyping the MUC5B gene in the Chinese population. One hundred three patients with pneumonia and 360 patients with autoimmune diseases (ADs) were recruited as disease controls. Our results indicated that the prevalence of the minor allele (T) of the polymorphism rs35705950 in healthy Chinese subjects was approximately 0.66%, which was lower than that described in the Caucasian population. The frequencies of the T allele were 3.33% and 2.22% in IPF and ILD patients, respectively, and these values were significantly higher than those of healthy controls ( P = 0.001, OR = 4.332 for IPF, and P = 0.002, OR = 2.855 for ILD). A stratified analysis showed that this variant in MUC5B associated with the risk for ILD mainly in older male Chinese subjects. No difference was observed between patients with pneumonia, AD patients, and healthy controls.

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The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.

D McShane, D. Bloch, Emma Healey … (1988)

The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with rheumatic diseases other than RA (non-RA). The new criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a "classification tree" schema is presented which performs equally as well as the traditional (4 of 7) format. The new criteria demonstrated 91-94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects.

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A common MUC5B promoter polymorphism and pulmonary fibrosis.

Max A Seibold, Anastasia Wise, Marcy Speer … (2011)

The mutations that have been implicated in pulmonary fibrosis account for only a small proportion of the population risk. 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. 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. A common polymorphism in the promoter of MUC5B is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis. Our findings suggest that dysregulated 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.).

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Telomerase mutations in families with idiopathic pulmonary fibrosis.

Mary Armanios, Julian J L Chen, Joy Cogan … (2007)

Idiopathic pulmonary fibrosis is progressive and often fatal; causes of familial clustering of the disease are unknown. Germ-line mutations in the genes hTERT and hTR, encoding telomerase reverse transcriptase and telomerase RNA, respectively, cause autosomal dominant dyskeratosis congenita, a rare hereditary disorder associated with premature death from aplastic anemia and pulmonary fibrosis. To test the hypothesis that familial idiopathic pulmonary fibrosis may be caused by short telomeres, we screened 73 probands from the Vanderbilt Familial Pulmonary Fibrosis Registry for mutations in hTERT and hTR. Six probands (8%) had heterozygous mutations in hTERT or hTR; mutant telomerase resulted in short telomeres. Asymptomatic subjects with mutant telomerase also had short telomeres, suggesting that they may be at risk for the disease. We did not identify any of the classic features of dyskeratosis congenita in five of the six families. Mutations in the genes encoding telomerase components can appear as familial idiopathic pulmonary fibrosis. Our findings support the idea that pathways leading to telomere shortening are involved in the pathogenesis of this disease. Copyright 2007 Massachusetts Medical Society.

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Author and article information

Contributors

Oliver Eickelberg: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 14 August 2014

Volume: 9

Issue: 8

Electronic Location Identifier: e104919

Affiliations

[1 ]Department of Medical Genetics, Nanjing University School of Medicine, Nanjing, China

[2 ]Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, China

[3 ]Department of Respirology, Medical School affiliated Drum Tower Hospital, Nanjing University, Nanjing, China

Helmholtz Zentrum München/Ludwig-Maximilians-University Munich, Germany

Author notes

* E-mail: wangyap@ 123456nju.edu.cn

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: YW. Performed the experiments: CW YZ WG HZ. Analyzed the data: CW YW. Contributed reagents/materials/analysis tools: LC LX YF DZ. Wrote the paper: CW YW.

Article

Publisher ID: PONE-D-14-07294

DOI: 10.1371/journal.pone.0104919

PMC ID: 4133265

PubMed ID: 25121989

SO-VID: f6c25ef0-2a8e-42c0-8c43-cfa4c3cad0c2

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 6 March 2014

Date accepted : 13 July 2014

Page count

Pages: 7

Funding

This work was partly supported by the National Natural Science Foundation of China (grant number: 81270152,81070273) and the Open Foundation of the State Key Laboratory of Pharmaceutical Biotechnology (grant number: KF-GN-201201). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Mucin 5B Promoter Polymorphism Is Associated with Susceptibility to Interstitial Lung Diseases in Chinese Males

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Abstract

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Most cited references 31

The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.

A common MUC5B promoter polymorphism and pulmonary fibrosis.

Telomerase mutations in families with idiopathic pulmonary fibrosis.

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