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MMP19 Variants in Familial and Sporadic Idiopathic Pulmonary Fibrosis

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Abstract

Background

Gene variants have been identified in patients with familial or sporadic idiopathic pulmonary fibrosis (IPF). These variants may partially account for the genetic risk of IPF. The aim of this study was to identify potential genes involved in both familial and sporadic IPF.

Methods

A Han family in northern China with four members diagnosed with IPF was investigated in this observational study. Whole-exome sequencing (WES) was used to identify germline variants underlying disease phenotypes in five members of this family. Candidate rare variants were validated by Sanger sequencing in samples from 16 family members and 119 patients with sporadic IPF. The plasma levels of proteins encoded by the above candidate genes were also examined in 16 family members, 119 other patients with sporadic IPF and 120 age- and sex-matched healthy controls.

Results

In a Chinese Han family, MMP19 c.1222 C > T was identified in all familial IPF patients and six offspring from generations III and IV. This variant introduces a premature stop codon, which may damage protein function. Sanger sequencing revealed that 7.6% (9/119) of sporadic IPF patients harbored three MMP19 variants. The genetic risk analysis for pulmonary fibrosis showed that MMP19 c.1499 C > T and c.1316G > A were significantly associated with an increased risk of IPF (OR 3.66, p = 0.028 and OR 8.64, p < 0.001, respectively). The plasma levels of MMP19 were significantly higher in patients with sporadic or familial IPF than in healthy controls (all p < 0.001).

Conclusions

MMP19 variants were identified in familial or sporadic IPF, thus providing a potential new clue into IPF pathogenesis.

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Abbreviations

1000 G:

1000 Genomes Project

COPD:

Chronic obstructive pulmonary disease

DLCO SB:

Diffusing capacity of the lung for carbon monoxide

EAS:

East Asians

FEV1 :

Forced expiratory volume in first second

FVC:

Forced vital capacity

GnomAD:

Genome Aggregation Database;

IPF:

Idiopathic pulmonary fibrosis

MMP19:

Matrix metalloproteinase-19

OR:

Odds ratio

PFTs:

Pulmonary function tests

TERT:

Telomerase reverse transcriptase

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Acknowledgements

We thank all participants who were involved in this study. We express our thanks to Miss Moyang Xu of University of Michigan, Ann Arbor for polishing language and grammas of the manuscript.

Funding

The work was supported by Reform and Development Program of Beijing Institute of Respiratory Medicine (Ggyfz202321) and by High Level Public Health Technology Talent Construction Project (DL-02-21).

Author information

Author notes

  1. Yali Fan and Chunming Zheng contributed equally to this work.

Authors and Affiliations

  1. Clinical Center for Interstitial Lung Diseases, Beijing Institute of Respiratory Medicine, Beijing Chaoyang Hospital, Capital Medical University, No.8 Worker’s Stadium, Chaoyang District, Beijing, 100020, China

    Yali Fan, Chunming Zheng, Ruimin Ma, Jingwei Wang, Shuqiao Yang & Qiao Ye

  2. Department of Respiratory Medicine and Critical Care, Beijing Jishuitan Hospital, Beijing, 100035, China

    Yali Fan

  3. Department of Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China

    Chunming Zheng

  4. Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China

    Shuqiao Yang

  5. Department of Occupational Medicine and Toxicology, Beijing Chaoyang Hospital, Capital Medical University, No.8 Worker’s Stadium, Chaoyang District, Beijing, 100020, China

    Qiao Ye

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Contributions

YF and CZ designed the work, analyzed the data and wrote the manuscript. RM collected the data and contributed to analysis of data. JW and SY made contributions to the conception of the work and interpretation of data. QY participated in the study design and execution, as well as revising of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Qiao Ye.

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The authors declare no competing interests.

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The study was approved by the Institutional Review Board (IRB) of Beijing Chao-Yang Hospital (2018-KE-289).

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Informed consent was obtained from all individual participants included in the study.

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Fan, Y., Zheng, C., Ma, R. et al. MMP19 Variants in Familial and Sporadic Idiopathic Pulmonary Fibrosis. Lung 201, 571–580 (2023). https://doi.org/10.1007/s00408-023-00652-4

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