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Evidence for shared genetic risk factors between lymphangioleiomyomatosis and pulmonary function

Xavier Farré, Roderic Espín, Alexandra Baiges, Eline Blommaert, Wonji Kim, Krinio Giannikou, Carmen Herranz, Antonio Román, Berta Sáez, Álvaro Casanova, Julio Ancochea, Claudia Valenzuela, Piedad Ussetti, Rosalía Laporta, José A. Rodríguez-Portal, Coline H.M. van Moorsel, Joanne J. van der Vis, Marian J.R. Quanjel, Mireia Tena-Garitaonaindia, Fermín Sánchez de Medina, Francesca Mateo, María Molina-Molina, Sungho Won, David J. Kwiatkowski, Rafael de Cid, Miquel Angel Pujana
ERJ Open Research 2021; DOI: 10.1183/23120541.00375-2021
Xavier Farré
1Genomes for Life – GCAT Lab Group, Institut Germans Trias i Pujol (IGTP), Badalona, Catalonia, Spain
17These two authors contributed equally as first authors
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Roderic Espín
2ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain
17These two authors contributed equally as first authors
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Alexandra Baiges
2ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain
17These two authors contributed equally as first authors
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Eline Blommaert
2ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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Wonji Kim
3Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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Krinio Giannikou
4Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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Carmen Herranz
2ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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Antonio Román
5Lung Transplant Unit, Pneumology Service, Lymphangioleiomyomatosis Clinic, Vall d'Hebron University Hospital, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
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Berta Sáez
5Lung Transplant Unit, Pneumology Service, Lymphangioleiomyomatosis Clinic, Vall d'Hebron University Hospital, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
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Álvaro Casanova
6Pneumology Service, University Hospital of Henares, University Francisco de Vitoria, Coslada, Madrid, Spain
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Julio Ancochea
7Pneumology Service, La Princesa Research Institute, University Hospital La Princesa, Madrid, Spain
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Claudia Valenzuela
7Pneumology Service, La Princesa Research Institute, University Hospital La Princesa, Madrid, Spain
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Piedad Ussetti
8Pneumology Service, University Hospital Clinica Puerta del Hierro, Majadahonda, Madrid, Spain
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Rosalía Laporta
8Pneumology Service, University Hospital Clinica Puerta del Hierro, Majadahonda, Madrid, Spain
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José A. Rodríguez-Portal
9Medical-Surgical Unit of Respiratory Diseases, University Hospital Virgen del Rocío, Institute of Biomedicine of Seville (IBiS), Seville, Spain
10Biomedical Research Network Centre in Respiratory Diseases (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
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Coline H.M. van Moorsel
11Interstitial Lung Disease (ILD) Center of Excellence, St. Antonius Hospital, Nieuwegein, The Netherlands
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Joanne J. van der Vis
11Interstitial Lung Disease (ILD) Center of Excellence, St. Antonius Hospital, Nieuwegein, The Netherlands
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Marian J.R. Quanjel
11Interstitial Lung Disease (ILD) Center of Excellence, St. Antonius Hospital, Nieuwegein, The Netherlands
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  • ORCID record for Marian J.R. Quanjel
Mireia Tena-Garitaonaindia
12Department of Biochemistry and Molecular Biology II, School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain
13Biomedical Research Network Centre in Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
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Fermín Sánchez de Medina
13Biomedical Research Network Centre in Hepatic and Digestive Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
14Department of Pharmacology, School of Pharmacy, Instituto de Investigación Biosanitaria ibs.GRANADA, University of Granada, Granada, Spain
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Francesca Mateo
2ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain
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María Molina-Molina
10Biomedical Research Network Centre in Respiratory Diseases (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
15Interstitial Lung Disease Unit, Department of Respiratory Medicine, University Hospital of Bellvitge, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain
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Sungho Won
16Department of Public Health Sciences, Interdisciplinary Program of Bioinformatics, Institute of Health and Environment, Seoul National University, Seoul, South Korea
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David J. Kwiatkowski
4Cancer Genetics Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
18Joint senior authors
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Rafael de Cid
1Genomes for Life – GCAT Lab Group, Institut Germans Trias i Pujol (IGTP), Badalona, Catalonia, Spain
18Joint senior authors
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  • For correspondence: miguelangel.pujana@gmail.com rdecid@igtp.cat
Miquel Angel Pujana
2ProCURE, Catalan Institute of Oncology, Oncobell, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain
18Joint senior authors
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  • For correspondence: miguelangel.pujana@gmail.com rdecid@igtp.cat
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Abstract

Introduction Lymphangioleiomyomatosis (LAM) is a rare low-grade metastasising disease characterised by cystic lung destruction. The genetic basis of LAM remains incompletely determined, and the disease cell-of-origin is uncertain. We analysed the possibility of a shared genetic basis between LAM and cancer, and LAM and pulmonary function.

Methods The results of genome-wide association studies (GWASs) of LAM, 17 cancer types, and spirometry measures (forced expiratory volume in 1-second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and peak expiratory flow (PEF)) were analysed for genetic correlations, shared genetic variants, and causality. Genomic and transcriptomic data were examined, and immunodetection assays were performed to evaluate pleiotropic genes.

Results There were no significant overall genetic correlations between LAM and cancer, but LAM correlated negatively with FVC and PEF, and a trend in the same direction was observed for FEV1. Twenty-two shared genetic variants were uncovered between LAM and pulmonary function, while seven shared variants were identified between LAM and cancer. The LAM-pulmonary function shared genetics identified four pleiotropic genes previously recognised in LAM single-cell transcriptomes: ADAM12, BNC2, NR2F2, and SP5. We had previously associated NR2F2 variants with LAM, and we identified its functional partner NR3C1 as another pleotropic factor. NR3C1 expression was confirmed in LAM lung lesions. Another candidate pleiotropic factor, CNTN2, was found more abundant in plasma of LAM patients than that of healthy women.

Conclusions This study suggests the existence of a common genetic aetiology between LAM and pulmonary function.

Footnotes

This manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.

Conflict of interest: Xavier Farré has nothing to disclose.

Conflict of interest: Roderic Espín has nothing to disclose.

Conflict of interest: Alexandra Baiges has nothing to disclose.

Conflict of interest: Eline Blommaert has nothing to disclose.

Conflict of interest: Wonji Kim has nothing to disclose.

Conflict of interest: Krinio Giannikou has nothing to disclose.

Conflict of interest: Carmen Herranz has nothing to disclose.

Conflict of interest: Antonio Román has nothing to disclose.

Conflict of interest: Berta Sáez has nothing to disclose.

Conflict of interest: Álvaro Casanova has nothing to disclose.

Conflict of interest: Julio Ancochea has nothing to disclose.

Conflict of interest: Claudia Valenzuela has nothing to disclose.

Conflict of interest: Piedad Ussetti has nothing to disclose.

Conflict of interest: Rosalía Laporta has nothing to disclose.

Conflict of interest: José A. Rodríguez-Portal has nothing to disclose.

Conflict of interest: Coline H.M. van Moorsel has nothing to disclose.

Conflict of interest: Joanne J. van der Vis has nothing to disclose.

Conflict of interest: Marian J.R. Quanjel has nothing to disclose.

Conflict of interest: Mireia Tena-Garitaonaindia has nothing to disclose.

Conflict of interest: Fermín Sánchez de Medina has nothing to disclose.

Conflict of interest: Francesca Mateo has nothing to disclose.

Conflict of interest: María Molina-Molina has nothing to disclose.

Conflict of interest: Sungho Won has nothing to disclose.

Conflict of interest: David J Kwiatkowski has nothing to disclose.

Conflict of interest: Rafael de Cid has nothing to disclose.

Conflict of interest: Miquel Angel Pujana has nothing to disclose.

This is a PDF-only article. Please click on the PDF link above to read it.

  • Received June 2, 2021.
  • Accepted September 17, 2021.
  • Copyright ©The authors 2021
http://creativecommons.org/licenses/by-nc/4.0/

This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions{at}ersnet.org

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Evidence for shared genetic risk factors between lymphangioleiomyomatosis and pulmonary function
Xavier Farré, Roderic Espín, Alexandra Baiges, Eline Blommaert, Wonji Kim, Krinio Giannikou, Carmen Herranz, Antonio Román, Berta Sáez, Álvaro Casanova, Julio Ancochea, Claudia Valenzuela, Piedad Ussetti, Rosalía Laporta, José A. Rodríguez-Portal, Coline H.M. van Moorsel, Joanne J. van der Vis, Marian J.R. Quanjel, Mireia Tena-Garitaonaindia, Fermín Sánchez de Medina, Francesca Mateo, María Molina-Molina, Sungho Won, David J. Kwiatkowski, Rafael de Cid, Miquel Angel Pujana
ERJ Open Research Jan 2021, 00375-2021; DOI: 10.1183/23120541.00375-2021

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Evidence for shared genetic risk factors between lymphangioleiomyomatosis and pulmonary function
Xavier Farré, Roderic Espín, Alexandra Baiges, Eline Blommaert, Wonji Kim, Krinio Giannikou, Carmen Herranz, Antonio Román, Berta Sáez, Álvaro Casanova, Julio Ancochea, Claudia Valenzuela, Piedad Ussetti, Rosalía Laporta, José A. Rodríguez-Portal, Coline H.M. van Moorsel, Joanne J. van der Vis, Marian J.R. Quanjel, Mireia Tena-Garitaonaindia, Fermín Sánchez de Medina, Francesca Mateo, María Molina-Molina, Sungho Won, David J. Kwiatkowski, Rafael de Cid, Miquel Angel Pujana
ERJ Open Research Jan 2021, 00375-2021; DOI: 10.1183/23120541.00375-2021
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