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
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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.
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- Received June 2, 2021.
- Accepted September 17, 2021.
- Copyright ©The authors 2021
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