Evidence for shared genetic risk factors between lymphangioleiomyomatosis and pulmonary function

This research was supported by Asociacion Espanola de LAM; The LAM Foundation Seed Grant 2019; Carlos III Institute of Health grants PI18/01029, PI21/01306 and ICI19/00047 (co-funded by European Regional Development Fund (ERDF), "A way to build Europe"); Ministry of Economy and Competitivity grant SAF2017-88457-R; the Generalitat de Catalunya SGR 2017-449 and 2017-529; PERIS PFI-Salut SLT017-20-000076; and the CERCA Program to IDIBELL and Institut Germans Trias i Pujol. X. Farre is supported by the VEIS project (001-P-001647, ERDF Operational Programme of Catalonia 2014-2020; co-funded by ERDF, "A way to build Europe"). Funding information for this article has been deposited with the Crossref Funder Registry.
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 of LAM, 17 cancer types and spirometry measures (forced expiratory volume in 1 s (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. 22 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.
Asociacion Espanola de LAM
LAM Foundation Seed Grant 2019
Instituto de Salud Carlos III PI18/01029 PI21/01306 ICI19/00047
European Regional Development Fund (ERDF), "A way to build Europe"
Ministry of Economy and Competitivity SAF2017-88457-R
Generalitat de Catalunya
General Electric SGR 2017-449 2017-529
PERIS PFI-Salut SLT017-20-000076
CERCA Program
VEIS project 001-P-001647
ERDF, "A way to build Europe" ERDF Operational Programme of Catalonia 2014-2020