Evidence for shared genetic risk factors between lymphangioleiomyomatosis and pulmonary function

Area of Science:

• Genetics
• Pulmonology
• Oncology

Background:

• Lymphangioleiomyomatosis (LAM) is a rare disease causing lung destruction with an uncertain genetic basis and cell-of-origin.
• Investigating shared genetic factors between LAM, cancer, and pulmonary function is crucial for understanding disease mechanisms.

Purpose of the Study:

• To explore the potential shared genetic basis between LAM and cancer.
• To investigate the genetic correlation and causality between LAM and pulmonary function.

Main Methods:

• Genome-wide association studies (GWAS) of LAM, 17 cancer types, and spirometry measures (FEV1, FVC, FEV1/FVC, PEF).
• Analysis of genetic correlations, shared variants, and causality using genomic and transcriptomic data.
• Evaluation of pleiotropic genes through immunodetection assays.

Main Results:

• No significant overall genetic correlation between LAM and cancer.
• Negative genetic correlation observed between LAM and FVC, PEF, and a trend with FEV1.
• Identified 22 shared genetic variants between LAM and pulmonary function, and seven between LAM and cancer.
• Discovered four pleiotropic genes (ADAM12, BNC2, NR2F2, SP5) common to LAM and pulmonary function genetics.
• Identified NR3C1 as a functional partner of NR2F2, with confirmed expression in LAM lesions.
• Found CNTN2 more abundant in plasma of LAM patients.

Conclusions:

• Suggests a common genetic etiology between LAM and pulmonary function.
• Highlights potential pleiotropic genes involved in LAM pathogenesis and pulmonary function.