Genes associated with genetic and rare lung diseases and the risk of lung cancer.

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Rosenberger, Albert ORCID: 0000-0001-7848-1332, Bickeböller, Heike, Christiani, David C, Caporaso, Neil E, Liu, Geoffrey, Bojesen, Stig E, Le Marchand, Loic, Albanes, Demetrios, Aldrich, Melinda C, Tardon, Adonina et al (show 24 more authors) , Fernández-Tardón, Guillermo, Rennert, Gad, Field, John K, Davies, Michael PA ORCID: 0000-0002-7609-4977, Kiemeney, Lambertus A, Lazarus, Philip, Zienolddiny, Shanbeh, Lam, Stephen, Schabath, Matthew B, Andrew, Angeline S, Arnold, Susanne M, Goodman, Gary E, Doherty, Jennifer A, Taylor, Fiona, Cox, Angela, Woll, Penella J, Risch, Angela, Johansson, Mikael, Brennan, Paul, Landi, Maria Teresa, Shete, Sanjay S, Hung, Rayjean J, Amos, Christopher I and INTEGRAL-ILCCO Consortium (2025) Genes associated with genetic and rare lung diseases and the risk of lung cancer. Res Sq. rs.3.rs-7029929. ISSN 2693-5015, 2693-5015

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Abstract

BACKGROUND: We investigated whether markers, genes or terms of the Human Phenotype Ontology associated with genetic or rare diseases (GARDs) that affect airway or lung function are associated with lung cancer. METHODS: Genes of interest were extracted from GARD, OMIM, ORPHANET and Monarch Initiative. Individual SNP, gene level and gene-set analyses were performed for 52,207 SNPs, 1,677 genes or for 620 terms of the Human Phenotype Ontology. The analysis included 14,068 lung cancer cases and 12,390 cancer-free control subjects of European descent from the International Lung Cancer Consortium ILCCO. RESULTS: The marker rs56113850 (OR=0.893, 95%CI: 0.862-0.924) was associated with lung cancer (p=1.2×10-10). This marker is located in CYP2A6 as well as in an enhancer region of LTBP4, which is associated with cutis laxa. A suggestive significant association was observed for two markers associated with the DMD gene, which is linked to Duchenne muscular dystrophy. The gene sets "Abnormal circulating adrenocorticotropin concentration" and "Central nervous system neoplasm" were found to be significantly enriched with GARD genes, and can therefore be considered to be associated with lung cancer. CONCLUSIONS: Genes associated with genetic and rare lung diseases do not generally appear to carry risk factors for lung cancer. However, genes associated with the hypothalamic-pituitary-adrenal axis show some, but rather weak or complex, associations with lung cancer. Tests at the gene level provide extremely inhomogeneous results, even when applied to the same data.

Item Type:	Article
Uncontrolled Keywords:	CYP2A6, DMD, GARD, Hypothalamic-Pituitary-Adrenal axis, LTBP4, OMIM, Orphanet, adrenocorticotropic hormone, gene-based test, gene-set analysis, genomic marker, lung cancer, rare disease
Divisions:	Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	16 Sep 2025 15:12
Last Modified:	10 Dec 2025 13:31
DOI:	10.21203/rs.3.rs-7029929/v1
Open Access URL:	https://www.researchsquare.com/article/rs-7029929/...
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3194457
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