{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T05:14:58Z","timestamp":1764652498301,"version":"3.46.0"},"reference-count":105,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T00:00:00Z","timestamp":1764374400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"S\u00e3o Paulo Research Foundation","doi-asserted-by":"crossref","award":["2024\/20055-9"],"award-info":[{"award-number":["2024\/20055-9"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003593","name":"National Council for Scientific and Technological Development","doi-asserted-by":"publisher","award":["88887.823904\/2023-00"],"award-info":[{"award-number":["88887.823904\/2023-00"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"FAPESP","doi-asserted-by":"publisher","award":["2024\/20061-9"],"award-info":[{"award-number":["2024\/20061-9"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"CNPq","doi-asserted-by":"publisher","award":["305906\/2024-0"],"award-info":[{"award-number":["305906\/2024-0"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cystic fibrosis (CF) is a rare genetic disease caused by pathogenic variants in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene, with wide clinical variability influence not only by the CFTR genotype but also by environmental and modifier genes such as ADAM33 (A Disintegrin and Metalloproteinase Domain 33). The rs2280091 variant in ADAM33 may affect lung function and contribute to differences in disease severity. This study investigated the association between this genetic variant and lung function in CF patients. This cross-sectional study included 55 CF patients from a Brazilian center, with diagnosis confirmed by sweat testing and CFTR genotyping. Pulmonary function was evaluated by spirometry before and after bronchodilator (BD) administration according to the American Thoracic Society\/European Respiratory Society guidelines, analyzing Forced Vital Capacity (FVC), Forced Expiratory Volume in one second (FEV1), FEV1\/FVC ratio, Forced Expiratory Flow at 25%, 50%, and 75% of FVC (FEF25%, FEF50%, and FEF75%), mean Forced Expiratory Flow between 25% and 75% of FVC (FEF25\u201375%), and Maximal Expiratory Forced Flow (MEF). The ADAM33 rs2280091 variant was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and statistical analyses included Kruskal\u2013Wallis and Mann\u2013Whitney tests, chi-square (\u03c72) tests, and calculation of odds ratios (ORs) with 95% confidence intervals (95% CI). The study included 55 CF patients, predominantly female (96.4%) and Caucasian (52.7%), with a median age of 17 years. CFTR genotyping revealed F508del\/F508del as the most common genotype (52.7%). Analysis of the ADAM33 rs2280091 variant demonstrated that the AA genotype was most frequent in both CF patients (69.1%) and healthy controls (78.6%). Notably, the GG genotype was significantly enriched in CF patients (18.2%) compared with the controls (0.02%), yielding an odds ratio of 12.06 (95% CI: 4.86\u201329.91), while the G allele was also associated with increased disease risk (24.5% vs. 11.6%). Pulmonary function assessment indicated that carriers of the GG genotype or G allele had higher Forced Expiratory Flow parameters (FEF25%, FEF50%, FEF25\u201375%, and MEF) and improved BD responsiveness, suggesting a potential modulatory role of ADAM33 in peripheral airway function in CF. The G allele of the ADAM33 rs2280091 variant was more frequent among recruited CF patients and associated with improved peripheral airway function and BD response. These findings may reflect a survivor effect, in which carriers of this allele are more likely to reach clinical follow-up and recruitment rather than indicating a direct association with increased disease risk.<\/jats:p>","DOI":"10.3390\/ijms262311583","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T08:13:49Z","timestamp":1764576829000},"page":"11583","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Role of the ADAM33 rs2280091 Variant in Modulating Lung Function in Cystic Fibrosis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-9549-6069","authenticated-orcid":false,"given":"Vin\u00edcius Santiago","family":"dos Santos","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Biology and Genetics, Postgraduate Program of Health Sciences, Postgraduate Program of Health Data Science, University of S\u00e3o Francisco (Universidade S\u00e3o Francisco\u2014USF), Bragan\u00e7a Paulista 12916-900, SP, Brazil"},{"name":"Laboratory of Clinical and Molecular Microbiology, Postgraduate Program of Health Sciences, Postgraduate Program of Health Data Science, University of S\u00e3o Francisco (Universidade S\u00e3o Francisco\u2014USF), Bragan\u00e7a Paulista 12916-900, SP, Brazil"},{"name":"LunGuardian Research Group\u2014Epidemiology of Respiratory and Infectious Diseases, Postgraduate Program of Health Sciences, Postgraduate Program of Health Data Science, University of S\u00e3o Francisco (Universidade S\u00e3o Francisco\u2014USF), Bragan\u00e7a Paulista 12916-900, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9920-5058","authenticated-orcid":false,"given":"Lucas Silva","family":"Mello","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology and Genetics, Postgraduate Program of Health Sciences, Postgraduate Program of Health Data Science, University of S\u00e3o Francisco (Universidade S\u00e3o Francisco\u2014USF), Bragan\u00e7a Paulista 12916-900, SP, Brazil"},{"name":"Laboratory of Clinical and Molecular Microbiology, Postgraduate Program of Health Sciences, Postgraduate Program of Health Data Science, University of S\u00e3o Francisco (Universidade S\u00e3o Francisco\u2014USF), Bragan\u00e7a Paulista 12916-900, SP, Brazil"},{"name":"LunGuardian Research Group\u2014Epidemiology of Respiratory and Infectious Diseases, Postgraduate Program of Health Sciences, Postgraduate Program of Health Data Science, University of S\u00e3o Francisco (Universidade S\u00e3o Francisco\u2014USF), Bragan\u00e7a Paulista 12916-900, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5494-2171","authenticated-orcid":false,"given":"Luiz Felipe Azevedo","family":"Marques","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology and Genetics, Postgraduate Program of Health Sciences, Postgraduate Program of Health Data Science, University of S\u00e3o Francisco (Universidade S\u00e3o Francisco\u2014USF), Bragan\u00e7a Paulista 12916-900, SP, Brazil"},{"name":"Laboratory of Clinical and Molecular Microbiology, Postgraduate Program of Health Sciences, Postgraduate Program of Health Data Science, University of S\u00e3o Francisco (Universidade S\u00e3o Francisco\u2014USF), Bragan\u00e7a Paulista 12916-900, SP, Brazil"},{"name":"LunGuardian Research Group\u2014Epidemiology of Respiratory and Infectious Diseases, Postgraduate Program of Health Sciences, Postgraduate Program of Health Data Science, University of S\u00e3o Francisco (Universidade S\u00e3o Francisco\u2014USF), Bragan\u00e7a Paulista 12916-900, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7825-3761","authenticated-orcid":false,"given":"Luana Rodrigues","family":"Silva","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology and Genetics, Postgraduate Program of Health Sciences, Postgraduate Program of Health Data Science, University of S\u00e3o Francisco (Universidade S\u00e3o Francisco\u2014USF), Bragan\u00e7a Paulista 12916-900, SP, Brazil"},{"name":"Laboratory of Clinical and Molecular Microbiology, Postgraduate Program of Health Sciences, Postgraduate Program of Health Data Science, University of S\u00e3o Francisco (Universidade S\u00e3o Francisco\u2014USF), Bragan\u00e7a Paulista 12916-900, SP, Brazil"},{"name":"LunGuardian Research Group\u2014Epidemiology of Respiratory and Infectious Diseases, Postgraduate Program of Health Sciences, Postgraduate Program of Health Data Science, University of S\u00e3o Francisco (Universidade S\u00e3o Francisco\u2014USF), Bragan\u00e7a Paulista 12916-900, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2813-2887","authenticated-orcid":false,"given":"Carmen S\u00edlvia","family":"Bertuzzo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Campinas (Universidade de Campinas\u2014Unicamp), Campinas 13083-970, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3387-5642","authenticated-orcid":false,"given":"Jos\u00e9 Dirceu","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Campinas (Universidade de Campinas\u2014Unicamp), Campinas 13083-970, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4955-4234","authenticated-orcid":false,"given":"Fernando Augusto Lima","family":"Marson","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology and Genetics, Postgraduate Program of Health Sciences, Postgraduate Program of Health Data Science, University of S\u00e3o Francisco (Universidade S\u00e3o Francisco\u2014USF), Bragan\u00e7a Paulista 12916-900, SP, Brazil"},{"name":"Laboratory of Clinical and Molecular Microbiology, Postgraduate Program of Health Sciences, Postgraduate Program of Health Data Science, University of S\u00e3o Francisco (Universidade S\u00e3o Francisco\u2014USF), Bragan\u00e7a Paulista 12916-900, SP, Brazil"},{"name":"LunGuardian Research Group\u2014Epidemiology of Respiratory and Infectious Diseases, Postgraduate Program of Health Sciences, Postgraduate Program of Health Data Science, University of S\u00e3o Francisco (Universidade S\u00e3o Francisco\u2014USF), Bragan\u00e7a Paulista 12916-900, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,29]]},"reference":[{"key":"ref_1","first-page":"332","article-title":"Phenotype of CF and the Effects of Possible Modifier Genes","volume":"2","author":"Acton","year":"2001","journal-title":"Paediatr. Respir. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1097\/MCP.0000000000000824","article-title":"Emerging Clinical Perspectives in Cystic Fibrosis Liver Disease","volume":"27","author":"Athwal","year":"2021","journal-title":"Curr. Opin. Pulm. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S2213-2600(19)30337-6","article-title":"The Future of Cystic Fibrosis Care: A Global Perspective","volume":"8","author":"Bell","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Trouv\u00e9, P., Saint Pierre, A., and F\u00e9rec, C. (2024). Cystic Fibrosis: A Journey through Time and Hope. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25179599"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e28984","DOI":"10.1016\/j.heliyon.2024.e28984","article-title":"CFTR Pathogenic Variants Spectrum in a Cohort of Mexican Patients with Cystic Fibrosis","volume":"10","author":"Cubas","year":"2024","journal-title":"Heliyon"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1542\/pir.2019-0212","article-title":"Cystic Fibrosis","volume":"42","author":"Dickinson","year":"2021","journal-title":"Pediatr. Rev."},{"key":"ref_7","first-page":"654","article-title":"CFTR and cystic fibrosis, a 50-year long history","volume":"37","author":"Becq","year":"2021","journal-title":"Med. Sci."},{"key":"ref_8","first-page":"584","article-title":"Cystic Fibrosis: Current Concepts","volume":"78","author":"Reyes","year":"2021","journal-title":"Bol. Med. Hosp. Infant. Mex."},{"key":"ref_9","unstructured":"Sankari, A., and Sharma, S. (2025). Cystic Fibrosis. StatPearls, StatPearls Publishing."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Earnest, A., Salimi, F., Wainwright, C.E., Bell, S.C., Ruseckaite, R., Ranger, T., Kotsimbos, T., and Ahern, S. (2020). Lung Function over the Life Course of Paediatric and Adult Patients with Cystic Fibrosis from a Large Multi-Centre Registry. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-74502-1"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Meneses, D.G., Dos Santos, F.R., Botelho, A.J., Bispo, L.M., Matos, C.G., Propheta, V.G.S., Rodrigues, A.F., Oliveira, G.U., da Silva, A.M., and Gurgel, R.Q. (2024). Diagnosis of Cystic Fibrosis: A High Heterogeneity of Symptoms and Genotypes in a Brazil Population. BMC Pediatr., 24.","DOI":"10.1186\/s12887-024-04891-z"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Marson, F.A.d.L., Hortencio, T.D.R., Aguiar, K.C.A., Ribeiro, J.D., and CYFIUC Group (2015). Demographic, Clinical, and Laboratory Parameters of Cystic Fibrosis during the Last Two Decades: A Comparative Analysis. BMC Pulm. Med., 15.","DOI":"10.1186\/1471-2466-15-3"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Marques, L.S., Firmida, M.C., and Marson, F.A.L. (2024). Were Deaths Recorded in Brazil Due to Cystic Fibrosis or Pulmonary Fibrosis? A Data-Based Analysis. Front. Med., 11.","DOI":"10.3389\/fmed.2024.1459785"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Scotet, V., L\u2019Hostis, C., and F\u00e9rec, C. (2020). The Changing Epidemiology of Cystic Fibrosis: Incidence, Survival and Impact of the CFTR Gene Discovery. Genes, 11.","DOI":"10.3390\/genes11060589"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Azoicai, A.N., Lupu, A., Trandafir, L.M., Alexoae, M.M., Alecsa, M., Starcea, I.M., Cuciureanu, M., Knieling, A., Salaru, D.L., and Hanganu, E. (2024). Cystic Fibrosis Management in Pediatric Population-from Clinical Features to Personalized Therapy. Front. Pediatr., 12.","DOI":"10.3389\/fped.2024.1393193"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s13223-023-00760-z","article-title":"Association between Cystic Fibrosis Exacerbations, Lung Function, T2 Inflammation and Microbiological Colonization","volume":"19","author":"Albon","year":"2023","journal-title":"Allergy Asthma Clin. Immunol."},{"key":"ref_17","first-page":"198","article-title":"Pulmonary Function, Functional Capacity and Quality of Life in Adults with Cystic Fibrosis","volume":"21","author":"Lopes","year":"2015","journal-title":"Rev. Port. Pneumol. (2006)"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1146\/annurev-med-042921-021447","article-title":"Cystic Fibrosis Modulator Therapies","volume":"74","author":"Jia","year":"2023","journal-title":"Annu. Rev. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"240045","DOI":"10.1183\/16000617.0045-2024","article-title":"New Drugs, New Challenges in Cystic Fibrosis Care","volume":"33","author":"Fajac","year":"2024","journal-title":"Eur. Respir. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s40348-025-00194-0","article-title":"Progress of Personalized Medicine of Cystic Fibrosis in the Times of Efficient CFTR Modulators","volume":"12","author":"Pallenberg","year":"2025","journal-title":"Mol. Cell. Pediatr."},{"key":"ref_21","first-page":"e20210237","article-title":"Routine Spirometry in Cystic Fibrosis Patients: Impact on Pulmonary Exacerbation Diagnosis and FEV1 Decline","volume":"48","author":"Rodrigues","year":"2022","journal-title":"J. Bras. Pneumol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Sepahzad, A., Morris-Rosendahl, D.J., and Davies, J.C. (2021). Cystic Fibrosis Lung Disease Modifiers and Their Relevance in the New Era of Precision Medicine. Genes, 12.","DOI":"10.3390\/genes12040562"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Butnariu, L.I., \u021aarc\u0103, E., Cojocaru, E., Rusu, C., Mois\u0103, \u0218.M., Leon Constantin, M.-M., Gorduza, E.V., and Trandafir, L.M. (2021). Genetic Modifying Factors of Cystic Fibrosis Phenotype: A Challenge for Modern Medicine. J. Clin. Med., 10.","DOI":"10.3390\/jcm10245821"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1097\/MCP.0000000000000479","article-title":"Disease-Modifying Genetic Factors in Cystic Fibrosis","volume":"24","author":"Marson","year":"2018","journal-title":"Curr. Opin. Pulm. Med."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Marson, F.A.L., Bertuzzo, C.S., and Ribeiro, J.D. (2017). Personalized or Precision Medicine? The Example of Cystic Fibrosis. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2017.00390"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1002\/ppul.20198","article-title":"Modifier Genes in Cystic Fibrosis","volume":"39","author":"Davies","year":"2005","journal-title":"Pediatr. Pulmonol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ramananda, Y., Naren, A.P., and Arora, K. (2024). Functional Consequences of CFTR Interactions in Cystic Fibrosis. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25063384"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Aalbers, B.L., Bronsveld, I., Hofland, R.W., and Heijerman, H.G.M. (2021). Management of Individual Patient Expectations When Starting with Highly Effective CFTR Modulators. J. Pers. Med., 11.","DOI":"10.3390\/jpm11080811"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.jcf.2019.12.015","article-title":"Clinical Effect of Lumacaftor\/Ivacaftor in F508del Homozygous CF Patients with FEV1 \u2265 90% Predicted at Baseline","volume":"19","author":"Aalbers","year":"2020","journal-title":"J. Cyst. Fibros."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"22","DOI":"10.24953\/turkjpediatr.2025.4680","article-title":"Eligibility of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Modulator Therapies: Cohort of Cystic Fibrosis Registry of T\u00fcrkiye","volume":"67","author":"Serbes","year":"2025","journal-title":"Turk. J. Pediatr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.jcf.2025.02.012","article-title":"Cystic Fibrosis Year in Review 2024","volume":"24","author":"Alameeri","year":"2025","journal-title":"J. Cyst. Fibros."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1016\/j.jcf.2024.04.013","article-title":"Heterogeneity in Response to Elexacaftor\/Tezacaftor\/Ivacaftor in People with Cystic Fibrosis","volume":"23","author":"Alicandro","year":"2024","journal-title":"J. Cyst. Fibros."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41467-023-36244-2","article-title":"Future Therapies for Cystic Fibrosis","volume":"14","author":"Allen","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Sleziak, J., Gawor, A., B\u0142a\u017cejewska, M., Antosz, K., and Gomu\u0142ka, K. (2024). ADAM33\u2019s Role in Asthma Pathogenesis: An Overview. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25042318"},{"key":"ref_35","first-page":"8437348","article-title":"ADAM33 Silencing Inhibits Vascular Smooth Muscle Cell Migration and Regulates Cytokine Secretion in Airway Vascular Remodeling via the PI3K\/AKT\/mTOR Pathway","volume":"2022","author":"Yan","year":"2022","journal-title":"Can. Respir. J."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Vishweswaraiah, S., Ramachandra, N.B., Joshi, N., Parthasarathi, A., Kaleem Ullah, M., Siddaiah, J.B., Holla, A.D., Chakraborty, S., Agrawal, A., and Mahesh, P.A. (2023). Association between ADAM33 Single-Nucleotide Polymorphisms and Treatment Response to Inhaled Corticosteroids and a Long-Acting Beta-Agonist in Asthma. Diagnostics, 13.","DOI":"10.3390\/diagnostics13030405"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kansal, H., Chopra, V., Garg, K., and Sharma, S. (2025). Impact of Genetic Variants in the MMP and ADAM Genes towards Chronic Obstructive Pulmonary Disease Susceptibility and Lung Function in the North Indian Population. Mol. Biol. Rep., 52.","DOI":"10.1007\/s11033-025-10695-w"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1164\/rccm.2210006","article-title":"Seeking Modifier Genes in Cystic Fibrosis","volume":"167","author":"Accurso","year":"2003","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1513\/pats.200605-129JG","article-title":"Strategies for Identifying Modifier Genes in Cystic Fibrosis","volume":"4","author":"Boyle","year":"2007","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1002\/humu.23220","article-title":"Exomic Variants of an Elderly Cohort of Brazilians in the ABraOM Database","volume":"38","author":"Naslavsky","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1093\/aje\/kwn359","article-title":"Hardy-Weinberg Equilibrium Testing of Biological Ascertainment for Mendelian Randomization Studies","volume":"169","author":"Rodriguez","year":"2009","journal-title":"Am. J. Epidemiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1177\/003335490912400320","article-title":"OpenEpi: A Web-Based Epidemiologic and Statistical Calculator for Public Health","volume":"124","author":"Sullivan","year":"2009","journal-title":"Public Health Rep."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Blayac, M., Coll, P., Urbach, V., Fanen, P., Epaud, R., and Lanone, S. (2022). The Impact of Air Pollution on the Course of Cystic Fibrosis: A Review. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.908230"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1164\/rccm.200306-779OC","article-title":"Effect of Ambient Air Pollution on Pulmonary Exacerbations and Lung Function in Cystic Fibrosis","volume":"169","author":"Goss","year":"2004","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e37","DOI":"10.1016\/S2213-2600(16)30188-6","article-title":"Classification of CFTR Mutation Classes","volume":"4","author":"Marson","year":"2016","journal-title":"Lancet Respir. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"24","DOI":"10.5339\/qmj.2021.24","article-title":"First Report of the Cystic Fibrosis Transmembrane Conductance Regulator Mutation c.1521_1523delCTT (p. Phe508del) in Two Qatari Patients with Cystic Fibrosis","volume":"2021","author":"AbdulWahab","year":"2021","journal-title":"Qatar Med. J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e444","DOI":"10.5001\/omj.2022.101","article-title":"Prevalence and Characteristics of Cystic Fibrosis in Omani Children: A Multi-Center Cross-Sectional Study","volume":"37","year":"2022","journal-title":"Oman Med. J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1590\/s1806-37562017000000065","article-title":"Brazilian Guidelines for the Diagnosis and Treatment of Cystic Fibrosis","volume":"43","author":"Athanazio","year":"2017","journal-title":"J. Bras. Pneumol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.jcf.2020.08.007","article-title":"Extensive CFTR Sequencing through NGS in Brazilian Individuals with Cystic Fibrosis: Unravelling Regional Discrepancies in the Country","volume":"20","author":"Athanazio","year":"2021","journal-title":"J. Cyst. Fibros."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Pereira, S.V.-N., Ribeiro, J.D., Ribeiro, A.F., Bertuzzo, C.S., and Marson, F.A.L. (2019). Novel, Rare and Common Pathogenic Variants in the CFTR Gene Screened by High-Throughput Sequencing Technology and Predicted by in Silico Tools. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-42404-6"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1097\/MPA.0000000000000963","article-title":"Pancreatic Insufficiency in Cystic Fibrosis: Influence of Inflammatory Response Genes","volume":"47","author":"Marson","year":"2018","journal-title":"Pancreas"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Castaldo, A., Cernera, G., Iacotucci, P., Cimbalo, C., Gelzo, M., Comegna, M., Di Lullo, A.M., Tosco, A., Carnovale, V., and Raia, V. (2020). TAS2R38 Is a Novel Modifier Gene in Patients with Cystic Fibrosis. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-62747-9"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Dang, H., Polineni, D., Pace, R.G., Stonebraker, J.R., Corvol, H., Cutting, G.R., Drumm, M.L., Strug, L.J., O\u2019Neal, W.K., and Knowles, M.R. (2020). Mining GWAS and eQTL Data for CF Lung Disease Modifiers by Gene Expression Imputation. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0239189"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1002\/ppul.25237","article-title":"Differentially Expressed Genes Associated with Disease Severity in Siblings with Cystic Fibrosis","volume":"56","author":"Ekinci","year":"2021","journal-title":"Pediatr. Pulmonol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.jcf.2022.02.007","article-title":"Expression of Cystic Fibrosis Lung Disease Modifier Genes in Human Airway Models","volume":"21","author":"He","year":"2022","journal-title":"J. Cyst. Fibros."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2203","DOI":"10.1016\/j.ajhg.2024.08.004","article-title":"Genetic Modifiers of Body Mass Index in Individuals with Cystic Fibrosis","volume":"111","author":"Ling","year":"2024","journal-title":"Am. J. Hum. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"119765","DOI":"10.1016\/j.cca.2024.119765","article-title":"The Solute Carrier Family 26 Member 9 Modifies Rapidly Progressing Cystic Fibrosis Associated with Homozygous F508del CFTR Mutation","volume":"561","author":"Luo","year":"2024","journal-title":"Clin. Chim. Acta"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"M\u00e9sin\u00e8le, J., Ruffin, M., Guillot, L., and Corvol, H. (2022). Modifier Factors of Cystic Fibrosis Phenotypes: A Focus on Modifier Genes. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232214205"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"379","DOI":"10.12688\/f1000research.110472.3","article-title":"IL1B Gene Variants, but Not TNF, CXCL8, IL6 and IL10, Modify the Course of Cystic Fibrosis in Polish Patients","volume":"11","author":"Gabryel","year":"2022","journal-title":"F1000Research"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1016\/j.bbadis.2019.01.029","article-title":"Extent of Rescue of F508del-CFTR Function by VX-809 and VX-770 in Human Nasal Epithelial Cells Correlates with SNP Rs7512462 in SLC26A9 Gene in F508del\/F508del Cystic Fibrosis Patients","volume":"1865","author":"Kmit","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1002\/ppul.24005","article-title":"Interaction among Variants in the SLC Gene Family (SLC6A14, SLC26A9, SLC11A1, and SLC9A3) and CFTR Mutations with Clinical Markers of Cystic Fibrosis","volume":"53","author":"Pereira","year":"2018","journal-title":"Pediatr. Pulmonol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.gene.2017.07.068","article-title":"Association of Clinical Severity of Cystic Fibrosis with Variants in the SLC Gene Family (SLC6A14, SLC26A9, SLC11A1 and SLC9A3)","volume":"629","author":"Pereira","year":"2017","journal-title":"Gene"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Marson, F.A.L., Bertuzzo, C.S., Hortencio, T.D.R., Ribeiro, J.D., Bonadia, L.C., and Ribeiro, A.F. (2012). The ACE Gene D\/I Polymorphism as a Modulator of Severity of Cystic Fibrosis. BMC Pulm. Med., 12.","DOI":"10.1186\/1471-2466-12-41"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1590\/S1806-37132012000100008","article-title":"Cystic Fibrosis Transmembrane Conductance Regulator Gene Mutations and Glutathione S-Transferase Null Genotypes in Cystic Fibrosis Patients in Brazil","volume":"38","author":"Lima","year":"2012","journal-title":"J. Bras. Pneumol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Marson, F.A.d.L., Bertuzzo, C.S., Ribeiro, A.F., and Ribeiro, J.D. (2014). Polymorphisms in the Glutathione Pathway Modulate Cystic Fibrosis Severity: A Cross-Sectional Study. BMC Med. Genet., 15.","DOI":"10.1186\/1471-2350-15-27"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Marson, F.A.L., Bertuzzo, C.S., Ribeiro, A.F., and Ribeiro, J.D. (2012). Polymorphisms in ADRB2 Gene Can Modulate the Response to Bronchodilators and the Severity of Cystic Fibrosis. BMC Pulm. Med., 12.","DOI":"10.1186\/1471-2466-12-50"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.pulmoe.2019.09.003","article-title":"A Negative Screening of Rare Genetic Variants in the ADIPOQ and STATH Genes in Cystic Fibrosis","volume":"26","author":"Coutinho","year":"2020","journal-title":"Pulmonology"},{"key":"ref_68","first-page":"87","article-title":"TNF-Alpha Polymorphisms as a Potential Modifier Gene in the Cystic Fibrosis","volume":"5","author":"Coutinho","year":"2014","journal-title":"Int. J. Mol. Epidemiol. Genet."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Furgeri, D.T., Marson, F.A.d.L., Ribeiro, A.F., and Bertuzzo, C.S. (2012). Association between the IVS4G>T Mutation in the TCF7L2 Gene and Susceptibility to Diabetes in Cystic Fibrosis Patients. BMC Res. Notes, 5.","DOI":"10.1186\/1756-0500-5-561"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1007\/s00439-016-1684-4","article-title":"IL8 Gene as Modifier of Cystic Fibrosis: Unraveling the Factors Which Influence Clinical Variability","volume":"135","author":"Furlan","year":"2016","journal-title":"Hum. Genet."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.jped.2017.03.005","article-title":"Variants in the Interleukin 8 Gene and the Response to Inhaled Bronchodilators in Cystic Fibrosis","volume":"93","author":"Furlan","year":"2017","journal-title":"J. Pediatr. (Rio J.)"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1164\/rccm.202209-1653OC","article-title":"Genetic Modifiers of Cystic Fibrosis Lung Disease Severity: Whole-Genome Analysis of 7840 Patients","volume":"207","author":"Zhou","year":"2023","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1111\/crj.12046","article-title":"Polymorphisms of the ADAM33 Gene and Chronic Obstructive Pulmonary Disease Risk: A Meta-Analysis","volume":"8","author":"Aierken","year":"2014","journal-title":"Clin. Respir. J."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Del Mastro, R.G., Turenne, L., Giese, H., Keith, T.P., Van Eerdewegh, P., May, K.J.W., and Little, R.D. (2007). Mechanistic Role of a Disease-Associated Genetic Variant within the ADAM33 Asthma Susceptibility Gene. BMC Med. Genet., 8.","DOI":"10.1186\/1471-2350-8-46"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0006-291X(02)02976-5","article-title":"Human ADAM33: Protein Maturation and Localization","volume":"301","author":"Garlisi","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"4247","DOI":"10.1021\/bi0476230","article-title":"ADAM33 Enzyme Properties and Substrate Specificity","volume":"44","author":"Zou","year":"2005","journal-title":"Biochemistry"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/nature00878","article-title":"Association of the ADAM33 Gene with Asthma and Bronchial Hyperresponsiveness","volume":"418","author":"Little","year":"2002","journal-title":"Nature"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1007\/s10038-006-0081-6","article-title":"ADAM33 Polymorphisms Are Associated with Aspirin-Intolerant Asthma in the Japanese Population","volume":"52","author":"Sakagami","year":"2007","journal-title":"J. Hum. Genet."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.3892\/mmr.2013.1733","article-title":"ADAM33 Polymorphisms Are Associated with Asthma and a Distinctive Palm Dermatoglyphic Pattern","volume":"8","author":"Xue","year":"2013","journal-title":"Mol. Med. Rep."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"6459","DOI":"10.1158\/0008-5472.CAN-04-3728","article-title":"Polymorphisms Associated with Asthma Are Inversely Related to Glioblastoma Multiforme","volume":"65","author":"Schwartzbaum","year":"2005","journal-title":"Cancer Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1111\/j.1365-2222.2004.02008.x","article-title":"Polymorphisms in ADAM33 Are Associated with Allergic Rhinitis Due to Japanese Cedar Pollen","volume":"34","author":"Cheng","year":"2004","journal-title":"Clin. Exp. Allergy"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"79","DOI":"10.2500\/ajra.2010.24.3480","article-title":"Expression of a Disintegrin and Metalloproteinase 33 Protein in Nasal Polyposis: An Immunohistochemical Study","volume":"24","author":"Erbek","year":"2010","journal-title":"Am. J. Rhinol. Allergy"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Fachri, M., Hatta, M., Massi, M.N., Santoso, A., Wikanningtyas, T.A., Dwiyanti, R., Junita, A.R., Primaguna, M.R., and Sabir, M. (2021). The Strong Correlation between ADAM33 Expression and Airway Inflammation in Chronic Obstructive Pulmonary Disease and Candidate for Biomarker and Treatment of COPD. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-02615-2"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Siroux, V., Bouzigon, E., Dizier, M.-H., Pin, I., Demenais, F., Kauffmann, F., and EGEA Cooperative Group (2008). Replication of Association between ADAM33 Polymorphisms and Psoriasis. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0002448"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1089\/dna.2009.1002","article-title":"Association of ADAM33 Polymorphisms and Susceptibility to Psoriasis","volume":"29","author":"Deng","year":"2010","journal-title":"DNA Cell Biol."},{"key":"ref_86","first-page":"454","article-title":"ADAM 33 Gene V4 C\/G Rs2787094 Polymorphism in Psoriasis","volume":"119","author":"Akcilar","year":"2018","journal-title":"Bratisl. Lek Listy"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.clinbiochem.2008.12.014","article-title":"ADAM33 Genetic Polymorphisms and Risk of Atopic Dermatitis among Japanese Children","volume":"42","author":"Matsusue","year":"2009","journal-title":"Clin. Biochem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1159\/000335417","article-title":"ADAM33 as a Psoriasis Susceptibility Gene in the Han Population of Northeastern China","volume":"223","author":"Zhou","year":"2011","journal-title":"Dermatology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3548","DOI":"10.4049\/jimmunol.0801695","article-title":"Expression of ADAM33 Is a Novel Regulatory Mechanism in IL-18-Secreted Process in Gastric Cancer","volume":"182","author":"Kim","year":"2009","journal-title":"J. Immunol."},{"key":"ref_90","first-page":"2766","article-title":"Breast Cancer Is Associated with Methylation and Expression of the a Disintegrin and Metalloproteinase Domain 33 (ADAM33) Gene Affected by Endocrine-disrupting Chemicals","volume":"40","author":"Yang","year":"2018","journal-title":"Oncol Rep."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1007\/s13577-023-00898-3","article-title":"Role of ADAM33 Short Isoform as a Tumor Suppressor in the Pathogenesis of Thyroid Cancer via Oncogenic Function Disruption of Full-Length ADAM33","volume":"36","author":"Lan","year":"2023","journal-title":"Hum. Cell"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Seniski, G.G., Camargo, A.A., Ierardi, D.F., Ramos, E.A.S., Grochoski, M., Ribeiro, E.S.F., Cavalli, I.J., Pedrosa, F.O., de Souza, E.M., and Zanata, S.M. (2009). ADAM33 Gene Silencing by Promoter Hypermethylation as a Molecular Marker in Breast Invasive Lobular Carcinoma. BMC Cancer, 9.","DOI":"10.1186\/1471-2407-9-80"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Manica, G.C.M., Ribeiro, C.F., Oliveira, M.A.S.d., Pereira, I.T., Chequin, A., Ramos, E.A.S., Klassen, L.M.B., Sebasti\u00e3o, A.P.M., Alvarenga, L.M., and Zanata, S.M. (2017). Down Regulation of ADAM33 as a Predictive Biomarker of Aggressive Breast Cancer. Sci. Rep., 7.","DOI":"10.1038\/srep44414"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.atherosclerosis.2010.02.023","article-title":"ADAM33 Expression in Atherosclerotic Lesions and Relationship of ADAM33 Gene Variation with Atherosclerosis","volume":"211","author":"Holloway","year":"2010","journal-title":"Atherosclerosis"},{"key":"ref_95","first-page":"716","article-title":"Association of ADAM33 Gene Polymorphisms with Allergic Asthma","volume":"17","author":"Karimi","year":"2014","journal-title":"Iran. J. Basic Med. Sci."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Lesueur, F., Oudot, T., Heath, S., Foglio, M., Lathrop, M., Prud\u2019homme, J.-F., and Fischer, J. (2007). ADAM33, a New Candidate for Psoriasis Susceptibility. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0000906"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1093\/hmg\/ddac221","article-title":"Analysis of CF Patient Survival Confirms STAT3 as a CF-Modifying Gene with Changing Impact over Time","volume":"32","author":"Dunsche","year":"2023","journal-title":"Hum. Mol. Genet."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Uden, A., Dunsche, I., Janciauskiene, S., Gr\u00e4ber, S., Feng, L., Tamm, S., Hedtfeld, S., Stege, G., Jahn, K., and Kontsendorn, J. (2025). Genotype and Transcript Processing of the Tumour Necrosis Factor Receptor TNFRSF1A in Epithelial Cells: Implications for Survival in Cystic Fibrosis. eBioMedicine, 118.","DOI":"10.1016\/j.ebiom.2025.105848"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1002\/ppul.21026","article-title":"IL1B Polymorphisms Modulate Cystic Fibrosis Lung Disease","volume":"44","author":"Levy","year":"2009","journal-title":"Pediatr. Pulmonol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"100834","DOI":"10.1016\/j.waojou.2023.100834","article-title":"Polymorphism in ADAM33 Gene Associated with Asthmatics in West Bengal, India\u2014An Investigation by in-Silico Analysis","volume":"16","author":"Sultana","year":"2023","journal-title":"World Allergy Organ. J."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1007\/s00281-003-0153-z","article-title":"The Role of ADAM33 in the Pathogenesis of Asthma","volume":"25","author":"Cakebread","year":"2004","journal-title":"Springer Semin. Immunopathol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1097\/00063198-199711000-00002","article-title":"Early Pulmonary Disease in Cystic Fibrosis","volume":"3","author":"Accurso","year":"1997","journal-title":"Curr. Opin. Pulm. Med."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Khan, M.A., Ali, Z.S., Sweezey, N., Grasemann, H., and Palaniyar, N. (2019). Progression of Cystic Fibrosis Lung Disease from Childhood to Adulthood: Neutrophils, Neutrophil Extracellular Trap (NET) Formation, and NET Degradation. Genes, 10.","DOI":"10.3390\/genes10030183"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2101499","DOI":"10.1183\/13993003.01499-2021","article-title":"ERS\/ATS Technical Standard on Interpretive Strategies for Routine Lung Function Tests","volume":"60","author":"Stanojevic","year":"2022","journal-title":"Eur. Respir. J."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1183\/09031936.00080312","article-title":"ERS Global Lung Function Initiative. Multi-ethnic reference values for spirometry for the 3-95-yr age range: The global lung function 2012 equations","volume":"40","author":"Quanjer","year":"2012","journal-title":"Eur. Respir. J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11583\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T05:11:49Z","timestamp":1764652309000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11583"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,29]]},"references-count":105,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ijms262311583"],"URL":"https:\/\/doi.org\/10.3390\/ijms262311583","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,11,29]]}}}