{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:19:41Z","timestamp":1790803181326,"version":"4.1.0"},"reference-count":98,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,17]],"date-time":"2022-11-17T00:00:00Z","timestamp":1668643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["PMJ201810007620"],"award-info":[{"award-number":["PMJ201810007620"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Although cystic fibrosis (CF) is recognized as a monogenic disease, due to variants within the CFTR (Cystic Fibrosis Transmembrane Regulator) gene, an extreme clinical heterogeneity is described among people with CF (pwCF). Apart from the exocrine pancreatic status, most studies agree that there is little association between CFTR variants and disease phenotypes. Environmental factors have been shown to contribute to this heterogeneity, accounting for almost 50% of the variability of the lung function of pwCF. Nevertheless, pwCF with similar CFTR variants and sharing the same environment (such as in siblings) may have highly variable clinical manifestations not explained by CFTR variants, and only partly explained by environmental factors. It is recognized that genetic variants located outside the CFTR locus, named \u201cmodifier genes\u201d, influence the clinical expression of the disease. This short review discusses the latest studies that have described modifier factors associated with the various CF phenotypes as well as the response to the recent CFTR modulator therapies.<\/jats:p>","DOI":"10.3390\/ijms232214205","type":"journal-article","created":{"date-parts":[[2022,11,17]],"date-time":"2022-11-17T03:12:20Z","timestamp":1668654740000},"page":"14205","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Modifier Factors of Cystic Fibrosis Phenotypes: A Focus on Modifier Genes"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4129-4362","authenticated-orcid":false,"given":"Julie","family":"M\u00e9sin\u00e8le","sequence":"first","affiliation":[{"name":"Sorbonne Universit\u00e9, Inserm U938, Centre de Recherche Saint-Antoine (CRSA), 75012 Paris, France"},{"name":"Inovarion, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon","family":"Ruffin","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Inserm U938, Centre de Recherche Saint-Antoine (CRSA), 75012 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6853-7945","authenticated-orcid":false,"given":"Lo\u00efc","family":"Guillot","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Inserm U938, Centre de Recherche Saint-Antoine (CRSA), 75012 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7026-7523","authenticated-orcid":false,"given":"Harriet","family":"Corvol","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Inserm U938, Centre de Recherche Saint-Antoine (CRSA), 75012 Paris, France"},{"name":"Sorbonne Universit\u00e9, Assistance Publique-H\u00f4pitaux de Paris (AP-HP), H\u00f4pital Trousseau, Service de Pneumologie P\u00e9diatrique, 75012 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1126\/science.2475911","article-title":"Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA","volume":"245","author":"Riordan","year":"1989","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1016\/j.arcped.2015.04.015","article-title":"Challenges of personalized medicine for cystic fibrosis","volume":"22","author":"Corvol","year":"2015","journal-title":"Arch. Pediatr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1016\/S0140-6736(16)00576-6","article-title":"Cystic fibrosis","volume":"388","author":"Elborn","year":"2016","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.trsl.2015.04.008","article-title":"Translating the genetics of cystic fibrosis to personalized medicine","volume":"168","author":"Corvol","year":"2015","journal-title":"Transl. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nrg3849","article-title":"Cystic fibrosis genetics: From molecular understanding to clinical application","volume":"16","author":"Cutting","year":"2014","journal-title":"Nat. Rev. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1016\/j.jcf.2019.11.001","article-title":"Genetic variation in CFTR and modifier loci may modulate cystic fibrosis disease severity","volume":"19","author":"Paranjapye","year":"2020","journal-title":"J. Cyst. Fibros."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1046\/j.1469-1809.2003.00028.x","article-title":"The phenotypic consequences of CFTR mutations","volume":"67","author":"Rowntree","year":"2003","journal-title":"Ann. Hum. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1016\/0140-6736(90)92566-Z","article-title":"Independent genetic determinants of pancreatic and pulmonary status in cystic fibrosis","volume":"336","author":"Santis","year":"1990","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1375\/136905200320565256","article-title":"Categories of deltaF508 homozygous cystic fibrosis twin and sibling pairs with distinct phenotypic characteristics","volume":"3","author":"Mekus","year":"2000","journal-title":"Twin Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/j.jpeds.2010.05.018","article-title":"Quantification of the relative contribution of environmental and genetic factors to variation in cystic fibrosis lung function","volume":"157","author":"Collaco","year":"2010","journal-title":"J. Pediatr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1164\/rccm.200608-1164OC","article-title":"Heritability of lung disease severity in cystic fibrosis","volume":"175","author":"Vanscoy","year":"2007","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/j.1749-6632.2010.05879.x","article-title":"Modifier genes in Mendelian disorders: The example of cystic fibrosis","volume":"1214","author":"Cutting","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_13","first-page":"S3","article-title":"Genetics and modifier genes, atypical and rare forms","volume":"19","author":"Ferec","year":"2012","journal-title":"Arch. Pediatr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/S0022-3476(97)70025-8","article-title":"Longitudinal analysis of pulmonary function decline in patients with cystic fibrosis","volume":"131","author":"Corey","year":"1997","journal-title":"J. Pediatr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.jpeds.2007.03.006","article-title":"Risk factors for rate of decline in forced expiratory volume in one second in children and adolescents with cystic fibrosis","volume":"151","author":"Konstan","year":"2007","journal-title":"J. Pediatr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1002\/ppul.10100","article-title":"Predictors of deterioration of lung function in cystic fibrosis","volume":"33","author":"Schaedel","year":"2002","journal-title":"Pediatr. Pulmonol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Toledano, M.B., Mukherjee, S.K., Howell, J., Westaby, D., Khan, S.A., Bilton, D., and Simmonds, N.J. (2019). The emerging burden of liver disease in cystic fibrosis patients: A UK nationwide study. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0212779"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1093\/cid\/ciy215","article-title":"Changing Rates of Chronic Pseudomonas aeruginosa Infections in Cystic Fibrosis: A Population-Based Cohort Study","volume":"67","author":"Crull","year":"2018","journal-title":"Clin. Infect. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.jcf.2021.09.017","article-title":"Risk factors for Pseudomonas aeruginosa airway infection and lung function decline in children with cystic fibrosis","volume":"21","author":"Ruffin","year":"2022","journal-title":"J. Cyst. Fibros"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1702509","DOI":"10.1183\/13993003.02509-2017","article-title":"Risk factors for lung disease progression in children with cystic fibrosis","volume":"51","author":"Winkens","year":"2018","journal-title":"Eur. Respir. J."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Pittman, J.E., Noah, H., Calloway, H.E., Davis, S.D., Leigh, M.W., Drumm, M., Sagel, S.D., Accurso, F.J., Knowles, M.R., and Sontag, M.K. (2017). Early childhood lung function is a stronger predictor of adolescent lung function in cystic fibrosis than early Pseudomonas aeruginosa infection. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0177215"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1136\/adc.71.4.353","article-title":"Passive smoking and impaired lung function in cystic fibrosis","volume":"71","author":"Smyth","year":"1994","journal-title":"Arch. Dis. Child"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1001\/jama.299.4.417","article-title":"Interactions between secondhand smoke and genes that affect cystic fibrosis lung disease","volume":"299","author":"Collaco","year":"2008","journal-title":"JAMA"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Collaco, J.M., McGready, J., Green, D.M., Naughton, K.M., Watson, C.P., Shields, T., Bell, S.C., Wainwright, C.E., Group, A.S., and Cutting, G.R. (2011). Effect of temperature on cystic fibrosis lung disease and infections: A replicated cohort study. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0027784"},{"key":"ref_25","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_26","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1513\/AnnalsATS.201408-400OC","article-title":"Fine particulate matter exposure and initial Pseudomonas aeruginosa acquisition in cystic fibrosis","volume":"12","author":"Psoter","year":"2015","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1378\/chest.12-1005","article-title":"Impact of air pollution on cystic fibrosis pulmonary exacerbations: A case-crossover analysis","volume":"143","author":"Goeminne","year":"2013","journal-title":"Chest"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Psoter, K.J., De Roos, A.J., Wakefield, J., Mayer, J.D., and Rosenfeld, M. (2017). Air pollution exposure is associated with MRSA acquisition in young U.S. children with cystic fibrosis. BMC Pulm. Med., 17.","DOI":"10.1186\/s12890-017-0449-8"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e129","DOI":"10.1016\/j.jcf.2021.08.015","article-title":"Indoor air pollution exposure is associated with greater morbidity in cystic fibrosis","volume":"21","author":"Carson","year":"2021","journal-title":"J. Cyst. Fibros."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Psoter, K.J., De Roos, A.J., Wakefield, J., Mayer, J.D., and Rosenfeld, M. (2017). Seasonality of acquisition of respiratory bacterial pathogens in young children with cystic fibrosis. BMC Infect. Dis., 17.","DOI":"10.1186\/s12879-017-2511-9"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1017\/S0950268815002411","article-title":"Association of meteorological and geographical factors and risk of initial Pseudomonas aeruginosa acquisition in young children with cystic fibrosis","volume":"144","author":"Psoter","year":"2015","journal-title":"Epidemiol. Infect."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1164\/ajrccm.155.6.9196096","article-title":"Absence of health insurance is associated with decreased life expectancy in patients with cystic fibrosis","volume":"155","author":"Curtis","year":"1997","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1164\/ajrccm.163.6.9912100","article-title":"The Association of Socioeconomic Status with Outcomes in Cystic Fibrosis Patients in the United States","volume":"163","author":"Schechter","year":"2001","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/35057062","article-title":"Initial sequencing and analysis of the human genome","volume":"409","author":"Lander","year":"2001","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"1000 Genomes Project Consortium (2015). A global reference for human genetic variation. Nature, 526, 68\u201374.","DOI":"10.1038\/nature15393"},{"key":"ref_36","unstructured":"Vaincre-la-Mucoviscidose (2022). Registre Fran\u00e7ais de la Mucoviscidose\u2014Bilan des Donn\u00e9es 2020, Vaincre La Mucovisidose. Available online: https:\/\/www.vaincrelamuco.org\/sites\/default\/files\/registre_francais_de_la_mucoviscidose_bilan_2020.pdf."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8382","DOI":"10.1038\/ncomms9382","article-title":"Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis","volume":"6","author":"Corvol","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1038\/ng.2221","article-title":"Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis","volume":"44","author":"Sun","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Gong, J., Wang, F., Xiao, B., Panjwani, N., Lin, F., Keenan, K., Avolio, J., Esmaeili, M., Zhang, L., and He, G. (2019). Genetic association and transcriptome integration identify contributing genes and tissues at cystic fibrosis modifier loci. PLoS Genet., 15.","DOI":"10.1371\/journal.pgen.1008007"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1016\/j.jpeds.2015.01.044","article-title":"Variants in Solute Carrier SLC26A9 Modify Prenatal Exocrine Pancreatic Damage in Cystic Fibrosis","volume":"166","author":"Miller","year":"2015","journal-title":"J. Pediatr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1210\/clinem\/dgz102","article-title":"Genetic Modifiers of Cystic Fibrosis-Related Diabetes Have Extensive Overlap with Type 2 Diabetes and Related Traits","volume":"105","author":"Aksit","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1038\/s41436-020-01073-x","article-title":"Cystic fibrosis\u2013related diabetes onset can be predicted using biomarkers measured at birth","volume":"23","author":"Lin","year":"2021","journal-title":"Genet. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1164\/rccm.201603-0459OC","article-title":"Sources of Variation in Sweat Chloride Measurements in Cystic Fibrosis","volume":"194","author":"Collaco","year":"2016","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1164\/rccm.201701-0134OC","article-title":"Airway Mucosal Host Defense Is Key to Genomic Regulation of Cystic Fibrosis Lung Disease Severity","volume":"197","author":"Polineni","year":"2018","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Butnariu, L.I., \u021aarc\u0103, E., Cojocaru, E., Rusu, C., Mois\u0103, M., Constantin, M.-M.L., 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_46","doi-asserted-by":"crossref","unstructured":"Sepahzad, A., Morris-Rosendahl, D., and Davies, J. (2021). Cystic Fibrosis Lung Disease Modifiers and Their Relevance in the New Era of Precision Medicine. Genes, 12.","DOI":"10.3390\/genes12040562"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/ng.838","article-title":"Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2","volume":"43","author":"Wright","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1038\/nature07811","article-title":"Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease","volume":"458","author":"Gu","year":"2009","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.jpeds.2012.01.042","article-title":"Heritability of respiratory infection with Pseudomonas aeruginosa in cystic fibrosis","volume":"161","author":"Green","year":"2012","journal-title":"J. Pediatr."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Emond, M.J., Louie, T., Emerson, J., Chong, J.X., Mathias, R.A., Knowles, M.R., Rieder, M.J., Tabor, H.K., Nickerson, D.A., and Barnes, K.C. (2015). Exome Sequencing of Phenotypic Extremes Identifies CAV2 and TMC6 as Interacting Modifiers of Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1005424"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1038\/ng.2344","article-title":"Exome sequencing of extreme phenotypes identifies DCTN4 as a modifier of chronic Pseudomonas aeruginosa infection in cystic fibrosis","volume":"44","author":"Emond","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s00439-013-1363-7","article-title":"Unraveling the complex genetic model for cystic fibrosis: Pleiotropic effects of modifier genes on early cystic fibrosis-related morbidities","volume":"133","author":"Li","year":"2014","journal-title":"Hum. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5806","DOI":"10.1038\/s41598-020-62747-9","article-title":"TAS2R38 is a novel modifier gene in patients with cystic fibrosis","volume":"10","author":"Castaldo","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.jcf.2007.11.004","article-title":"Association of interleukin-10 gene haplotypes with Pseudomonas aeruginosa airway colonization in cystic fibrosis","volume":"7","author":"Tesse","year":"2008","journal-title":"J. Cyst. Fibros."},{"key":"ref_55","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_56","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.jcf.2005.04.001","article-title":"MBL2 polymorphisms screening in a regional Italian CF Center","volume":"4","author":"Trevisiol","year":"2005","journal-title":"J. Cyst. Fibros."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1038\/ejhg.2009.226","article-title":"Use of a modeling framework to evaluate the effect of a modifier gene (MBL2) on variation in cystic fibrosis","volume":"18","author":"McDougal","year":"2010","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1007\/s00125-009-1436-2","article-title":"A susceptibility gene for type 2 diabetes confers substantial risk for diabetes complicating cystic fibrosis","volume":"52","author":"Blackman","year":"2009","journal-title":"Diabetologia"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3627","DOI":"10.2337\/db13-0510","article-title":"Genetic modifiers of cystic fibrosis-related diabetes","volume":"62","author":"Blackman","year":"2013","journal-title":"Diabetes"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1172\/JCI129833","article-title":"Increased expression of anion transporter SLC26A9 delays diabetes onset in cystic fibrosis","volume":"130","author":"Lam","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1016\/j.cgh.2016.03.041","article-title":"Features of severe liver disease with portal hypertension in patients with cystic fibrosis","volume":"14","author":"Stonebraker","year":"2016","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"S29","DOI":"10.1016\/S1569-1993(11)60006-4","article-title":"Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease","volume":"10","author":"Debray","year":"2011","journal-title":"J. Cyst. Fibros."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1002\/hep.30148","article-title":"Cystic Fibrosis Liver Disease: Outcomes and Risk Factors in a Large Cohort of French Patients","volume":"69","author":"Boelle","year":"2019","journal-title":"Hepatology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1165\/rcmb.2002-0271OC","article-title":"Alpha 1-antitrypsin deficiency alleles in cystic fibrosis lung disease","volume":"29","author":"Frangolias","year":"2003","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1164\/rccm.200204-364OC","article-title":"End-organ dysfunction in cystic fibrosis: Association with angiotensin I converting enzyme and cytokine gene polymorphisms","volume":"167","author":"Arkwright","year":"2003","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_66","first-page":"913","article-title":"Liver disease in pediatric patients with cystic fibrosis is associated with glutathione S-transferase P1 polymorphism","volume":"36","author":"Flamant","year":"2002","journal-title":"Hepatology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1136\/jmg.38.5.310","article-title":"The mannose binding lectin gene influences the severity of chronic liver disease in cystic fibrosis","volume":"38","author":"Gabolde","year":"2001","journal-title":"J. Med. Genet."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/j.dld.2009.03.012","article-title":"An MBL2 haplotype and ABCB4 variants modulate the risk of liver disease in cystic fibrosis patients: A multicentre study","volume":"41","author":"Tomaiuolo","year":"2009","journal-title":"Dig. Liver Dis."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1001\/jama.2009.1295","article-title":"Genetic modifiers of liver disease in cystic fibrosis","volume":"302","author":"Bartlett","year":"2009","journal-title":"JAMA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1038\/s41436-019-0449-6","article-title":"SERPINA1 Z allele is associated with cystic fibrosis liver disease","volume":"21","author":"Boelle","year":"2019","journal-title":"Genet. Med."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Trouve, P., Genin, E., and Ferec, C. (2017). In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0173822"},{"key":"ref_72","unstructured":"HAS (2017). Protocole national de diagnostic et de soins (PNDS) Muocviscidose. Guide\u2014Affection de Longue Dur\u00e9e, HAS. Available online: https:\/\/www.has-sante.fr\/jcms\/c_2792719\/fr\/mucoviscidose."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/j.rmr.2015.11.010","article-title":"New therapies for cystic fibrosis targeting the CFTR gene or the CFTR protein","volume":"33","author":"Hubert","year":"2016","journal-title":"Rev. Mal. Respir."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"18825","DOI":"10.1073\/pnas.0904709106","article-title":"Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770","volume":"106","author":"Hadida","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1056\/NEJMoa1105185","article-title":"A CFTR potentiator in patients with cystic fibrosis and the G551D mutation","volume":"365","author":"Ramsey","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1016\/S2213-2600(14)70218-8","article-title":"Long-term safety and efficacy of ivacaftor in patients with cystic fibrosis who have the Gly551Asp-CFTR mutation: A phase 3, open-label extension study (PERSIST)","volume":"2","author":"McKone","year":"2014","journal-title":"Lancet Respir. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"828","DOI":"10.3389\/fphar.2018.00828","article-title":"SLC26A9 Gene Is Associated With Lung Function Response to Ivacaftor in Patients With Cystic Fibrosis","volume":"9","author":"Corvol","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_78","first-page":"4590","article-title":"Cystic fibrosis gene modifier SLC26A9 modulates airway response to CFTR-directed therapeutics","volume":"25","author":"Strug","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.jcf.2021.02.007","article-title":"SLC26A9 SNP rs7512462 is not associated with lung disease severity or lung function response to ivacaftor in cystic fibrosis patients with G551D-CFTR","volume":"20","author":"Eastman","year":"2021","journal-title":"J. Cyst. Fibros."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1056\/NEJMoa1409547","article-title":"Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR","volume":"373","author":"Wainwright","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1136\/thoraxjnl-2015-207369","article-title":"Lumacaftor\/ivacaftor for patients homozygous for Phe508del-CFTR: Should we curb our enthusiasm?","volume":"70","author":"Jones","year":"2015","journal-title":"Thorax"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1513\/AnnalsATS.201701-058OC","article-title":"An Observational Study of Outcomes and Tolerances in Patients with Cystic Fibrosis Initiated on Lumacaftor\/Ivacaftor","volume":"14","author":"Jennings","year":"2017","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S2213-2600(16)30427-1","article-title":"Assessment of safety and efficacy of long-term treatment with combination lumacaftor and ivacaftor therapy in patients with cystic fibrosis homozygous for the F508del-CFTR mutation (PROGRESS): A phase 3, extension study","volume":"5","author":"Konstan","year":"2017","journal-title":"Lancet Respir. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1164\/rccm.201906-1227OC","article-title":"Real-Life Safety and Effectiveness of Lumacaftor\u2013Ivacaftor in Patients with Cystic Fibrosis","volume":"201","author":"Burgel","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.jcf.2017.09.012","article-title":"Lumacaftor\/ivacaftor in patients with cystic fibrosis and advanced lung disease homozygous for F508del-CFTR","volume":"17","author":"Jain","year":"2018","journal-title":"J. Cyst. Fibros."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.jcf.2020.06.012","article-title":"Clinical response to lumacaftor-ivacaftor in patients with cystic fibrosis according to baseline lung function","volume":"20","author":"Burgel","year":"2020","journal-title":"J. Cyst. Fibros."},{"key":"ref_87","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_88","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/S2213-2600(16)30121-7","article-title":"Efficacy and safety of lumacaftor\/ivacaftor combination therapy in patients with cystic fibrosis homozygous for Phe508del CFTR by pulmonary function subgroup: A pooled analysis","volume":"4","author":"Elborn","year":"2016","journal-title":"Lancet Respir. Med."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"M\u00e9sin\u00e8le, J., Ruffin, M., Guillot, L., Bo\u00eblle, P.-Y., Corvol, H., and on behalf of the French CF Modifier Gene Study Investigators (2022). Factors Predisposing the Response to Lumacaftor\/Ivacaftor in People with Cystic Fibrosis. J. Pers. Med., 12.","DOI":"10.3390\/jpm12020252"},{"key":"ref_90","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_91","doi-asserted-by":"crossref","first-page":"3311","DOI":"10.1007\/s00018-020-03487-x","article-title":"Update on SLC6A14 in lung and gastrointestinal physiology and physiopathology: Focus on cystic fibrosis","volume":"77","author":"Ruffin","year":"2020","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.rmr.2020.02.008","article-title":"SLC6A14, un g\u00e8ne modificateur dans la mucoviscidose","volume":"37","author":"Ruffin","year":"2020","journal-title":"Rev. Mal. Respir."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1056\/NEJMoa1709847","article-title":"Tezacaftor\u2013Ivacaftor in Residual-Function Heterozygotes with Cystic Fibrosis","volume":"377","author":"Rowe","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1056\/NEJMoa1709846","article-title":"Tezacaftor\u2013Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del","volume":"377","author":"Munck","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1056\/NEJMoa1908639","article-title":"Elexacaftor\u2013Tezacaftor\u2013Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele","volume":"381","author":"Middleton","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1164\/rccm.202011-4153OC","article-title":"Rapid Improvement after Starting Elexacaftor\u2013Tezacaftor\u2013Ivacaftor in Patients with Cystic Fibrosis and Advanced Pulmonary Disease","volume":"204","author":"Burgel","year":"2021","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/j.jcf.2021.04.013","article-title":"Extracellular phosphate enhances the function of F508del-CFTR rescued by CFTR correctors","volume":"20","author":"Wang","year":"2021","journal-title":"J. Cyst. Fibros."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Pinto, M.C., Quaresma, M.C., Silva, I.A.L., Railean, V., Ramalho, S.S., and Amaral, M.D. (2021). Synergy in Cystic Fibrosis Therapies: Targeting SLC26A9. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222313064"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/14205\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:19:56Z","timestamp":1760145596000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/14205"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,17]]},"references-count":98,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232214205"],"URL":"https:\/\/doi.org\/10.3390\/ijms232214205","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,17]]}}}