2012 the Influence of Genetics on Cystic Fibrosis Phenotypes

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  2012; doi: 10.1101/cshperspect.a009548 Cold Spring Harb Perspect Med Michael R. Knowles and Mitchell Drumm   The Influence of Genetics on Cystic Fibrosis Phenotypes Subject Collection  Cystic Fibrosis The Cystic Fibrosis of Exocrine Pancreas Michael Wilschanski and Ivana Novak  The Cystic Fibrosis Airway Microbiome Susan V. Lynch and Kenneth D. Bruce  and StabilityFunctionTransmembrane Conductance Regulator Dynamics Intrinsic to Cystic Fibrosis Dokholyan, et al.P. Andrew Chong, Pradeep Kota, Nikolay V. Regulator (ABCC7) StructureCystic Fibrosis Transmembrane Conductance John F. Hunt, Chi Wang and Robert C. Ford  PerspectiveThe Cystic Fibrosis Gene: A Molecular Genetic Lap-Chee Tsui and Ruslan Dorfman  Cystic FibrosisStatus of Fluid and Electrolyte Absorption in M.M. Reddy and M. Jackson Stutts  Anion PermeationThe CFTR Ion Channel: Gating, Regulation, and Tzyh-Chang Hwang and Kevin L. Kirk  PhenotypesThe Influence of Genetics on Cystic Fibrosis Michael R. Knowles and Mitchell Drumm  CFTRAssessing the Disease-Liability of Mutations in Claude Ferec and Garry R. Cutting  Lessons from the Biochemical World −− Perspectives on Mucus Properties and Formation Gustafsson, et al.Daniel Ambort, Malin E.V. Johansson, Jenny K. Supramolecular Dynamics of Mucus Pedro Verdugo  from the PancreasTransepithelial Bicarbonate Secretion: Lessons Hyun Woo Park and Min Goo Lee  FibrosisCFTR, Mucins, and Mucus Obstruction in Cystic Callaghan Rose Silvia M. Kreda, C. William Davis and Mary  SecretionPhysiology of Epithelial Chloride and Fluid Raymond A. Frizzell and John W. Hanrahan For additional articles in this collection, see Copyright © 2012 Cold Spring Harbor Laboratory Press; all rights reserved  on May 15, 2013 - Published by Cold Spring Harbor Laboratory Press Downloaded from   The Influence of Genetics onCystic Fibrosis Phenotypes Michael R. Knowles 1 and Mitchell Drumm 2 1 Cystic Fibrosis-Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill,Chapel Hill, North Carolina 27514 2 Department of Pediatrics and Genetics and Genome Sciences, Case Western Reserve University, Cleveland,Ohio 44106-4948 Correspondence: Technologicaladvancesingeneticshavemadefeasibleandaffordablelargestudiestoiden-tify genetic variants that cause or modify a trait. Genetic studies have been carried out toassess variants in candidate genes, as well as polymorphisms throughout the genome, fortheir associations with heritable clinical outcomes of cystic fibrosis (CF), such as lungdisease, meconium ileus, and CF-related diabetes. The candidate gene approach has iden-tified some predicted relationships, while genome-wide surveys have identified severalgenesthatwouldnothavebeenobviousdisease-modifyingcandidates,suchasamethioninesulfoxidetransferase genethatinfluencesintestinalobstruction,oraregiononchromosome11 proximate to genes encoding a transcription factor and an apoptosis controller thatassociates with lung function. These unforeseen associations thus provide novel insightinto disease pathophysiology, as well as suggesting new therapeutic strategies for CF. C  ystic fibrosis (CF) is a Mendelian “mono-genic” recessive genetic disorder caused by mutations in the cystic fibrosis transmembraneconductanceregulator( CFTR )gene(Welshetal.2001). There is a broad range of age-of-onsetand disease activity for different organ systemsin CF, including lung disease, meconium ileus,diabetes, and liver disease, even for CF patientswho are homozygous for the most commonmutation,  F508del   (Cutting 2010). Therefore,non- CFTR  genetic variation and / or environ-mental influences must contribute to the vari-ability of clinical phenotypes.To enhance understanding of the pathogen-esis of organ-system disease in CF and identify novel therapies, it is key to determine the mag-nitude of environmental and genetic effects of non- CFTR  gene modifiers on clinical pheno-types. If variability in disease largely reflectsenvironmental influences, there should be in-tensified focus on these factors, which mightinclude the intensity of medical care, treatmentof different types of lung infections, socioeco-nomic status, and effect of geographical tem-perature (Schechter 2004; Collaco et al. 2010,2011). If the variability in clinical phenotypeslargely reflects genetic variation in the genome,it is key to determine which genes are involved,and the mechanism of biological effects. Re-cent evidence indicates that there is a strong Editors: John R. Riordan, Richard C. Boucher, and Paul M. QuintonAdditional Perspectives on Cystic Fibrosis available at www.perspectivesinmedicine.orgCopyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101 / cshperspect.a009548Cite this article as  Cold Spring Harb Perspect Med   2012;2:a009548 1     w    w    w .    p    e    r    s    p    e    c     t     i    v    e    s     i    n    m    e      d     i    c     i    n    e .    o    r    g  on May 15, 2013 - Published by Cold Spring Harbor Laboratory Press Downloaded from   influenceofnon- CFTR geneticvariantsonclin-ical phenotype in CF, but most of the geneticvariation has not yet been defined (Mekus et al.2000; Vanscoy et al. 2007).Recent advances in genetic technology andthe formation of The International CF GeneModifier Consortium put CF at the cuttingedge of gene-modifier research in “monogenic”disorders. This combination of events providesacriticalopportunityforCF,becauseidentifica-tion of the most important gene modifiers willprovide insight into the mechanisms of diseasepathogenesis, and offer the potential for novelprognostic approaches and therapies. This arti-cle provides an overview and update on the sta-tus of gene modifier research in CF. HETEROGENEITY OF CF CLINICALPHENOTYPES RELATED TO  CFTR MUTATIONSOverview CFisthemostcommonautosomalrecessivedis-order among Caucasians, and the median ageof survival is only   39 years, despite improvedtreatments. The cystic fibrosis transmembraneregulator ( CFTR ) gene encodes a 1480-aminoacidproteinthatfunctionsasacAMP-mediatedCl 2 channel, which plays a key role in hydratingairway secretions and regulating other cellularfunctions,includingNa þ transportinairwayep-ithelia(Welshetal.2001;Cutting2010).BecauseclinicaldiseaseinCFresultsprimarilyfrommu-tations in  CFTR , CF is termed a “monogenic”disorder. There are . 1500 mutations in  CFTR (see Cystic Fibrosis Gene Analysis Consortium, / cftr / ) and the mostprevalentmutationresultsindeletionofphenyl-alanine at position 508 (F508del), which occurson 70% of CF chromosomes in the U.S. Heterogeneity of Disease Related toMutations in  CFTR There is strong correlation between the gener-al type of   CFTR  mutation and disease pheno-type. Specifically, those mutations without re-sidual function, such as F508del, are associatedwith pancreatic exocrine insufficiency, whereas  10% of   CFTR  mutations retain some residualfunctionandareassociatedwithpancreaticexo-crine sufficiency. Indeed, patients with at leastone copy of a mutant  CFTR  allele with residu-al function have better nutritional status andmilder lung disease, even though there is broadheterogeneity of disease severity (Mickle andCutting 1993, 2000; The Cystic Fibrosis Geno-type-Phenotype Consortium 1993). The devel-opment of meconium ileus, CF related diabetes(CFRD), and severe CF liver disease with portalhypertension (CFLD) is largely confined to pa-tients with  CFTR  mutations with no residualfunction (Blackman et al. 2006, 2009b; Sontaget al. 2006; Bartlett et al. 2009; Moran et al.2009). However, among patients carrying twomutations with no residual function, there isalso a very broad range of lung disease severity,and there are strikingly different prevalences of meconium ileus, diabetes, and liver disease. HERITABILITY OF CLINICAL PHENOTYPESOverview Before extensive genetic data was available, theprevailing concept was that the heterogeneity of clinical phenotypes reflected differing mag-nitudes of genetic versus environmental influ-ences (Fig. 1) (Castaldo et al. 2001; Drumm2001; Davies et al. 2005). For example, obstruc-tive azoospermia (congenital bilateral absenceof the vas deferens, CBAVD), occurs in nearly all CF males, regardless of whether the  CFTR mutation has some residual function, or not;therefore,CBAVDisdeterminedbygeneticsun-derlying mutations in  CFTR  (Cutting 2010).CF-related diabetes (CFRD) and severe CF liverdiseasewithportalhypertension(CFLD)islim-ited to patients withtwo CFTR  mutationswith-outresidualfunction(Bartlettetal.2009;Black-man et al. 2009b; Moran et al. 2009). CFLDoccurs before adulthood in the vast majority of CF patients who develop CFLD. The preva-lence of CFRD is age-dependent, and occurs in  25%–35% of CF adults. Lung disease occursin patients regardless of whether  CFTR  muta-tions have residual function, or not, but the M.R. Knowles and M. Drumm2  Cite this article as  Cold Spring Harb Perspect Med   2012;2:a009548     w    w    w .    p    e    r    s    p    e    c     t     i    v    e    s     i    n    m    e      d     i    c     i    n    e .    o    r    g  on May 15, 2013 - Published by Cold Spring Harbor Laboratory Press Downloaded from   rangeofdisease severity isverygreat; thus,thereare likely major contributions from both non- CFTR  genetic modifiers and environmental in-fluences(Mekusetal.2000;Vanscoyetal.2007).Formal studies of genetic heritability of different clinical phenotypes have largely con-firmed previous speculations (see above), andclearly show major roles for non- CFTR  genet-ic variation in the different clinical phenotypes(Table 1). Genes that cause many “monogenic”disorders have been described, but there is littleknowledgeoftheotherspecificfactorsthatcon-tribute to variability of the clinical phenotype.Investigations of inbred mice provide evidencethat overall genetic background has a majoreffect on clinical phenotype in monogenic Table 1.  Heritability estimates for CF-related phenotypesPhenotypeLungfunctionPersistentinfection DiabetesMeconiumileus BMIWeightforheight References Heritability,all subjects0.54–1.0 0.76–0.85   1   1   0.6   0.8 Blackman et al.2006, 2008,2009b; Vanscoy et al. 2007;Stanke et al.2011; Greenet al. 2012Heritability,F508delonly 0.56–0.86 No estimate No estimate No estimate No estimate   0.6 Vanscoy et al.2007; Stankeet al. 2011 CFTRModifier genesCFTREnvironmentMendelianinheritanceCFTRCFTRCFTRCFTRCFTRCFTRCFTRComplexgeneticsMale genitalSweat ductExocrinepancreasEndocrinepancreasIntestineHepato-biliaryAirwaysCancerAsthmaInflammatorybowel disease Figure1. Schematicdisplayof themagnitude oftheeffect of mutant CFTR versus environmental influences andmodifier genes. (Image courtesy of Peter Durie, Toronto.) The Influence of Genetics on CF Phenotypes Cite this article as  Cold Spring Harb Perspect Med   2012;2:a009548  3     w    w    w .    p    e    r    s    p    e    c     t     i    v    e    s     i    n    m    e      d     i    c     i    n    e .    o    r    g  on May 15, 2013 - Published by Cold Spring Harbor Laboratory Press Downloaded from 
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