title: Genetic modifiers of liver disease in cystic fibrosis.
abstract: BACKGROUND
  A subset (approximately 3%-5%) of patients with cystic fibrosis (CF) develops severe liver disease with portal hypertension.
  
  
  OBJECTIVE
  To assess whether any of 9 polymorphisms in 5 candidate genes (alpha(1)-antitrypsin or alpha(1)-antiprotease [SERPINA1], angiotensin-converting enzyme [ACE], glutathione S-transferase [GSTP1], mannose-binding lectin 2 [MBL2], and transforming growth factor beta1 [TGFB1]) are associated with severe liver disease in patients with CF.
  
  
  METHODS
  Two-stage case-control study enrolling patients with CF and severe liver disease with portal hypertension (CFLD) from 63 CF centers in the United States as well as 32 in Canada and 18 outside of North America, with the University of North Carolina at Chapel Hill as the coordinating site. In the initial study, 124 patients with CFLD (enrolled January 1999-December 2004) and 843 control patients without CFLD were studied by genotyping 9 polymorphisms in 5 genes previously studied as modifiers of liver disease in CF. In the second stage, the SERPINA1 Z allele and TGFB1 codon 10 genotype were tested in an additional 136 patients with CFLD (enrolled January 2005-February 2007) and 1088 with no CFLD.
  
  
  METHODS
  Differences in distribution of genotypes in patients with CFLD vs patients without CFLD.
  
  
  RESULTS
  The initial study showed CFLD to be associated with the SERPINA1 Z allele (odds ratio [OR], 4.72; 95% confidence interval [CI], 2.31-9.61; P = 3.3 x 10(-6)) and with TGFB1 codon 10 CC genotype (OR, 1.53; 95% CI, 1.16-2.03; P = 2.8 x 10(-3)). In the replication study, CFLD was associated with the SERPINA1 Z allele (OR, 3.42; 95% CI, 1.54-7.59; P = 1.4 x 10(-3)) but not with TGFB1 codon 10. A combined analysis of the initial and replication studies by logistic regression showed CFLD to be associated with SERPINA1 Z allele (OR, 5.04; 95% CI, 2.88-8.83; P = 1.5 x 10(-8)).
  
  
  CONCLUSIONS
  The SERPINA1 Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater risk (OR, approximately 5) of developing severe liver disease with portal hypertension.
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Jaclyn R
authors.initials: JR
authors.lastname: Bartlett
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Friedman
authors.forename: Simon C
authors.initials: SC
authors.lastname: Ling
authors.forename: Rhonda G
authors.initials: RG
authors.lastname: Pace
authors.forename: Scott C
authors.initials: SC
authors.lastname: Bell
authors.forename: Billy
authors.initials: B
authors.lastname: Bourke
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Castaldo
authors.forename: Carlo
authors.initials: C
authors.lastname: Castellani
authors.forename: Marco
authors.initials: M
authors.lastname: Cipolli
authors.forename: Carla
authors.initials: C
authors.lastname: Colombo
authors.forename: John L
authors.initials: JL
authors.lastname: Colombo
authors.forename: Dominique
authors.initials: D
authors.lastname: Debray
authors.forename: Adriana
authors.initials: A
authors.lastname: Fernandez
authors.forename: Florence
authors.initials: F
authors.lastname: Lacaille
authors.forename: Milan
authors.initials: M
authors.lastname: Macek
authors.forename: Marion
authors.initials: M
authors.lastname: Rowland
authors.forename: Francesco
authors.initials: F
authors.lastname: Salvatore
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Taylor
authors.forename: Claire
authors.initials: C
authors.lastname: Wainwright
authors.forename: Michael
authors.initials: M
authors.lastname: Wilschanski
authors.forename: Dana
authors.initials: D
authors.lastname: Zemková
authors.forename: William B
authors.initials: WB
authors.lastname: Hannah
authors.forename: M James
authors.initials: MJ
authors.lastname: Phillips
authors.forename: Mary
authors.initials: M
authors.lastname: Corey
authors.forename: Julian
authors.initials: J
authors.lastname: Zielenski
authors.forename: Ruslan
authors.initials: R
authors.lastname: Dorfman
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Wang
authors.forename: Fei
authors.initials: F
authors.lastname: Zou
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Silverman
authors.forename: Mitchell L
authors.initials: ML
authors.lastname: Drumm
authors.forename: Fred A
authors.initials: FA
authors.lastname: Wright
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Lange
authors.forename: Peter R
authors.initials: PR
authors.lastname: Durie
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000150:complications* / Q000235:genetics*; D005260:Female; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006801:Humans; D006975:Hypertension, Portal / Q000209:etiology / Q000235:genetics; D007223:Infant; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics; D008107:Liver Diseases / Q000209:etiology* / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D037601:Mannose-Binding Lectin / Q000235:genetics; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D011110:Polymorphism, Genetic; D012306:Risk; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D055815:Young Adult; D000515:alpha 1-Antitrypsin / Q000235:genetics*
chemical_list: C445619:MBL2 protein, human; D037601:Mannose-Binding Lectin; C043392:SERPINA1 protein, human; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D000515:alpha 1-Antitrypsin; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D007703:Peptidyl-Dipeptidase A