Genetic Modifiers of Liver Disease in Cystic Fibrosis | Adolescent Medicine | JAMA | JAMA Network
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Original Contribution
September 9, 2009

Genetic Modifiers of Liver Disease in Cystic Fibrosis

Author Affiliations

Author Affiliations: Cystic Fibrosis/Pulmonary Research and Treatment Center (Drs Bartlett and Knowles, Ms Pace, and Mr Hannah) and Department of Genetics (Mr Wang and Dr Lange), School of Medicine, and Department of Biostatistics, School of Public Health (Mr Wang and Drs Zou, Wright, and Lange), University of North Carolina at Chapel Hill; Center for Molecular Biology and Pathology, Laboratory Corporation of America, Research Triangle Park, North Carolina (Dr Friedman); Division of Gastroenterology, Hepatology and Nutrition (Drs Ling and Durie), Pediatric Laboratory Medicine (Dr Phillips), Child Health Evaluative Sciences (Dr Corey), Genetics and Genome Biology (Drs Zielenski and Dorfman), and Physiology and Experimental Medicine (Dr Durie), The Hospital for Sick Children, and the University of Toronto (Drs Ling, Corey, and Durie); Toronto, Ontario, Canada; Adult Cystic Fibrosis Centre, Prince Charles Hospital, Chermside, Queensland, Australia (Dr Bell); Children's Research Centre, Our Lady's Children's Hospital, Crumlin (Drs Bourke and Rowland) and University College Dublin School of Medicine and Medical Science (Dr Rowland), Dublin, Ireland; CEINGE-Advanced Biotechnologies and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy (Drs Castaldo and Salvatore); Cystic Fibrosis Centre, Azienda Ospedaliera di Verona, Verona, Italy (Drs Castellani and Cipolli); CF Center, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, University of Milan, Milan, Italy (Dr C. Colombo); Department of Pediatrics, Pulmonary Section, University of Nebraska Medical Center, Omaha (Dr J. Colombo); Service d'Hépatologie Pédiatrique, Centre Hospitalier Universitaire de Bicêtre, Le Kremlin-Bicêtre Cedex, France (Dr Debray); Cystic Fibrosis Center, La Plata Children's Hospital, La Plata, Buenos Aires, Argentina (Dr Fernandez); the Pediatric Hepato-Gastroenterology-Nutrition Unit, Necker-Enfants Malades Hospital, Paris, France (Dr Lacaille); Departments of Biology and Medical Genetics (Dr Macek) and Pediatrics (Dr Zemková), Charles University and University Hospital Motol, Prague, Czech Republic; Department of Paediatric Gastroenterology, Academic Unit of Child Health, University of Sheffield, Sheffield, United Kingdom (Dr Taylor); Queensland Children's Respiratory Centre, Royal Children's Hospital, Brisbane, Queensland, Australia (Dr Wainwright); Department of Pediatric Gastroenterology, Hadassah Medical Organization, Jerusalem, Israel (Dr Wilschanski); Department of Pathology, University of Virginia, Charlottesville, Virginia (Dr Silverman); and Departments of Pediatrics and Genetics, Case Western Reserve University, Cleveland, Ohio (Dr Drumm).

JAMA. 2009;302(10):1076-1083. doi:10.1001/jama.2009.1295

Context A subset (≈ 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 (α1-antitrypsin or α1-antiprotease [SERPINA1], angiotensin-converting enzyme [ACE], glutathione S-transferase [GSTP1], mannose-binding lectin 2 [MBL2], and transforming growth factor β1 [TGFB1]) are associated with severe liver disease in patients with CF.

Design, Setting, and Participants 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.

Main Outcome Measures 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 × 10−6) and with TGFB1 codon 10 CC genotype (OR, 1.53; 95% CI, 1.16-2.03; P = 2.8 × 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 × 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 × 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, ≈ 5) of developing severe liver disease with portal hypertension.