Genetic Modifiers of Liver Disease in Cystic Fibrosis

Jaclyn R. Bartlett, Kenneth J. Friedman, Simon C. Ling, Rhonda G. Pace, Scott C. Bell, Billy Bourke, Giuseppe CAstaldo, Carlo Castellani, Marco Cipolli, Carla Colombo, John L. Colombo, Dominique Debray, Adriana Fernandez, Florence Lacaille, Milan Macek Jr., Marion Rowland, Francesco Salvatore, Christopher J. Taylor, Claire Wainwright, Michael Wilschanski, Dana Zemkova, William B. Hannah, M. James Phillips, Mary Corey, Julian Zielenski, Ruslan Dorfman, Yunfei Wang, Fei Zou, Lawrence M. Silverman, Mitchell L. Drumm, Fred A. Wright, Ethan M. Lange, Peter R. Durie and Michael R. Knowles (2009) Genetic Modifiers of Liver Disease in Cystic Fibrosis. JAMA, 302 10: 1076-1083. doi:10.1001/jama.2009.1295

Author Jaclyn R. Bartlett
Kenneth J. Friedman
Simon C. Ling
Rhonda G. Pace
Scott C. Bell
Billy Bourke
Giuseppe CAstaldo
Carlo Castellani
Marco Cipolli
Carla Colombo
John L. Colombo
Dominique Debray
Adriana Fernandez
Florence Lacaille
Milan Macek Jr.
Marion Rowland
Francesco Salvatore
Christopher J. Taylor
Claire Wainwright
Michael Wilschanski
Dana Zemkova
William B. Hannah
M. James Phillips
Mary Corey
Julian Zielenski
Ruslan Dorfman
Yunfei Wang
Fei Zou
Lawrence M. Silverman
Mitchell L. Drumm
Fred A. Wright
Ethan M. Lange
Peter R. Durie
Michael R. Knowles
Title Genetic Modifiers of Liver Disease in Cystic Fibrosis
Journal name JAMA   Check publisher's open access policy
ISSN 0098-7484
Publication date 2009-09-09
Year available 2009
Sub-type Article (original research)
DOI 10.1001/jama.2009.1295
Volume 302
Issue 10
Start page 1076
End page 1083
Total pages 8
Editor Dr Catherine D DeAngelis
Place of publication United States
Publisher American Medical Association
Collection year 2010
Language eng
Subject C1
920115 Respiratory System and Diseases (incl. Asthma)
110203 Respiratory Diseases
Formatted abstract
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.
Keyword Cystic fibrosis
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 100 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 113 times in Scopus Article | Citations
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Created: Tue, 23 Mar 2010, 12:06:20 EST by Lisa Hennell on behalf of Medicine - Princess Alexandra Hospital