Genetic modifiers of liver disease in cystic fibrosis.
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.
Bartlett
Jaclyn R
JR
Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Friedman
Kenneth J
KJ
Ling
Simon C
SC
Pace
Rhonda G
RG
Bell
Scott C
SC
Bourke
Billy
B
Castaldo
Giuseppe
G
Castellani
Carlo
C
Cipolli
Marco
M
Colombo
Carla
C
Colombo
John L
JL
Debray
Dominique
D
Fernandez
Adriana
A
Lacaille
Florence
F
Macek
Milan
M
Rowland
Marion
M
Salvatore
Francesco
F
Taylor
Christopher J
CJ
Wainwright
Claire
C
Wilschanski
Michael
M
Zemková
Dana
D
Hannah
William B
WB
Phillips
M James
MJ
Corey
Mary
M
Zielenski
Julian
J
Dorfman
Ruslan
R
Wang
Yunfei
Y
Zou
Fei
F
Silverman
Lawrence M
LM
Drumm
Mitchell L
ML
Wright
Fred A
FA
Lange
Ethan M
EM
Durie
Peter R
PR
Knowles
Michael R
MR
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*
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