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 Louis Colombo, Dominique Debray, Adriana Fernandez, Florence Lacaille, Milan Macek, Marion Rowland, Francesco Salvatore, Christopher J. Taylor, Claire Wainwright, Michael WilschanskiDana Zemková, 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

Research output: Contribution to journalArticle

169 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1076-1083
Number of pages8
JournalJAMA - Journal of the American Medical Association
Volume302
Issue number10
DOIs
StatePublished - Sep 9 2009

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Cystic Fibrosis
Liver Diseases
Alleles
Odds Ratio
Portal Hypertension
Codon
Confidence Intervals
Genotype
Mannose-Binding Lectin
Transforming Growth Factors
Peptidyl-Dipeptidase A
North America
Protease Inhibitors
Glutathione Transferase
Genes
Canada
Case-Control Studies
Logistic Models
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bartlett, J. R., Friedman, K. J., Ling, S. C., Pace, R. G., Bell, S. C., Bourke, B., ... Knowles, M. R. (2009). Genetic modifiers of liver disease in cystic fibrosis. JAMA - Journal of the American Medical Association, 302(10), 1076-1083. https://doi.org/10.1001/jama.2009.1295

Genetic modifiers of liver disease in cystic fibrosis. / Bartlett, Jaclyn R.; Friedman, Kenneth J.; Ling, Simon C.; Pace, Rhonda G.; Bell, Scott C.; Bourke, Billy; Castaldo, Giuseppe; Castellani, Carlo; Cipolli, Marco; Colombo, Carla; Colombo, John Louis; Debray, Dominique; Fernandez, Adriana; Lacaille, Florence; Macek, Milan; Rowland, Marion; Salvatore, Francesco; Taylor, Christopher J.; Wainwright, Claire; Wilschanski, Michael; Zemková, Dana; Hannah, William B.; Phillips, M. James; Corey, Mary; Zielenski, Julian; Dorfman, Ruslan; Wang, Yunfei; Zou, Fei; Silverman, Lawrence M.; Drumm, Mitchell L.; Wright, Fred A.; Lange, Ethan M.; Durie, Peter R.; Knowles, Michael R.

In: JAMA - Journal of the American Medical Association, Vol. 302, No. 10, 09.09.2009, p. 1076-1083.

Research output: Contribution to journalArticle

Bartlett, JR, Friedman, KJ, Ling, SC, Pace, RG, Bell, SC, Bourke, B, Castaldo, G, Castellani, C, Cipolli, M, Colombo, C, Colombo, JL, Debray, D, Fernandez, A, Lacaille, F, Macek, M, Rowland, M, Salvatore, F, Taylor, CJ, Wainwright, C, Wilschanski, M, Zemková, D, Hannah, WB, Phillips, MJ, Corey, M, Zielenski, J, Dorfman, R, Wang, Y, Zou, F, Silverman, LM, Drumm, ML, Wright, FA, Lange, EM, Durie, PR & Knowles, MR 2009, 'Genetic modifiers of liver disease in cystic fibrosis', JAMA - Journal of the American Medical Association, vol. 302, no. 10, pp. 1076-1083. https://doi.org/10.1001/jama.2009.1295
Bartlett JR, Friedman KJ, Ling SC, Pace RG, Bell SC, Bourke B et al. Genetic modifiers of liver disease in cystic fibrosis. JAMA - Journal of the American Medical Association. 2009 Sep 9;302(10):1076-1083. https://doi.org/10.1001/jama.2009.1295
Bartlett, Jaclyn R. ; Friedman, Kenneth J. ; Ling, Simon C. ; Pace, Rhonda G. ; Bell, Scott C. ; Bourke, Billy ; Castaldo, Giuseppe ; Castellani, Carlo ; Cipolli, Marco ; Colombo, Carla ; Colombo, John Louis ; Debray, Dominique ; Fernandez, Adriana ; Lacaille, Florence ; Macek, Milan ; Rowland, Marion ; Salvatore, Francesco ; Taylor, Christopher J. ; Wainwright, Claire ; Wilschanski, Michael ; Zemková, Dana ; Hannah, William B. ; Phillips, M. James ; Corey, Mary ; Zielenski, Julian ; Dorfman, Ruslan ; Wang, Yunfei ; Zou, Fei ; Silverman, Lawrence M. ; Drumm, Mitchell L. ; Wright, Fred A. ; Lange, Ethan M. ; Durie, Peter R. ; Knowles, Michael R. / Genetic modifiers of liver disease in cystic fibrosis. In: JAMA - Journal of the American Medical Association. 2009 ; Vol. 302, No. 10. pp. 1076-1083.
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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.",
author = "Bartlett, {Jaclyn R.} and Friedman, {Kenneth J.} and Ling, {Simon C.} and Pace, {Rhonda G.} and Bell, {Scott C.} and Billy Bourke and Giuseppe Castaldo and Carlo Castellani and Marco Cipolli and Carla Colombo and Colombo, {John Louis} and Dominique Debray and Adriana Fernandez and Florence Lacaille and Milan Macek and Marion Rowland and Francesco Salvatore and Taylor, {Christopher J.} and Claire Wainwright and Michael Wilschanski and Dana Zemkov{\'a} and Hannah, {William B.} and Phillips, {M. James} and Mary Corey and Julian Zielenski and Ruslan Dorfman and Yunfei Wang and Fei Zou and Silverman, {Lawrence M.} and Drumm, {Mitchell L.} and Wright, {Fred A.} and Lange, {Ethan M.} and Durie, {Peter R.} and Knowles, {Michael R.}",
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TY - JOUR

T1 - Genetic modifiers of liver disease in cystic fibrosis

AU - Bartlett, Jaclyn R.

AU - Friedman, Kenneth J.

AU - Ling, Simon C.

AU - Pace, Rhonda G.

AU - Bell, Scott C.

AU - Bourke, Billy

AU - Castaldo, Giuseppe

AU - Castellani, Carlo

AU - Cipolli, Marco

AU - Colombo, Carla

AU - Colombo, John Louis

AU - Debray, Dominique

AU - Fernandez, Adriana

AU - Lacaille, Florence

AU - Macek, Milan

AU - Rowland, Marion

AU - Salvatore, Francesco

AU - Taylor, Christopher J.

AU - Wainwright, Claire

AU - Wilschanski, Michael

AU - Zemková, Dana

AU - Hannah, William B.

AU - Phillips, M. James

AU - Corey, Mary

AU - Zielenski, Julian

AU - Dorfman, Ruslan

AU - Wang, Yunfei

AU - Zou, Fei

AU - Silverman, Lawrence M.

AU - Drumm, Mitchell L.

AU - Wright, Fred A.

AU - Lange, Ethan M.

AU - Durie, Peter R.

AU - Knowles, Michael R.

PY - 2009/9/9

Y1 - 2009/9/9

N2 - 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.

AB - 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.

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