Genetic Modifiers of Liver Disease in Cystic Fibrosis

被引：215

作者：

Bartlett, Jaclyn R. ^{[1
]}

Friedman, Kenneth J. ^{[5
]}

Ling, Simon C. ^{[6
,7
]}

Pace, Rhonda G. ^{[1
]}

Bell, Scott C. ^{[8
]}

Bourke, Billy ^{[9
]}

Castaldo, Giuseppe ^{[11
,12
]}

Castellani, Carlo ^{[13
]}

Cipolli, Marco ^{[13
]}

Colombo, Carla ^{[14
]}

Colombo, John L. ^{[15
]}

Debray, Dominique ^{[16
]}

Fernandez, Adriana ^{[17
]}

Lacaille, Florence ^{[18
]}

Macek, Milan, Jr. ^{[19
,20
]}

Rowland, Marion ^{[9
,10
]}

Salvatore, Francesco ^{[11
,12
]}

Taylor, Christopher J. ^{[22
]}

Wainwright, Claire ^{[23
]}

Wilschanski, Michael ^{[24
]}

Zemkova, Dana ^{[21
]}

Hannah, William B. ^{[1
]}

Phillips, M. James

Corey, Mary ^{[7
]}

Zielenski, Julian

Dorfman, Ruslan

Wang, Yunfei ^{[2
,3
,4
]}

Zou, Fei ^{[3
,4
]}

Silverman, Lawrence M. ^{[25
]}

Drumm, Mitchell L. ^{[26
,27
]}

Wright, Fred A. ^{[3
,4
]}

Lange, Ethan M. ^{[2
,3
,4
]}

Durie, Peter R. ^{[6
,7
]}

Knowles, Michael R. ^{[1
]}

Clancy, J. P.

Sindel, L. J.

Roberts, D. M.

Roberts, V.

Radford, P. J.

Argel, N.

Morgan, W. J.

Douthit, J. L.

Schellhase, D. E.

Anderson, P.

Taggart, A.

Morrissey, B.

Platzker, A. C. G.

Woo, M. S.

Fukushima, L.

Hsu, E.

机构：

[1] Univ N Carolina, Cyst Fibrosis Pulm Res & Treatment Ctr, 7019 Thurston Bowles Bldg,CB 7248, Chapel Hill, NC 27599 USA

[2] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

[3] Univ N Carolina, Sch Med, Chapel Hill, NC 27599 USA

[4] Univ N Carolina, Sch Publ Hlth, Dept Biostat, Chapel Hill, NC 27599 USA

[5] Lab Corp Amer, Ctr Mol Biol & Pathol, Res Triangle Pk, NC USA

[6] Hosp Sick Children, Div Gastroenterol Hepatol & Nutr, Toronto, ON M5G 1X8, Canada

[7] Univ Toronto, Toronto, ON, Canada

[8] Prince Charles Hosp, Adult Cyst Fibrosis Ctr, Chermside, Qld, Australia

[9] Our Ladys Childrens Hosp, Childrens Res Ctr, Crumlin, Ireland

[10] Univ Coll Dublin, Sch Med & Med Sci, Dublin 2, Ireland

[11] Univ Naples Federico II, CEINGE Adv Biotechnol, Naples, Italy

[12] Univ Naples Federico II, Dept Biochem & Med Biotechnol, Naples, Italy

[13] Azienda Osped Verona, Cyst Fibrosis Ctr, Verona, Italy

[14] Univ Milan, CF Ctr, Fdn IRCCS Osped Maggiore Policlin, Milan, Italy

[15] Univ Nebraska Med Ctr, Dept Pediat, Pulm Sect, Omaha, NE USA

[16] Ctr Hosp Univ Bicetre, Serv Hepatol Pediat, Le Kremlin Bicetre, France

[17] La Plata Childrens Hosp, Cyst Fibrosis Ctr, Buenos Aires, DF, Argentina

[18] Hop Necker Enfants Malad, Pediat Hepatogastroenterol Nutr Unit, Paris, France

[19] Charles Univ Prague, Dept Biol, Prague, Czech Republic

[20] Charles Univ Prague, Dept Med Genet, Prague, Czech Republic

[21] Charles Univ Prague, Dept Pediat, Prague, Czech Republic

[22] Univ Sheffield, Acad Unit Child Hlth, Dept Paediat Gastroenterol, Sheffield, S Yorkshire, England

[23] Royal Childrens Hosp, Queensland Childrens Resp Ctr, Brisbane, Qld, Australia

[24] Hadassah Med Org, Dept Pediat Gastroenterol, Jerusalem, Israel

[25] Univ Virginia, Dept Pathol, Charlottesville, VA 22903 USA

[26] Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA

[27] Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA

来源：

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION | 2009年 / 302卷 / 10期

基金：

美国国家卫生研究院;

关键词：

TRANSMEMBRANE CONDUCTANCE REGULATOR; ALPHA-1-ANTITRYPSIN DEFICIENCY; LUNG-DISEASE; RISK-FACTORS; ALPHA(1)-ANTITRYPSIN DEFICIENCY; SEVERITY; EPIDEMIOLOGY; ASSOCIATION; EXPRESSION; CIRRHOSIS;

D O I：

10.1001/jama.2009.1295

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Context A subset (approximate to 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 beta 1 [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 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, approximate to 5) of developing severe liver disease with portal hypertension. JAMA. 2009;302(10):1076-1083

引用

页码：1076 / 1083

页数：8

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