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JAMA. 2009 Sep 9;302(10):1076-83. doi: 10.1001/jama.2009.1295.

Genetic modifiers of liver disease in cystic fibrosis.

Collaborators (279)

Clancy JP, Sindel LJ, Roberts DM, Roberts V, Radford PJ, Argel N, Morgan WJ, Douthit JL, Schellhase DE, Anderson P, Taggart A, Morrissey B, Platzker AC, Woo MS, Fukushima L, Hsu E, Shay GF, Hardy KA, Moss RB, Dunn CE, Pian MS, Wojtczak HA, Burns L, Henig NR, Nielson DW, Landon C, Thompson A, Accurso FJ, Nick JA, Jones M, Lapin C, Drapeau VM, Egan ME, Padman R, Winnie GB, George C, Olson EL, Light MJ, Geller DE, Gondor M, Flanary J, Stecenko AA, Guill MF, McColley SA, McColley SA, Potter EM, Chung Y, Garvey M, Howenstine MS, Sannuti A, Yeley J, Sloven DG, Ahrens RC, Teresi M, Riva CM, Davis S, Quiniones-Ellis B, Gabor C, Lever TF, Welch R, Cairns A, Corrigan M, Zeitlin PL, Brass L, Dorkin H, Levy H, Huntington I, O'Sullivan BP, Simon RH, Nasr SZ, Lumeng N, Ball ME, Toder DS, Honicky RE, Fitch S, Contreras L, Regelmann WE, Phillips JR, McNamara J, Johnson M, Ruiz FE, Adcock KG, Konig P, Black P, Weigel JD, Noyes BE, Kociela VL, Ferkol T Jr, Boyle M, Colombo JL, Brascia T, Parker HW, Zanni RL, Fiel SB, Lomas P, Taylor-Cousar J, Borowitz D, DeCelie-Germana JK, Cohen R, Gannon M, DiMango EA, Mencin AA, Lobritto SJ, Benitez M, Walker PA, Berdella MN, Langfelder-Schwind E, Ren CL, Rovitelli AK, Anbar RD, Lindner DM, Perciaccante RG, Dozor AJ, Knowles MR, Leigh MW, Taylor-Cousar J, Voynow JA, Auten KJ, Schechter MS, Omlor GJ, Ouellette DA, Karp CL, Joseph PM, Konstan MW, McCoy KS, Royce F, Bartosik S, Vauthy PA, Vauthy ML, Kramer JC, Hensel S, Perez CR, Thomas NJ, Hess JC, Holsclaw DS, Scanlin TF, Rubenstein R, Murray C, Skotleski M, Fiel SB, Sexauer WP, Ko A, Hillman J, Orenstein DM, Schechter MS, Flume PA, Brown D, Schoumacher R, Culbreath B, Moore PE, Slovis B, Dambro N, Garbarz J, Hiatt PW, Olivier KN, Amaro R, Macleod L, Liou TG, Froh DK, Epstein CE, Schmidt J, Elliot G, Williams R, Anderson M, Gadd J, Gibson RL, McNamara S, Worrell K, Moskowitz SM, McCarthy M, Llewellyn C, Wicks S, Moffett KS, Baer LS, do Pico GA, Makholm LM, Rock MJ, Osmond SR, Biller J, Miller T, Fernandez A, Renteria F, Bell SC, Wainwright C, Lewindon P, Selvadurai H, Gaskin K, Van Biervliet S, Montgomery M, Rabin HR, Leong J, Zuberbuhler P, Brown NE, Tabak J, Davidson AG, Nakielna EM, Habbick B, Waters I, Wiltse S, Kepron W, Pasterkamp H, Garey DN, Bishop G, Noseworthy M, Michael RT, Dale AM, Gosse FA, Robinson W, Durie PR, Corey M, Freitag A, Pedder L, Van Wylick R, Lougheed MD, Kodiattu L, Jackson M, Malhotra K, Lyttle B, Paterson NA, Aaron S, Boland M, Kovesi T, Smith A, Kumar VJ, Zinger S, Tullis E, Simard F, Rivard L, Cantin A, Cote G, Lands LC, Marcotte JE, Matouk E, Berthiaume Y, Jeanneret A, Van Spall M, Rivard G, Boucher J, Petit N, Holmes B, Cotton D, Ramlall K, Repetto G, Macek M Jr, Vavrova V, Bartosova J, Fila L, Debray D, Lacaille F, Munck A, Tümmler B, Rowland M, Bourke B, Canny G, Gallagher C, Rivlin J, Picard E, Blau H, Wilschanski M, Springer C, Kerem E, Yahav Y, Bujanover Y, Casciaro R, Colombo C, Castaldo G, Salvatore F, Raia V, Cipolli M, Castellani C, Sinaasappel M, Dooijes D, Ling SC, Kayserova H, Ozcelik U, Kiper N, Dogru D, Taylor CJ, McGaw J.

Author information

  • 1Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Abstract

CONTEXT:

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.

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, approximately 5) of developing severe liver disease with portal hypertension.

Comment in

PMID:
19738092
[PubMed - indexed for MEDLINE]
PMCID:
PMC3711243
Free PMC Article
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