Analysis of Keratin Polypeptides 8 and 19 Variants in Inflammatory Bowel Disease

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Clinical Gastroenterology and Hepatology Volume 5, Issue 7, July 2007, Pages 857-864

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doi:10.1016/j.cgh.2007.02.017 Copyright © 2007 AGA Institute Published by Elsevier Ltd.

Original article—alimentary tract

Analysis of Keratin Polypeptides 8 and 19 Variants in Inflammatory Bowel Disease

Guo–Zhong Tao, Pavel Strnad, Qin Zhou, Ahmad Kamal, Leilei Zhang‡, Nahid D. Madani, Subra Kugathasan§, R. Brant¶, Judy H. Cho, M. Bishr y, and H. Duerr‡, # #Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania‡Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PennsylvaniaDepartment of Medicine, Palo Alto Veterans Affairs Medical Center and Stanford University Digestive Disease Center, Palo Alto, CaliforniaIBD Center, Section of Digestive Diseases, Department of Medicine, Yale University, New Haven, Connecticut§Medical College of Wisconsin, Milwaukee, Wisconsin¶Department of Medicine, School of Medicine and the Department of Epidemiology, Bloomberg School of Public Health, The s Hopkins University School of Medicine, Baltimore, land Available online 16 May 2007.

Background/Aims: Keratin-8 (KRT8)–null mice develop spontaneous colitis and predisposition to liver injury. Human studies show that some KRT8 variants predispose to end-stage liver disease and progression and suggest that such variants might associate with UC or CD. We asked whether mutations in KRT8 or KRT19, the major intestinal keratins, are associated with UC/CD. Methods: Exonic regions of the KRT8/KRT19 genes were polymerase chain reaction–amplified using genomic DNA from 2 independent groups. Group I included 91 unrelated patients with CD, 93 unrelated patients with UC, and 70 unrelated/unaffected volunteers. KRT8 variants were also tested with pyrosequencing in Group II that included 682 independent nuclear families with both parents and at least 1 CD/UC-affected offspring and 273 unaffected controls. Both cohorts were enriched for familial IBD. Results: In Group I, KRT19 variants were identified in CD/UC patients within the promoter and exons 1+2, with similar mutation frequencies in the control/CD/UC groups. In contrast, 16 of 184 CD+UC patients harbored KRT8 heterozygous variants involving Gly62-to-Cys and Arg341-to-His and a novel Arg341-to-Cys, which were noted in 4 volunteers (Arg341-to-His) and correlated with extensive UC (P = .005). One family with unaffected parents had 3 pediatric-affected siblings with severe disease, 2 of whom are compound heterozygous (Gly62-to-Cys/Arg341-to-His). However, there was no significant departure from random transmission of the 3 alleles in Group II IBD families. Conclusions: KRT8 and KRT19 variants are not overtransmitted or associated with familial IBD, although a potential role in sporadic IBD cannot be excluded. A novel but rare keratin-8 Arg341-to-Cys is identified in IBD patients. Abbreviations: Ab, antibody; CD, crohn’s disease; CI, confidence interval; DHPLC, denaturing high-performance liquid chromatography; IBD, inflammatory bowel disease; IF, intermediate filaments; K, proteins; KRT8, keratin-8; OR, odds ratio; PCR, polymerase chain reaction; SDS, sodium dodecylsulfate; TDT, transmission/disequilibrium test; UC, ulcerative colitis.

Supported by the Broad Medical Research Program, Department of Veterans Affairs Merit Award, and NIH grant DK47918 (M.B.O.); The Meyerhoff Inflammatory Bowel Disease Center, Crohn’s & Colitis Foundation of America, and NIH GCRC grant RR00052 (S.R.B.); NIH grant DK062422 (J.H.C.); and NIH grant DK062420 (R.H.D.). We are also grateful for Fellowship support by the Crohn’s & Colitis Foundation of America (G-Z.T.), Department of Veteran Affairs Research Enhancement Award Program (Q.Z.), and fellowship support by the European Molecular Biology Organization (P.S.).Drs Tao, Strnad, and Zhou contributed equally to this work and Drs Cho, y, and Duerr had equal senior author contributions.Address correspondence to: Bishr y, Palo Alto VA Medical Center, 3801 Miranda Ave, Mail Code 154J, Palo Alto, California 94304. fax: .

Clinical Gastroenterology and Hepatology Volume 5, Issue 7, July 2007, Pages 857-864