Keratin variants are overrepresented in primary biliary cirrhosis and associate with disease severity

Authors

  • Bihui Zhong,

    Corresponding author
    1. Division of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
    2. Palo Alto VA Medical Center and Stanford University School of Medicine, Palo Alto, CA
    • Division of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, PR China
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    • These authors contributed equally to this work.

  • Pavel Strnad,

    1. Palo Alto VA Medical Center and Stanford University School of Medicine, Palo Alto, CA
    2. Department of Internal Medicine I, University Medical Center Ulm, Ulm, Germany
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    • These authors contributed equally to this work.

  • Carlo Selmi,

    1. Division of Internal Medicine and Hepatobiliary Immunopathology Unit, Rozzano, Italy
    2. University of Milan, Rozzano, Italy
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  • Pietro Invernizzi,

    1. Division of Internal Medicine and Hepatobiliary Immunopathology Unit, Rozzano, Italy
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  • Guo-Zhong Tao,

    1. Palo Alto VA Medical Center and Stanford University School of Medicine, Palo Alto, CA
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  • Angela Caleffi,

    1. Center for Hemochromatosis, Department of Internal Medicine, University of Modena and Reggio Emilia, Modena, Italy
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  • Minhu Chen,

    1. Division of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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  • Ilaria Bianchi,

    1. Division of Internal Medicine and Hepatobiliary Immunopathology Unit, Rozzano, Italy
    2. University of Milan, Rozzano, Italy
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  • Mauro Podda,

    1. Division of Internal Medicine and Hepatobiliary Immunopathology Unit, Rozzano, Italy
    2. University of Milan, Rozzano, Italy
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  • Antonello Pietrangelo,

    1. Center for Hemochromatosis, Department of Internal Medicine, University of Modena and Reggio Emilia, Modena, Italy
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  • M. Eric Gershwin,

    1. Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis, Davis, CA
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  • M. Bishr Omary

    Corresponding author
    1. Department of Molecular & Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, MI
    • University of Michigan, School of Medicine, Department of Molecular & Integrative Physiology, 7744 Medical Science II, 1301 E. Catherine Street, Ann Arbor, MI 48109
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  • Potential conflict of interest: Nothing to report.

Abstract

Keratins (K) 8 and 18 variants predispose carriers to the development of end-stage liver disease and patients with chronic hepatitis C to disease progression. Hepatocytes express K8/K18, whereas biliary epithelia express K8/K18/K19. K8-null mice, which are predisposed to liver injury, spontaneously develop anti-mitochondrial antibodies (AMA) and have altered hepatocyte mitochondrial size and function. There is no known association of K19 with human disease and no known association of K8/K18/K19 with human autoimmune liver disease. We tested the hypothesis that K8/K18/K19 variants associate with primary biliary cirrhosis (PBC), an autoimmune cholestatic liver disease characterized by the presence of serum AMA. In doing so, we analyzed the entire exonic regions of K8/K18/K19 in 201 Italian patients and 200 control blood bank donors. Five disease-associated keratin heterozygous variants were identified in patients versus controls (K8 G62C/R341H/V380I, K18 R411H, and K19 G17S). Four variants were novel and included K19 G17S/V229M/N184N and K18 R411H. Overall, heterozygous disease-associated keratin variants were found in 17 of 201 (8.5%) PBC patients and 4 of 200 (2%) blood bank donors (P < 0.004, odds ratio = 4.53, 95% confidence interval = 1.5–13.7). Of the K19 variants, K19 G17S was found in three patients but not in controls and all K8 R341H (eight patients and three controls) associated with concurrent presence of the previously described intronic K8 IVS7+10delC deletion. Notably, keratin variants associated with disease severity (12.4% variants in Ludwig stage III/IV versus 4.2% in stages I/II; P < 0.04, odds ratio = 3.25, 95% confidence interval = 1.02–10.40), but not with the presence of AMA. Conclusion: K8/K18/K19 variants are overrepresented in Italian PBC patients and associate with liver disease progression. Therefore, we hypothesize that K8/K18/K19 variants may serve as genetic modifiers in PBC. (HEPATOLOGY 2009.)

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