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

Bihui Zhong, Pavel Strnad, Carlo Selmi, Pietro Invernizzi, Guo Zhong Tao, Angela Caleffi, Minhu Chen, Ilaria Bianchi, Mauro Podda, Antonello Pietrangelo, M. Eric Gershwin, M. Bishr Omary

Research output: Contribution to journalArticle

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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 diseaseassociated keratin variants were found in 17 of 201 (8.5%)PBCpatients 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.

Original languageEnglish (US)
Pages (from-to)546-554
Number of pages9
JournalHepatology
Volume50
Issue number2
DOIs
StatePublished - 2009

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Biliary Liver Cirrhosis
Keratins
Liver Diseases
Anti-Idiotypic Antibodies
Blood Banks
Blood Donors
Disease Progression
Hepatocytes
Odds Ratio
Confidence Intervals
Keratin-8
Mitochondrial Size
Keratin-18
K-18 conjugate
End Stage Liver Disease
Chronic Hepatitis C
Autoimmune Diseases
Epithelium
Liver
Wounds and Injuries

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

Zhong, B., Strnad, P., Selmi, C., Invernizzi, P., Tao, G. Z., Caleffi, A., ... Omary, M. B. (2009). Keratin variants are overrepresented in primary biliary cirrhosis and associate with disease severity. Hepatology, 50(2), 546-554. https://doi.org/10.1002/hep.23041

Keratin variants are overrepresented in primary biliary cirrhosis and associate with disease severity. / Zhong, Bihui; Strnad, Pavel; Selmi, Carlo; Invernizzi, Pietro; Tao, Guo Zhong; Caleffi, Angela; Chen, Minhu; Bianchi, Ilaria; Podda, Mauro; Pietrangelo, Antonello; Gershwin, M. Eric; Omary, M. Bishr.

In: Hepatology, Vol. 50, No. 2, 2009, p. 546-554.

Research output: Contribution to journalArticle

Zhong, B, Strnad, P, Selmi, C, Invernizzi, P, Tao, GZ, Caleffi, A, Chen, M, Bianchi, I, Podda, M, Pietrangelo, A, Gershwin, ME & Omary, MB 2009, 'Keratin variants are overrepresented in primary biliary cirrhosis and associate with disease severity', Hepatology, vol. 50, no. 2, pp. 546-554. https://doi.org/10.1002/hep.23041
Zhong, Bihui ; Strnad, Pavel ; Selmi, Carlo ; Invernizzi, Pietro ; Tao, Guo Zhong ; Caleffi, Angela ; Chen, Minhu ; Bianchi, Ilaria ; Podda, Mauro ; Pietrangelo, Antonello ; Gershwin, M. Eric ; Omary, M. Bishr. / Keratin variants are overrepresented in primary biliary cirrhosis and associate with disease severity. In: Hepatology. 2009 ; Vol. 50, No. 2. pp. 546-554.
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title = "Keratin variants are overrepresented in primary biliary cirrhosis and associate with disease severity",
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 diseaseassociated keratin variants were found in 17 of 201 (8.5{\%})PBCpatients 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.",
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T1 - Keratin variants are overrepresented in primary biliary cirrhosis and associate with disease severity

AU - Zhong, Bihui

AU - Strnad, Pavel

AU - Selmi, Carlo

AU - Invernizzi, Pietro

AU - Tao, Guo Zhong

AU - Caleffi, Angela

AU - Chen, Minhu

AU - Bianchi, Ilaria

AU - Podda, Mauro

AU - Pietrangelo, Antonello

AU - Gershwin, M. Eric

AU - Omary, M. Bishr

PY - 2009

Y1 - 2009

N2 - 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 diseaseassociated keratin variants were found in 17 of 201 (8.5%)PBCpatients 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.

AB - 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 diseaseassociated keratin variants were found in 17 of 201 (8.5%)PBCpatients 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.

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