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Hepatitis B virus pre-S2 start codon mutations in Indonesian liver disease patients

World Journal of Gastroenterology 2012年第38期18卷 5418-5426页

作者： Andi Utama Marlinang Diarta Siburian Ismail Fanany Mariana Destila Bayu Intan Rama Dhenni Tri Shinta Kurniasih Syafruddin AR Lelosutan Wenny Astuti Achwan Nasrul Zubir Arnelis Benyamin Lukito Irawan Yusuf laurentius adrianus lesmana Ali Sulaiman Molecular Epidemiology Division Mochtar Riady Institute for Nanotechnology Universitas Pelita Harapan Lippo Karawaci Tangerang 15810 Banten Indonesia Gastroentero-Hepatology Division Department of Internal Medicine Gatot Soebroto Hospital Jakarta 10410 Indonesia Department of Internal Medicine Mataram General Hospital Mataram 83127 Indonesia Gastroentero-Hepatology Division Department of Internal Medicine M. Djamil Hospital Padang 25127 Indonesia Department of Internal Medicine Siloam Hospital Lippo Karawaci Tangerang 15810 Banten Indonesia Faculty of Medicine Hasanuddin University Makassar 90245 Indonesia Hepatology Division Department of Internal Medicine Faculty of Medicine University of Indonesia Jakarta 10430 Indonesia

AIM: To identify the prevalence of pre-S2 start codon mutations and to assess their association with liver disease progression. METHODS: The mutations were identified by direct sequencing from 73 asymptomatic carriers, 66 chronic hepatitis (CH), 66 liver cirrhosis (LC) and 63 hepatocellular carcinoma (HCC) patients. Statistical significances were determined using Fisher's exact test, χ 2 test, and t -test analyses whenever appropriate. Pre-S mutation as a risk factor for advanced liver disease was estimated by unconditional logistic regression model adjusted with age, sex, and hepatitis B e antigen (HBeAg). P < 0.05 was considered significant. RESULTS: Mutation of the hepatitis B virus (HBV) pre-S2 start codon was found in 59 samples from 268 subjects (22.0%), with higher prevalence in patients with cirrhosis 27/66 (40.9%) followed by HCC 18/63 (28.6%), chronic hepatitis 12/66 (18.2%) and asymptomatic carriers 2/73 (2.7%) (P < 0.001). Logistic regression analysis showed that pre-S2 start codon mutation was an independent factor for progressive liver disease. Other mutations, at T130, Q132, and A138, were also associated with LC and HCC, although this was not statistically significant when adjusted for age, sex, and HBeAg. The prevalence of pre-S2 start codon mutation was higher in HBV/B than in HBV/C (23.0% vs 19.1%), whilst the prevalence of T130, Q132, and A138 mutation was higher in HBV/C than in HBV/B. The prevalence of pre-S2 start codon mutation was higher in LC (38.9%) and HCC (40.0%) than CH (5.6%) in HBeAg(+) group, but it was similar between CH, LC and HCC in HBeAg(-) group. CONCLUSION: Pre-S2 start codon mutation was higher in Indonesian patients compared to other Asian countries, and its prevalence was associated with advanced liver disease, particularly in HBeAg(+) patients.

关键词： Hepatitis B virus Pre-S2 start codon Liver disease Hepatitis B e antigen seroconversion Indonesia

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Association of core promoter mutations of hepatitis B virus and viral load is different in HBeAg(+) and HBeAg(-) patients

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World Journal of Gastroenterology 2011年第6期17卷 708-716页

作者： Andi Utama Marlinang Diarta Siburian Sigit Purwantomo Mariana Destila Bayu Intan Tri Shinta Kurniasih Susan Tai Rino Alvani Gani laurentius adrianus lesmana All Sulaiman Wenny Astuti Achwan Soewignjo Soemohardjo Arnelis Nasrul Zubir Julius Syafruddin AR Lelosutan Benyamin Lukito Tantoro Harmono Molecular Epidemiology Division Mochtar Riady Institute for Nanotechnology Universitas Pelita Harapan Lippo Karawaci Tangerang 15810 Indonesia Hepatology Division Department of Intemal Medicine Faculty of Medicine University of Indonesia Jakarta 10430 Indonesia Department of Internal Medicine Mataram General Hospital Mataram 83127 Indonesia Gastroentero-Hepatology Division Department of Internal Medicine Dr. M. Jamil Hospital Padang 25127 Indonesia Gastroentero-Hepatology Division Department of Intemal Medicine Dr. Gatot Soebroto Hospital Jakarta 10410 Indonesia Department of Internal Medicine Siloam Hospital Lippo Village Tangerang 15810 Indonesia Department of Internal Medicine Dr. Moewardi Hospital Surakarta 57126 Indonesia

AIM:To identify the prevalence of hepatitis B e antigen (HBeAg) and to assess the association of hepatitis B virus (HBV) core promoter mutations and viral load in Indonesian ***:Sixty-four patients with chronic hepatitis,65 with liver cirrhosis and 50 with hepatocellular carcinoma were included in this *** and hepatitis B e antibody (HBeAb) tests were performed using enzyme-linked immunosorbent assay and the mutations were analyzed by *** load was measured by real-time polymerase chain ***:Of 179 patients,108 (60.3%) were HBeAg(-) and 86 (79.6%) of these HBeAg(-) patients had been *** A1896 mutation was not found in HBeAg(+) patients,however,this mutation was detected in 70.7% of HBeAg(-) *** mutation was frequently found when HBeAg was not expressed (87.7%),compared to that found in HBeAg seroconverted patients (65.1%).The A1899 mutation was also more prevalent in HBeAg(-) than in HBeAg(+) patients (P=0.004).The T1762/A1764 mutation was frequently found in both HBeAg(+) and HBeAg(-) patients,however,the prevalence of this mutation did not significantly differ among the two groups (P=0.054).In HBeAg(+) patients,the T1762/A1764 mutation was correlated with lower HBV DNA (P < 0.001).The A1899 mutation did not correlate with HBV DNA (P=0.609).In HBeAg(-) patients,the T1762/A1764 mutation alone was not correlated with HBV DNA (P=0.095),however,the presence of either the T1762/A1764 or A1896 mutations was associated with increased HBV DNA (P < 0.001).CONCLUSION:The percentage of HBeAg(-) patients is high in Indonesia,and most of the HBeAg(-) patients had been *** A1896 mutation was most likely the major cause of HBeAg *** T1762/A1764 mutation alone was associated with lower viral loads in HBeAg(+) patients,but not in HBeAg(-) patients.

关键词： Hepatitis B e antibody Hepatitis B e antigen Hepatitis B virus Indonesia Precore/core promoter mutations Viral load

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Hepatitis B virus subgenotypes and basal core promoter mutations in Indonesia

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World Journal of Gastroenterology 2009年第32期15卷 4028-4036页

作者： Andi Utama Sigit Purwantomo Marlinang Diarta Siburian Rama Dhenni Rino Alvani Gani Irsan Hasan Andri Sanityoso Upik Anderiani Miskad Fardah Akil Irawan Yusuf Wenny Astuti Achwan Soewignjo Soemohardjo Syafruddin AR Lelosutan Ruswhandi Martamala Benyamin Lukito Unggul Budihusodo laurentius adrianus lesmana Ali Sulaiman Susan Tai Molecular Epidemiology Division Mochtar Riady Institute for NanotechnologyLippo KarawaciTangerangBanten 15810Indonesia Hepatology Division Department of Internal MedicineFaculty of MedicineUniversity of IndonesiaJakarta 10430Indonesia Center of Gastroentero-Hepatology Department of Internal MedicineFaculty of MedicineHasanuddin UniversityMakassar 90245Indonesia Department of Internal Medicine Mataram General HospitalMataram 83127Indonesia Gastroentero-Hepatology Division Department of Internal MedicineGatot Soebroto HospitalJakarta 10410Indonesia Department of Internal Medicine Siloam Hospital Lippo KarawaciTangerang Banten 15810Indonesia

AIM： To identify the distribution of hepatitis B virus （HBV） subgenotype and basal core promoter （BCP） mutations among patients with HBV-associated liver disease in Indonesia.METHODS： Patients with chronic hepatitis （CH, n =61）, liver cirrhosis （LC, n = 62）, and hepatocellular carcinoma （HCC, n = 48） were included in this study. HBV subgenotype was identified based on S or preS gene sequence, and mutations in the HBx gene including the overlapping BCP region were examined by direct sequencing.RESULTS： HBV genotype B （subgenotypes B2, B3, B4, 85 and B7） the major genotype in the samples, accounted for 75.4%, 71.0% and 75.0% of CH, LC and HCC patients, respectively, while the genotype C （subgenotypes C1, C2 and C3） was detected in 24.6%, 29.0%, and 25.0% of CH, LC, and HCC patients, respectively. Subgenotypes B3 （84.9%） and C1 （82.2%） were the main subgenotype in HBV genotype B and C, respectively. Serotype adw2 （84.9%） and adrq＋（89.4%） were the most prevalent in HBV genotype B and C, respectively. Double mutation （A1762T/G1764A） in the BCP was significantly higher in LC （59.7%） and HCC （54.2%） than in CH （19.7%）, suggesting that this mutation was associated with severity of liver disease. The T1753V was also higher in LC （46.8%）, but lower in HCC （22.9%） and CH （18.0%）, suggesting that this mutation may be an indicator of cirrhosis.CONCLUSION： HBV genotype B/B3 and C/C1 are the major genotypes in Indonesia. Mutations in BCP, such as A1762T/G1764A and T1753V, might have an association with manifestations of liver disease.

关键词： Basal core promoter mutation Hepatitis Bvirus Indonesia Liver disease Subgenotype

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