Tohoku J. Exp. Med., 2009, 218(4)

Nucleotide Substitutions of Hepatitis E Virus Genomes Associated with Fulminant Hepatitis and Disease Severity

JUN INOUE,¹ MASAHARU TAKAHASHI,² HITOSHI MIZUO,³ KAZUYUKI SUZUKI,⁴ TATSUYA AIKAWA,⁵ TOORU SHIMOSEGAWA¹ and HIROAKI OKAMOTO²

¹Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
²Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
³Department of Internal Medicine, Kin-ikyo Chuo Hospital, Sapporo, Japan
⁴First Department of Internal Medicine, Iwate Medical University, Morioka, Iwate, Japan
⁵Aikawa Internal Medicine Hospital, Mito, Ibaraki, Japan

Hepatitis E virus (HEV) is one of the causative agents of acute or fulminant hepatitis. Viral factors may play a role in the pathogenesis of fulminant hepatitis E. We aimed to investigate the nucleotide substitutions of the HEV genome affecting the severity of hepatitis E. The comparison of 28 reported full-length nucleotide sequences of genotype 4 HEV showed that the substitution of C at nucleotide 5907 (C5907) was most closely associated with fulminant hepatitis (fulminant hepatitis, 100%; acute hepatitis, 39.1%; p = 0.0204). Analyzing the full-length sequences of 28 genotype-4 and 11 genotype-3 HEV retrievable from DNA databases and 35 partial sequences recovered from patients with acute or fulminant hepatitis, we show that the presence of both U3148 and C5907 is associated with fulminant hepatitis in patients with HEV of genotype 4 (p = 0.0042) and genotype 3 or 4 (p = 0.0009), and that the prothrombin activity is significantly lower in patients infected with HEV carrying U3148 and C5907 than in those without the substitutions (p = 0.0069). U3148 and C5907 are silent substitutions that do not change amino acid. However, since U3148 is located at the RNA helicase domain and C5907 is located within the capsid gene, the secondary structure of the HEV RNA genome carrying U3148 and C5907 may be favorable for translation of the viral proteins. C5907 was associated with high HEV load (≥ 10⁵ copies/ml) at initial examination (p = 0.0427). We propose that U3148 and C5907 are associated with the severity of hepatitis E.

Keywords —— hepatitis E virus; genotype; full-length sequence; U3148; C5907.

© 2009 Tohoku University Medical Press

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Tohoku J. Exp. Med., 2009, 218, 279-284

Correspondence: Hiroaki Okamoto, M.D., Ph.D., Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke-Shi, Tochigi-Ken 329-0498, Japan.

e-mail: hokamoto@jichi.ac.jp