Karasawa T, Shirasawa T, Okawa Y, Kuramoto A, Shimada N, Aizawa Y, Zeniya M, Toda G
First Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan.
J Gastroenterol. 1997 Oct;32(5):611-22. doi: 10.1007/BF02934110.
To elucidate the relationship between the frequency of core mutations and precore mutation of hepatitis B virus (HBV) in Japanese HBV carriers, we investigated the nucleotide sequence of the precore/core region of HBV in 26 Japanese HBV carriers [15 who were HBe antigen-negative (HBeAg-) and 11 who were HBeAg-positive (HBeAg+)]. The number of amino acid changes (5.9 +/- 3.8) in the core region of HBV in HBeAg-carriers was significantly greater than that in the HBeAg+ carriers (1.5 +/- 1.0; P < 0.005). The precore stop codon mutation was found in 93.3% of HBeAg-negative HBV carriers, while no precore mutation was found in the HBeAg-positive HBV carriers, suggesting that the frequency of core mutations may be associated with the presence of the precore stop codon mutation. However, there was no significant difference in the frequency of amino acid changes among HBeAg-HBV carriers. The mean number of core amino acid changes of liver cirrhosis patients, chronic active hepatitis patients, chronic persistent hepatitis patients, and asymptomatic carriers were 2.7 +/- 1.5, 6.0 +/- 2.2, 4.7 +/- 1.2, and 8.4 +/- 5.3, respectively. We detected hot spots for core mutations, which showed characteristic localizations and specific substitutions: Gly-87, Leu-97, and Thr-130 were detected exclusively in patients with chronic liver disease with or without HBeAg. To address further the relationship between frequency of core mutations and the presence of the precore stop codon mutation, we investigated the precore/core nucleotide sequence serially along with seroconversion in three patients with chronic hepatitis B in whom the hepatitis either became inactive or remained active after the seroconversion. Emergence of the precore stop codon mutation and a significant increase in core amino-acid changes after seroconversion were noted in all three patients. Our results suggest a close association between the frequency of core amino acid changes and the presence of the precore stop codon mutation; some characteristic core mutations may be associated with the clinical course of chronic hepatitis B in Japanese patients.
为阐明日本乙肝病毒（HBV）携带者中核心突变频率与前核心突变之间的关系，我们调查了26名日本HBV携带者[15名HBe抗原阴性（HBeAg-）和11名HBeAg阳性（HBeAg+）]的HBV前核心/核心区域的核苷酸序列。HBeAg携带者中HBV核心区域的氨基酸变化数量（5.9±3.8）显著高于HBeAg+携带者（1.5±1.0；P<0.005）。在93.3%的HBeAg阴性HBV携带者中发现了前核心终止密码子突变，而在HBeAg阳性HBV携带者中未发现前核心突变，这表明核心突变频率可能与前核心终止密码子突变的存在有关。然而，HBeAg-HBV携带者之间的氨基酸变化频率没有显著差异。肝硬化患者、慢性活动性肝炎患者、慢性持续性肝炎患者和无症状携带者的核心氨基酸变化平均数分别为2.7±1.5、6.0±2.2、4.7±1.2和8.4±5.3。我们检测到了核心突变热点，其显示出特征性定位和特定替换：Gly-87、Leu-97和Thr-130仅在有或无HBeAg的慢性肝病患者中检测到。为进一步探讨核心突变频率与前核心终止密码子突变存在之间的关系，我们对三名慢性乙型肝炎患者进行了连续的前核心/核心核苷酸序列分析以及血清学转换，这三名患者在血清学转换后肝炎要么转为非活动性要么仍为活动性。在所有三名患者中均注意到血清学转换后前核心终止密码子突变的出现以及核心氨基酸变化的显著增加。我们的结果表明核心氨基酸变化频率与前核心终止密码子突变的存在密切相关；一些特征性核心突变可能与日本患者慢性乙型肝炎的临床病程有关。
