만성B형간염에서 Core 유전자내 결손변이형의 발견 및 임상적 의의
Detection of Core Gene Deletion and Its Clinical Significance in Chronic Hepatitis B Virus infection
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배경 : 만성B형간염의 경과 중 HBV에 대한 숙주의 면역 압력이 가해지는 면역제거 시기 때 HBV 유전자의 면역 인지부위에점변이나 결손 등의 변이가 생김으로써 숙주의 면역 공격을 회피하게 되고 이로써 지속적인 감염상태를 유지할 수 있게 된다. 본연구에서는 국내의 HBV core 유전자내 결손변이형의 빈도를 조사하고, 결손변이형의 분자생물학적 특성 및 임상적 의의를 알아보고자 하였다.방법 : Precore와 core 영역에 대한 HBV PCR검사에서 양성을 보인 276명을 대상으로 521 bp 크기의 야생형 증폭산물과 함께이보다 작은 크기의 band를 보이는 결손변이형 증폭산물에 대해염기서열분석을 시행하였고, 217명의 환자들에 대한 병록기록을검토하였다.결과 : 276명 중 35명(12.7%)에서 core 유전자내 결손을 보였고, 결손변이형은 항상 야생형과 공존하는 것으로 나타났다. 결손변이형 35예 중 17예에서 염기서열분석 결과를 얻었는데 이 중 16예는 core 유전자의 중간부위인 nt 2000-2200 사이에서 다양한크기의 결손이 관찰됐으며, 26예(74.3%)가 HBe Ag 양성이었고,7예(20.0%)가 anti-HBe Ab 양성이었다. 야생형군과 결손변이형군 간에 AST, ALT 및 HBV DNA 정량값의 유의한 차이는 관찰되지 않았다. 결론 : HBV core 유전자내 결손은 만성B형간염 환자에서 비교적 자주 관찰되는 변이로 각 환자에서 관찰되는 결손위치라든가 임상상태에 있어 공통적인 특징을 갖는다. 그러나 아직까지 이러한 결손의 기전이라든가 결손변이형의 출현과 소멸이 갖는 임상적인 의의가 명확히 밝혀지지 않은 상태이며, 향후 만성B형간염 환자를 대상으로 한 지속적인 추적검사를 통하여 core 유전자내 결손이 갖는 면역학적 및 임상적 의미를 알 수 있을 것으로 생각된다.
Abstract
Background : In the course of chronic hepatitis B virus (HBV) infections, a point mutation or core gene deletion has been attributed to play a role in persistence of HBV infection. This study was undertaken to determine the prevalence of core gene deletion in chronic HBV infections, molecular characteristics, and its clinical significance. Methods : Among 276 patients with positive results in HBV PCR for precore and core region, patients with smaller bands in addition to the band of expected wild type size, suggestive of deletion, were analyzed by direct sequencing, and hospital records were reviewed on 217 patients. Results : The prevalence of core gene deletion among patients with positivity in HBV PCR was 12.7% (35/276) and they always existed together with wild type. Seventeen patients were further studied by direct sequencing and 16 patients had similar positions of deletion in the center of core gene (nt 2000-2200). Of 35 patients with core gene deletion, 26 (74.3%) were HBeAg-positive and 7 (20.0%) were anti-HBe-positive. There were no significant differences in AST, ALT and HBV DNA quantitation between the wild type and the deletion groups. Conclusions : HBV core gene deletion is frequently found in chronic HBV infections and has some common features in deleted position, serologic markers and clinical state. However, the mechanism and time at which deletion mutants appear and disappear, and their clinical significances are not fully understood. By longitudinal studies for chronic hepatitis B patients, we should be able to demonstrate the immunologic significance of the core gene deletion mutation. (Korean J Lab Med 2004; 24: 371-6)
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