신생아 담즙정체성 간질환에서 간조직 유전자의 발현 양상 = Patterns of Intrahepatic Gene Expression in Neonatal Cholestasis

국문 초록 (Abstract)

목 적: 담즙정체를 보이는 환자의 간조직에서 cDNA microarray를 이용한 유전자 발현 분석을 통 하여 담도 폐쇄증의 발생과정에 관여하는 유전자를 규명하고자 연구를 시행하였다. 방 법: 환자의 간조직은 담즙정체를 보이는 11명의 환자로부터 진단적 간생검시 얻은 간조직의 일부를 이용하였다. 이들의 원인 질환은 담도 폐쇄증이 7명, 신생아 간염 증후군이 4명이었다. 정상대조군의 간조직은 생체부분 간이식시 성인 공여자로부터 얻은 간조직의 일부를 이용하였다. 간조직에서 분리된 mRNA를 4.7K 인간유전자 cDNA microarray를 이용하여 유전자 발현의 양상을 분석하였다. 결 과: 분석한 4,700종의 유전자 중 담즙정체 환자 11명 모두의 간조직에서 발현이 증가된 유전자는 17종이 발견되었고, 발현이 감소된 유전자는 20종이 발견되었다. 담도 폐쇄증 환자와 신생아 간염 증후군 환자 사이에 49종의 유전자에서 발현의 차이가 관찰되었고, 특히 담도 폐쇄증에서는 발현이 증가하였으나 신생아 간염 증후군에서는 발현이 감소된 유전자는 24종이었으며 이들 유전자 발현의 차이에 의해서 두 군간의 감별이 가능하였다. 결 론: 신생아 간질환에서 담도 폐쇄증 환자들은 모두 일정한 양상을 보여주어 이에 대한 분석을 통하여 담도 폐쇄증의 조기 감별 진단을 할 수 있을것을 시사하였다. 또한 담도 폐쇄증에서 특이 발현을 보이는 유전자의 추가적인 기능 연구를 시행함으로써 담도 폐쇄증의 원인을 규명하는데 도움을 줄 수 있을 것으로 생각한다.

다국어 초록 (Multilingual Abstract)

Purpose: To identify genes specifically expressed in biliary atresia, we compared the patterns of gene expression between biliary atresia and neonatal hepatitis syndrome using cDNA microarray analysis. Methods: Liver tissues were taken from livers of 11 patients (7 patients with biliary atresia and four with neonatal hepatitis) with neonatal cholestasis by needle biopsy. Normal control could be obtained from donor liver tissue during living-related liver transplantation. Total RNA was extracted from each samples and reversely transcribed to make cDNA. Then fluorescent cDNA were pooled and hybridized to the clones on the microarray. Fluorescence intensities at the immobilized targets were measured. Utilizing cDNA arrays of 4.7 K human genes, gene expression profiles were analyzed. Results: Among 4,700 microarray clones, 17 cDNA clones were significantly over-expressed in all 11 patients with neonatal cholestasis, while 20 clones were significantly decreased. Genome-wide expression analysis was carried out in livers obtained at the time of diagnosis. We could identify 49 genes, in which there showed differential expression between biliary atresia and neonatal hepatitis syndrome. Conclusion: This study shows the pattern of differentially expressed genes in biliary atresia and neonatal hepatitis syndrome. We believe that this study can contribute to the understanding of pathogenesis of neonatal cholestasis.

참고문헌 (Reference)

• 1 "신생아 담즙정체증의 원인질환 및 장기추적 예후인자에 관한 고찰" 2 : 46-58, 1999
• 2 "소아에서 생체부분간이식의 적응증과 예후" 41 : 622-31, 1998
• 3 "Use of cDNA microarray to analyse gene expression patterns in human cancer" 14 : 457-60, 1996
• 4 "Unraveling the pathogenesis and etiology of biliary atresia" 57 : 87-94, 2005
• 5 "The ultrasonographic 'triangular cord' coupled with gallbladder images in the diagnostic prediction of biliary atresia from infantile intrahepatic cholestasis" 34 : 1706-10, 1999
• 6 "The pattern of differentially expressed genes in biliary atresia" 18 : 392-6, 2003
• 7 "Sonographic diagnosis of biliary atresia in pediatric patients using the" 181 : 1387-90, 2003
• 8 "Sequential treatment of biliary atresia with Kasai portoenterostomy and liver transplantation:a review" 20 : 1994
• 9 "Presence of human papillomavirus in extrahepatic biliary atresia" 27 : 530-5, 1998
• 10 "Pathogenesis and outcome of biliary atresia:current concepts" 37 : 4-21, 2003
• 11 "Mirodissection is essential for gene expression profiling of clinically resected cancer tissues" 117 : 109-16, 2002
• 12 "MR cholangiography in the evaluation of neonatal cholestasis:initial results" 222 : 687-91, 2002
• 13 "MR cholangiography in neonates and infants:feasibility and preliminary applications" 170 : 27-31, 1998
• 14 "Liver disease in children 2nd ed" Lippincott Williams & Wilkins press 239-52, 2001
• 15 "Liver biopsy in neonatal cholestasis:a review on statistical grounds" 10 : 793-9, 1997
• 16 "Laser capture microdissection in pathology" 53 : 666-72, 2000
• 17 "Is the Kasai operation still indicated in children older than 3 months diagnosed with biliary atresia" 138 : 224-8, 2001
• 18 "Increased intrahepatic messenger RNA expression of interleukins 2,6,and 8 in human cirrhosis" 107 : 789-98, 1994
• 19 "In situ CD14 expression in biliary atresia:comparison between early and late stages" 36 : 240-3, 2001
• 20 "Immunohistochemistry of the liver and biliary tree in extrahepatic biliary atresia" 36 : 1017-25, 2001
• 21 "Immaturity of the enterohepatic circulation in early life" 346-54, jpediatrgastroenterolnutr1983
• 22 "Identification of transforming growth factors actively transcribed during the progress of liver fibrosis in biliary atresia" 39 : 702-8, 2004
• 23 "Histological grading and staging of chronic hepatitis" 22 : 696-9, 1995
• 24 "High throughput analysis of differential gene expression" 30 (30): 286-96, 1998
• 25 "Hepatobiliary scanning in the diagnosis of biliary atresia" 7 (7): 110-3, 2001
• 26 "Hepatic overexpression of MHC class II antigens and macrophage-associated antigens(CD68)in patients with biliary atresia of poor prognosis" 32 : 590-3, 1997
• 27 "Genetic induction of proinflammatory immunity in children with biliary atresia" 360 : 1653-9, 2002
• 28 "Fundamentals of cDNA microarray data analysis" 19 : 649-59, 2003
• 29 "Extrahepatic biliary atresia:a disease or a phenotype" 35 : 1297-304, 2002
• 30 "Expression profiling using cDNA microarray" 21 : 10-4, 1999
• 31 "Expression of connective tissue growth factor in experimental rat and human liver fibrosis" 30 : 968-76, 1999
• 32 "Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts" 27 : 1475-82, 1998
• 33 "Detection of group C rotavirus in infants with extrahepatic biliary atresia" 174 : 8-15, 1996
• 34 "Cytomegalovirus and human herpesvirus 6,but not human papillomavirus,are present in neonatal giant cell hepatitis and extrahepatic biliary atresia" 3 : 367-73, 2000
• 35 "Coordinate expression of regulatory genes differentiates embryonic and perinatal forms of biliary atresia" 39 : 954-62, 2004
• 36 "Biliary atresia:pathogenesis and treatment" 18 : 281-93, 1998
• 37 "Biliary atresia:feasibility of mangafodipir trisodium-enhanced MR cholangiography for evaluation" 235 : 250-8, 2005
• 38 "Biliary atresia:current concepts and research directions" 23 : 1682-92, 1996
• 39 "Biliary atresia-surgical management and treatment options as they relate to outcome" 4 : 24-33, 1998
• 40 "Biliary atresia is associated with CD4 Th1 cell-mediated portal tract inflammation" 56 : 79-87, 2004
• 41 "Biliary atresia" 35 : 11-6, 2002
• 42 "Autoimmune hepatitis as a late complication of liver transplantation" 32 : 131-6, 2001
• 43 "Altered expression of genes involved in hepatic morphogenesis and fibrogenesis are identified by cDNA microarray analysis in biliary atresia" 38 : 567-76, 2003