https://scholars.lib.ntu.edu.tw/handle/123456789/112009
標題: | 染色體5q22-34區域之肝細胞癌易感受基因定位:連鎖和家族為基礎的相關性分析 Genetic Mapping of Hepatocelular Carcinoma Susceptibility Locus in the Chromosome 5q22-34 Candidate Region: Linkage Analysis and Family-based Association Study |
作者: | 陳嘉珮 Chen, Chia-Pei |
關鍵字: | 肝細胞癌;連鎖不平衡;細胞激素;B型肝炎;連鎖分析;linkage analysis;hepatocellular carcinoma;hepatitis B virus;linkage disequilibrium;cytokine | 公開日期: | 2004 | 摘要: | 背景:以往對肝癌組織的研究發現5q染色體常有LOH現象。慢性hepatic necroinflammatory disease是導致肝細胞癌(hepatocellular carcinoma;HCC)的重要致病機轉,目前已知5q22-34區域群聚許多細胞激素基因,可能在產生發炎和免疫調控上扮演重要角色。本研究同時進行連鎖分析和傳遞不平衡檢定(transmission/disequilibrium test;TDT),探尋是否在染色體5q22-34區域可能存在HCC易感受基因。 方法:共有71個多發病例家族和253個病例-雙親三元體。於染色體5q22-34間,選取11個microsatellite標記,標記間距為0.19-8.43 cM。我們對多發病例家族進行多點LOD score及無母數連鎖(nonparametric linkage;NPL)Z score分析,以single allele及multiallelic test進行TDT分析。利用permutation test進行100,000次模擬試驗計算empirical P值,並以Bonferroni’s程序進行多重比較校正。 結果:對全部家族,或以指標病例是否具酗酒習慣、HBV基因型進行分層分析,均未發現任何值得注意的連鎖或連鎖不平衡訊息。但依指標病例之HBV DNA濃度為106 copies/mL作切點分層,發現5q31.1區域的D5S2117在HBV DNA濃度≧106 copies/mL的家族,multiallele 檢定P值為0.00155,且220鹼基數之allele的empirical P=0.082。對於12個男性指標病例、無酗酒習慣且HBV DNA濃度≧106 copies/mL之多發病例家族的連鎖分析,發現最高LOD score=1.56064、NPL Z sore=1.45467(P value=0.059582),落在5q23.2區域的標記D5S471位置。 結論:5q23.2-31.1染色體區段綿亙7.96 cM可能含有HCC易感受基因,一旦被證實,此基因可能和高病毒複製活性所引起的HCC有關。未來需於此段染色體區域進行精密定位分析。 Background: Frequent loss-of-heterozygosity on chromosome 5q has been reported in hepatocellular carcinoma (HCC). Chronic phasic necroinflammation is an important mechanism responsible for hepatocarcinogenesis, and chromosomal region 5q22-34 contains cluster of cytokine genes that may mediate inflammation response. The aim of this study was to perform both linkage analysis and transmission/disequilibrium test (TDT) to explore whether there exist a HCC susceptibility gene on 5q22-34. We also assessed the possible HBV-gene interaction by using analyses stratified according to HBV genotype and DNA levels. Method: There were 71 HCC multiplex families and 253 case-parent triads. We genotyped a total of 11 microsatellite markers with intermarker distance 0.19~8.43 cM. Multipoint LOD score and multipoint nonparametric linkage (NPL) Z score were calculated for linkage analysis. TDT was performed with the use of single allelic and multiallelic tests. Empirical P values were calculated using the permutation test with 100,000 simulations. Bonferroni’s correction procedure was used to adjust for multiple testing. Results: We did not detect any notable linkage or linkage disequilibrium (LD) signal overall or in any subgroup analysis stratified by HBV genotype. In families each with a patient having HBV DNA levels of 106 copies/mL or greater (75 families); however, we detected a significant LD signal at marker D5S2117 within 5q31.1 (multiallelic test P=0.00155); the empirical P for the 220 base-pair allele was 0.082. Linkage analysis in 12 families with high viral replication activity(≧106 copies/mL) and no female or alcoholic patients also revealed a suggestive linkage signal at marker D5S471 within 5q23.2, giving the maximum multipoint LOD score and multipoint NPL Z score of 1.56064 and 1.45467 (P value=0.059582), respectively. Conclusion: 5q23.2-31.1 chromosomal region across 7.96 cM may contains a HCC-susceptibility locus. If confirmed, this locus may be specially associated with high HBV replication activity-related HCC. Further fine mapping studies with a larger number of families in this chromosomal region is needed. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/56195 | 其他識別: | zh-TW |
顯示於: | 流行病學與預防醫學研究所 |
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