Genetic Mapping of Hepatocelular Carcinoma Susceptibility Locus in the Chromosome 5q22-34 Candidate Region: Linkage Analysis and Family-based Association Study
Date Issued
2004
Date
2004
Author(s)
Chen, Chia-Pei
DOI
zh-TW
Abstract
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.
Subjects
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
SDGs
Type
thesis
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