Shih W-L, Yu M-W, Chen P-J, Yeh S-H, Lo M-T, Chang H-C, Liaw Y-F, Lin S-M, Liu C-J, Lee S-D, Lin C-L, Hsiao C K, Yang S-Y, Chen C-J
Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan.
Oncogene. 2006 May 25;25(22):3219-24. doi: 10.1038/sj.onc.1209345.
Chromosome 4q is one of the most common regions with a high frequency of allelic loss in hepatocellular carcinoma (HCC). To identify the HCC-susceptibility locus on chromosome 4q, we have performed linkage and family-based association analyses on Chinese families with HCC from Taiwan, where hepatitis B is hyperendemic. Using 77 microsatellite markers spanning chromosome 4q on 52 multiplex families, we found suggestive evidence of linkage to 4q22.3-28.1 with a maximum two-point heterogeneity LOD (HLOD) score of 2.55 at marker D4S3240 on chromosome 4q25. Multipoint analyses with microsatellite markers in the region 4q22.3-28.1 resulted in a maximum HLOD score of 3.12 and a maximum nonparametric linkage (NPL) Z score of 1.98 (pointwise P=0.0080; region-wide empirical P=0.021) for D4S3240. The evidence for linkage to D4S3240 was seen mostly in a subset of 28 families lacking affected parents, which showed multipoint HLOD and NPL scores of 3.25 and 2.79 (pointwise P=0.0028; region-wide empirical P=0.008), respectively. Family-based association analyses of the 77 microsatellite markers in 191 families (53 multiplex plus 138 singleton families) using the pedigree disequilibrium test provide further support for observed linkage. Additional genotyping in the 52 multiplex families informative for linkage analyses was performed for 29 single-nucleotide polymorphisms around D4S3240. A common haplotype (at markers rs7442180 and rs221330) positioned approximately 873 kb away from D4S3240 was associated with HCC, with P=0.0074.
4号染色体长臂是肝细胞癌（HCC）中等位基因缺失高频出现的最常见区域之一。为了确定4号染色体长臂上的HCC易感基因座，我们对来自台湾的HCC中国家系进行了连锁分析和基于家系的关联分析，台湾是乙肝高度流行地区。我们使用跨越4号染色体长臂的77个微卫星标记对52个多位点家系进行分析，发现在4q22.3 - 28.1区域存在连锁的提示性证据，在4号染色体长臂25区的标记D4S3240处，最大两点异质性LOD（HLOD）分数为2.55。对4q22.3 - 28.1区域的微卫星标记进行多点分析，结果显示D4S3240的最大HLOD分数为3.12，最大非参数连锁（NPL）Z分数为1.98（逐点P = 0.0080；全区域经验P = 0.021）。与D4S3240连锁的证据主要出现在28个没有患病父母的家系子集中，这些家系的多点HLOD和NPL分数分别为3.25和2.79（逐点P = 0.0028；全区域经验P = 0.008）。使用家系不平衡检验对191个家系（53个多位点家系加138个单人家系）中的77个微卫星标记进行基于家系的关联分析，为观察到的连锁提供了进一步支持。对52个可用于连锁分析的多位点家系进行了额外的基因分型，检测了D4S3240周围的29个单核苷酸多态性。一个位于距D4S3240约873 kb处的常见单倍型（标记为rs7442180和rs221330）与HCC相关，P = 0.0074。
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