An intronic single nucleotide polymorphism in the MUTYH gene is associated with increased risk for HCV-induced hepatocellular carcinoma
An intronic single nucleotide polymorphism in the MUTYH gene is associated with increased risk for HCV-induced hepatocellular carcinoma
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DOI：
10.1016/j.freeradbiomed.2018.09.010
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发表时间：
2018-12-01
影响因子：
7.4
通讯作者：
Kato, Junji
中科院分区：
文献类型：
--
作者：
Sakurada, Akira;Miyanishi, Koji;Kato, Junji
背景与目的：碱基切除修复基因在人类肝癌发生中的作用尚未被研究。在这里，我们调查这些基因的变异和发展的肝细胞癌（HCC）的风险之间的关系。方法：在碱基切除修复基因（包括MUTYH，OGG 1和MTH 1）的19个标签SNP的基因分型使用iPLEX检测;一个显着的SNP被发现并确认在日本慢性丙型肝炎（CHC）患者（n=38 HCC和55对照）。通过荧光素酶测定确定修饰内含子变体的效果。用MUTYH基因敲除小鼠检测氧化应激和DNA修复酶在肝癌发生中的作用。结果：MUTYH基因中的一个内含子SNP（rs3219487）与肝癌发生有显著相关性。A/A和G/A基因型患者发生肝癌的风险高于G/G基因型患者（OR = 9.27，95% CI = 2.39-32.1，P = 0.0005）。两种外周血单个核细胞中的MUTYH mRNA水平在G/A或A/A基因分型的受试者中均显著较低（分别为P = 0.0157和0.0108）。我们发现MUTYH启动子区域中的-2000通过插入rs3219487的主要等位基因序列参与MUTYH的增强表达。在MUTYH基因敲除小鼠中观察到肝脏肿瘤12个月的高铁饮食后，但没有肿瘤的发展时，饮食抗氧化剂（N-乙酰-L-半胱氨酸）也provided.Conclusions：CHC患者与rs3219487腺嘌呤等位基因有显着增加的风险发展为肝癌。铁相关氧化应激的MUTYH缺失小鼠易发生肝肿瘤，除非通过饮食抗氧化剂预防。
Background & aims: The role of base excision repair genes in human hepatocarcinogenesis has not yet been explored. Here, we investigated relationships between variants of these genes and the risk of developing hepatocellular carcinoma (HCC).Methods: Nineteen tagging SNPs in base excision repair genes (including MUTYH, OGG1 and MTH1) were genotyped using iPLEX assays; one significant SNP was found and confirmed in Japanese patients with chronic hepatitis C (CHC) (n=38 HCC and 55 controls). The effects of modifying the intronic variants were determined by luciferase assays. MUTYH-null mice were used to examine the involvement of oxidative stress and DNA repair enzymes in hepatocarcinogenesis.Results: Significant associations were found for a single intron SNP (rs3219487) in the MUTYH gene. The risk of developing HCC in patients with A/A or G/A genotypes was higher than in those with the G/G genotype (OR = 9.27, 95% CI = 2.39-32.1, P = 0.0005). MUTYH mRNA levels in both peripheral mononuclear cells were significantly lower in G/A or A/A genotyped subjects (P = 0.0157 and 0.0108, respectively). We found that -2000 in the MUTYH promoter region is involved in enhanced expression of MUTYH by insertion of a major allele sequence of rs3219487. Liver tumors were observed in MUTYH-null mice after 12 months' high iron diet, but no tumors developed when dietary anti-oxidant (N-Acetyl-L-cysteine) was also provided.Conclusions: CHC patients with the rs3219487 adenine allele had a significantly increased risk of developing HCC. MUTYH-null mice with iron-associated oxidative stress were susceptible to development of liver tumors unless prevented by dietary anti-oxidants.