维生素B12代谢基因多态与胃癌的相关性研究

发布时间：2017-12-27 22:30

本文关键词：维生素B12代谢基因多态与胃癌的相关性研究　出处：《兰州大学》2017年博士论文　论文类型：学位论文

【摘要】：背景和目的胃癌是全世界范围内癌症死亡的最主要原因之一。越来越多的研究表明维生素B12的代谢稳态在胃癌的整个发生发展过程中起着非常重要的作用。探讨影响维生素B12代谢的遗传变异与胃癌发生风险的相关性,不仅有助于揭示胃癌发生机制,也对早期风险预测和预后有着重要意义。近年来全基因组关联分析技术在全基因组范围内发现多个与人类维生素B12水平显著相关的遗传多态位点,据此我们提出假设:显著影响人体维生素B12的遗传多态位点可能参与了胃癌的发生发展。在本论文中,我们将深入研究在中国汉族人群中维生素B12代谢相关基因的遗传多态与胃癌的相关性。方法和结果我们从全基因组关联分析数据中选择了与维生素B12浓度相关性最高的8个遗传多态位点,包括位于Fucosyltransferase 2 (FUT2)基因的rs602662、rs601338 和 rs492602,Cubilin (CUBN)基因的 rs1801222 和 rs11254363,Methylmalonyl-CoA mutase ( MUT) 基因的 rs9473558和rs9473555 ,Transcobalamin I (TCN1)基因的rs526934。病例对照的关联研究包括492例胃癌患者,与550例年龄性别匹配的非癌症对照。在单位点关联分析中,我们发现TCN1的遗传多塔rs526943与胃癌的发生显著相关,与野生型A等位基因、野生型纯合子AA基因型比较,TCN1G等位基因(OR=1.25, 95% CI = 1.03-1.52,p = 0.031)和 GG 基因型(OR=2.06,95% CI=1.24-3.42,p=0.0043)可显著增加胃癌的患病风险。在单倍型分析中,我们发现不同的CUBN单倍型与胃癌的患病风险密切相关。通过分别与野生型rs1801222C/rs11254363A单倍型比较,结果显示rs1801222T/rs11254363A(OR=1.40,95% CI=1.05-1.86,p=0.021)和 rs11801222C/rs11254363G (OR=4.39, 95% CI=2.32-8.30, p0.0001 单倍型会明显提高胃癌的患病风险,而rs1801222T/rs11254363G(0R=0.43, 95%CI=0. 25-0. 37,p=0. 002)所表现出的是保护作用,即此种单倍型基因型可降低胃癌患病风险。结论影响维生素B12在人体循环中浓度的相关基因的变异体与胃癌患病风险休戚相关。这个研究为我们揭示了参与维生素B12代谢的基因在胃癌致病作用中起到了很重要的作用,与此同时更进一步揭示了饮食、遗传学与人类肿瘤三者之间相互作用和影响的关系。
[Abstract]:Background and objective gastric cancer is one of the most important causes of cancer death worldwide. More and more studies have shown that the metabolic homeostasis of vitamin B12 plays a very important role in the development of gastric cancer. To explore the correlation between the genetic variation of vitamin B12 metabolism and the risk of gastric cancer is not only helpful for revealing the mechanism of gastric cancer, but also for early risk prediction and prognosis. In recent years, genome-wide association analysis found that genetic polymorphism was significantly associated with multiple levels of vitamin B12 in the human genome wide, we hypothesized that genetic polymorphisms significantly affect human vitamin B12 may participate in the occurrence and development of gastric cancer. In this paper, we will study the correlation between the genetic polymorphism of vitamin B12 metabolism related genes and gastric cancer in Chinese Han population. Methods and results we analyze data from genome-wide association selected 8 genetic polymorphism and the highest concentration of vitamin B12 correlation, including 2 in Fucosyltransferase (FUT2) gene rs602662, rs601338 and rs492602, Cubilin (CUBN) gene rs1801222 and rs11254363 Methylmalonyl-CoA mutase (MUT) gene rs9473558 and rs9473555, Transcobalamin I (TCN1) rs526934 gene. The case-control association study included 492 patients with gastric cancer and 550 non cancer controls matched by age and sex. In the analysis of unit correlation, we found a significant relationship between genetic multitower rs526943 and gastric cancer TCN1, compared with the wild-type A allele and wild-type homozygote AA genotype, TCN1G allele (OR=1.25 95%, CI = 1.03-1.52, P = 0.031) and GG (OR= 2.06,95% genotype CI=1.24-3.42, p=0.0043) can significantly increase the risk of gastric cancer. In haplotype analysis, we found that different CUBN haplotypes are closely related to the risk of gastric cancer. By comparing with the wild type rs1801222C/rs11254363A haplotype, the results showed that rs1801222T/rs11254363A (OR=1.40,95% CI=1.05-1.86 p=0.021) and rs11801222C/rs11254363G (OR=4.39, 95% CI=2.32-8.30, P0.0001 haplotypes will significantly increase the risk of stomach cancer and rs1801222T/rs11254363G (0R=0.43, 95%CI=0., 25-0. 37, p=0. 002) is shown by the protective effect, namely the haplotype genotype can reduce gastric cancer risk. Conclusion the related gene variants that affect the concentration of vitamin B12 in human circulation are closely related to the risk of gastric cancer. This research has revealed that the genes involved in vitamin B12 metabolism play an important role in the pathogenicity of gastric cancer. At the same time, we further reveal the relationship between diet, genetics and human tumor three interactions.
【学位授予单位】：兰州大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R735.2

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