本文關鍵詞：維生素B12代謝基因多態(tài)與胃癌的相關性研究　出處：《蘭州大學》2017年博士論文　論文類型：學位論文

  更多相關文章： 維生素B12 胃癌 單核苷酸多態(tài)性 鈷胺轉運蛋白1 肘臀蛋白

【摘要】：背景和目的胃癌是全世界范圍內癌癥死亡的最主要原因之一。越來越多的研究表明維生素B12的代謝穩(wěn)態(tài)在胃癌的整個發(fā)生發(fā)展過程中起著非常重要的作用。探討影響維生素B12代謝的遺傳變異與胃癌發(fā)生風險的相關性,不僅有助于揭示胃癌發(fā)生機制,也對早期風險預測和預后有著重要意義。近年來全基因組關聯分析技術在全基因組范圍內發(fā)現多個與人類維生素B12水平顯著相關的遺傳多態(tài)位點,據此我們提出假設:顯著影響人體維生素B12的遺傳多態(tài)位點可能參與了胃癌的發(fā)生發(fā)展。在本論文中,我們將深入研究在中國漢族人群中維生素B12代謝相關基因的遺傳多態(tài)與胃癌的相關性。方法和結果我們從全基因組關聯分析數據中選擇了與維生素B12濃度相關性最高的8個遺傳多態(tài)位點,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。病例對照的關聯研究包括492例胃癌患者,與550例年齡性別匹配的非癌癥對照。在單位點關聯分析中,我們發(fā)現TCN1的遺傳多塔rs526943與胃癌的發(fā)生顯著相關,與野生型A等位基因、野生型純合子AA基因型比較,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)可顯著增加胃癌的患病風險。在單倍型分析中,我們發(fā)現不同的CUBN單倍型與胃癌的患病風險密切相關。通過分別與野生型rs1801222C/rs11254363A單倍型比較,結果顯示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 單倍型會明顯提高胃癌的患病風險,而rs1801222T/rs11254363G(0R=0.43, 95%CI=0. 25-0. 37,p=0. 002)所表現出的是保護作用,即此種單倍型基因型可降低胃癌患病風險。結論影響維生素B12在人體循環(huán)中濃度的相關基因的變異體與胃癌患病風險休戚相關。這個研究為我們揭示了參與維生素B12代謝的基因在胃癌致病作用中起到了很重要的作用,與此同時更進一步揭示了飲食、遺傳學與人類腫瘤三者之間相互作用和影響的關系。
[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.
【學位授予單位】：蘭州大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R735.2

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