Xu Wei, Cheng Yuelei, Zhu Huirong
From the Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Medicine (Baltimore). 2016 May;95(20):e3700. doi: 10.1097/MD.0000000000003700.
High blood homocysteine levels may risk gastric cancer. However, observational studies have been plagued by chance, bias, confounding, or reverse causality. In this study, we assessed the relationship between blood homocysteine levels and gastric cancer by using a Mendelian randomization method, which is independent of nongenetic confounding.We took 2 steps to perform Mendelian randomization analysis. First, we evaluated the methylenetetrahydrofolate reductase (MTHFR) C677T association with gastric cancer by a meta-analysis of case-control studies including 7566 patients with gastric cancer and 10 640 control subjects from 27 Case-Control studies. Second, MTHFR C677T polymorphism, which affects the blood homocysteine levels, was used as an instrumental variable to calculate the risk and estimate the association of gastric cancer with this single nucleotide polymorphism (SNP). We obtained an estimate to the association of blood total homocysteine levels with this SNP from a meta-analysis of Genome-Wide Association Studies (GWAS), which comprises a total of 44 147 individuals.In our Mendelian randomization analysis, we demonstrated a significant effect of the blood homocysteine levels on gastric cancer risk, representing an OR of 2.56 (95% CI = 2.41-2.72; P = 5.0×10) for gastric cancer per 1-SD increase in the natural log-transformed blood total homocysteine levels.We proved that there is a causal relationship between blood total homocysteine and risk of gastric cancer, and this study will add insight into the treatment and pathology research of gastric cancer.
血液中高同型半胱氨酸水平可能会增加患胃癌的风险。然而，观察性研究一直受到偶然性、偏倚、混杂因素或反向因果关系的困扰。在本研究中，我们使用孟德尔随机化方法评估了血液同型半胱氨酸水平与胃癌之间的关系，该方法独立于非遗传混杂因素。我们采取了两个步骤来进行孟德尔随机化分析。首先，我们通过对27项病例对照研究中的7566例胃癌患者和10640例对照受试者进行病例对照研究的荟萃分析，评估了亚甲基四氢叶酸还原酶（MTHFR）C677T与胃癌的关联。其次，将影响血液同型半胱氨酸水平的MTHFR C677T多态性用作工具变量，以计算风险并估计胃癌与这种单核苷酸多态性（SNP）的关联。我们从一项涵盖总共44147人的全基因组关联研究（GWAS）荟萃分析中获得了血液总同型半胱氨酸水平与该SNP关联的估计值。在我们的孟德尔随机化分析中，我们证明了血液同型半胱氨酸水平对胃癌风险有显著影响，自然对数转换后的血液总同型半胱氨酸水平每增加1个标准差，胃癌的比值比为2.56（95%CI = 2.41 - 2.72；P = 5.0×10）。我们证明了血液总同型半胱氨酸与胃癌风险之间存在因果关系，这项研究将为胃癌的治疗和病理学研究提供新的见解。
