亚甲基四氢叶酸还原酶基因C677T多态性预测中国高血压人群新发恶性肿瘤风险

Cancer has become one of the leading causes of death among Chinese adults. Hypertension often co-exists among cancer patients, but it is unknown if hypertension and cancer are causally linked and whether they share a common risk factor. Methylenetetrahydrofolate reductase (MTHFR) is the main regulatory enzyme for folate metabolism, and MTHFR gene C677T homozygous mutation is a known risk factor for hypertension. Previous studies also showed a significant association between MTHFR 677 TT genotype and the risk of various types of cancer. Furthermore, some previous study has raised the concern that folic acid supplementation may increase the risk of cancer. Our previous study in Chinese hypertensive adults showed that MTHFR gene C677T homozygous mutation is very common (about 20% versus 10%) and is an important risk factor of hypertension. To date, there is a particular lack of large prospective Chinese cohort studies to determine if MTHFR 677 TT genotype can predict incident cancer among hypertensive patients and whether folic acid supplementation can enhance or attenuate the risk of cancer according to MTHFR C677T genotypes. .This proposal will leverage our two well-established, prospective, Chinese hypertensive adults cohorts (N=29,130) drawn from different geographic regions. In a community-based prospective cohort (n=8,428), we will investigate if MTHFR C677T polymorphism can predict the development of cancer. In a randomized, double-blind, controlled trial of folic acid supplementation for primary prevention of stroke (n=20,702), we will examine the effect of folic acid supplementation on the development of cancer, and further test gene-folic acid interaction, that is, whether MTHFR C677T polymorphism modifies the effect of folic acid supplementation on incident cancer. Findings from this project will lay an important foundation for developing evidence-based, cost-effective strategies for the prediction and prevention of new onset cancer in Chinese hypertensive populations. .

高血压和恶性肿瘤均属老年人群的高发慢性病，但两种疾病之间的相互关系鲜有研究。项目前期研究工作发现，中国高血压人群叶酸代谢关键酶-亚甲基四氢叶酸还原酶(MTHFR)基因的677TT基因型比例远高于西方人群。以往研究表明，MTHFR基因 677TT基因型与肿瘤患病密切相关。本项目旨在证实下列假设：MTHFR基因C677T多态性能够预测高血压人群新发恶性肿瘤的风险。项目主要研究内容：（1）对已建立的大样本(n=8428) 高血压社区自然人群队列进行长程随访，研究MTHFR基因 C677T多态性对该队列新发恶性肿瘤风险的预测效果；（2）通过已建立的大样本(n=20,702)、长程随访（平均4.5年）、随机对照补充叶酸的高血压干预人群队列，确定MTHFR基因 C677T不同基因型（CC、CT、TT）人群补充叶酸对新发恶性肿瘤风险的影响。从而为高血压人群恶性肿瘤发病风险的预警和早期干预提供新策略。

背景：亚甲基四氢叶酸还原酶(MTHFR)是叶酸代谢过程中的关键酶，MTHFR基因最常见多态性为677位核苷酸C→T置换(C677T)，使酶活性下降60%，导致叶酸水平下降和Hcy水平升高。我国高血压人群MTHFR 677 TT基因型、叶酸缺乏的比例明显高于西方人群。然而，既往研究结果提示MTHFR C677T基因多态性与恶性肿瘤的关联性存在不一致性；这些研究产生差异除了与不同人群的遗传背景有差异外，还与人群叶酸缺乏的比例有关。本项目旨在证实下列假设：MTHFR基因C677T多态性能够预测高血压人群新发恶性肿瘤的风险。.主要研究内容：探讨MTHFR基因 C677T多态性对该队列新发恶性肿瘤风险的预测效果，确定MTHFR基因C677T不同基因型（CC、CT、TT）人群补充叶酸对新发恶性肿瘤风险的影响。.重要结果和关键数据：本项目研究人群源于CSPPT。CSPPT研究共入组20,702例无脑卒中和心肌梗死病史的成人高血压受试者，根据MTHFR C677T 基因型进行分层后，随机、双盲每日服用内含10毫克依那普利和0.8毫克叶酸的单片复方制剂--依那普利叶酸片（n=10348），或者单纯10毫克的依那普利片（n=10354）。平均随访干预周期为4.5年。结果表明：（1）在单纯使用依那普利治疗组，与MTHFR 677 CC基因型比较，TT基因型人群恶性肿瘤风险显著增加；补充叶酸总体不会增加肿瘤风险，在TT基因型伴低叶酸水平的受试者中观察到补充叶酸显著降低新发恶性肿瘤的风险。主要结果发表于国际肿瘤学杂志。（2）对补充叶酸对脑卒中、慢性肾脏病及高尿酸血症等终点的作用进行一系列分析，结果表明补充叶酸显著降低我国高血压人群21%首发脑卒中风险，降低31%胆固醇水平升高导致的卒中风险；降低基线合并糖尿病患者52%新发蛋白尿风险；降低尿酸水平。主要结果发表于JAMA、Stroke、Neurology、Hypertension等杂志。 .科学意义：本项目通过精准的试验设计和结果解析，对长期以来西方国家在叶酸预防脑卒中、与恶性肿瘤相关的安全性争议给出了确切答案；本项目研究结果在我国的有效推广对我国脑卒中、慢性肾脏病及恶性肿瘤的防治具有重要的临床与公共卫生学价值。