Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China.
Cancer Epidemiol Biomarkers Prev. 2020 Feb;29(2):487-492. doi: 10.1158/1055-9965.EPI-19-0724. Epub 2019 Nov 20.
The association of plasma homocysteine level (PHL) with gastric cancer risk was reported in observational studies. However, the causality is challenging due to confounding factors and the lack of evidence from well-designed cohort studies. Herein, we performed a two-sample Mendelian randomization (MR) analysis to investigate whether PHL is causally related to gastric cancer risk.
We performed the MR analysis based on the results from genome-wide association studies consisting of 2,631 patients with gastric cancer and 4,373 controls. An externally weighted genetic risk score (wGRS) was constructed with 15 SNPs with well-established associations with PHL. We utilized logistic regression model to estimate associations of PHL-related SNPs and wGRS with gastric cancer risk in total population and in strata by sex, age, and study site, in addition to a series of sensitivity analyses.
High genetically predicted PHL was associated with an increased gastric cancer risk (per SD increase in the wGRS: OR = 1.07; 95% confidence interval, 1.01-1.12; = 0.011), which was consistent in sensitivity analyses. Subgroup analyses provided evidence of a stronger association with gastric cancer risk in women than in men. MR-Egger and weighted median regression suggested that potentially unknown pleiotropic effects were not biasing the association between PHL and gastric cancer risk.
These results revealed that genetically predicted high PHL was associated with an increased gastric cancer risk, suggesting that high PHL may have a causal role in the etiology of gastric cancer.
These findings provide causal inference for PHL on gastric cancer risk, suggesting a causal role of high PHL in the etiology of gastric cancer.
观察性研究报道了血浆同型半胱氨酸水平（PHL）与胃癌风险之间的关联。然而，由于混杂因素和缺乏来自精心设计的队列研究的证据，因果关系具有挑战性。在此，我们进行了两样本孟德尔随机化（MR）分析，以研究 PHL 是否与胃癌风险存在因果关系。
我们基于包含 2631 例胃癌患者和 4373 例对照的全基因组关联研究结果进行了 MR 分析。使用与 PHL 具有明确关联的 15 个 SNP 构建了加权遗传风险评分（wGRS）。我们利用逻辑回归模型，在总人群以及按性别、年龄和研究地点分层的人群中，估计与 PHL 相关的 SNP 和 wGRS 与胃癌风险之间的关联，此外还进行了一系列敏感性分析。
高遗传预测 PHL 与胃癌风险增加相关（wGRS 每增加一个标准差：OR=1.07；95%置信区间，1.01-1.12； =0.011），敏感性分析结果一致。亚组分析提供了证据表明，女性与男性相比，与胃癌风险的关联更强。MR-Egger 和加权中位数回归表明，潜在的未知的混杂效应不会影响 PHL 与胃癌风险之间的关联。
这些结果表明，遗传预测的高 PHL 与胃癌风险增加相关，提示高 PHL 可能在胃癌的发病机制中起因果作用。
这些发现为 PHL 对胃癌风险的因果关系提供了证据，提示高 PHL 在胃癌的发病机制中起因果作用。
