Various genetic and environmental factors or their interactions may result in the failure of folic acid therapy for hyperhomocysteinemia (HHcy). We hypothesized that an optimal predictive model of gene-environment interactions could be constructed to predict the efficacy of folic acid therapy in HHcy. A prospective cohort study of 638 HHcy patients was performed. The patients were treated with oral folic acid (5 mg/d) for 90 days. We used conditional inference tree model to stratify the failure risk of folic acid therapy synthesizing information from a weighted genetic risk score (wGRS) and environmental exposures, simultaneously interpreting the gene-environment interaction network in predicting the efficacy of HHcy. We detected high-order interactions between medical history of stroke, coronary heart disease (CHD), wGRS, and baseline total homocysteine (tHcy) on the failure risk of folic acid therapy. The wGRS in fourth quartile had 3.73-fold increased failure risk of folic acid treatment (odds ratio = 3.73, 95% confidence interval: 1.47-9.45). Stroke was identified as the key discriminator among the variables examined. A total of 3.3% of participants in failure group were at the lowest failure risk of folic acid therapy (nonstroke, non-CHD, baseline tHcy ≤ 31.1 μmol/L, wGRS ≤ 1.05). Individuals with stroke but with wGRS > 1.05 were at the highest failure risk of folic acid therapy (91.0% of participants in failure group). Medical history of stroke, CHD, wGRS, and baseline tHcy were consistently identified as significant risk factors for the failure risk of folic acid therapy. The multiple interactions between genetic and environmental factors can be visually presented via the conditional inference tree model.

中文翻译：

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基于预测模型识别基因-环境相互作用对叶酸治疗高同型半胱氨酸血症疗效的影响

各种遗传和环境因素或其相互作用可能导致叶酸治疗高同型半胱氨酸血症 (HHcy) 失败。我们假设可以构建基因-环境相互作用的最佳预测模型来预测叶酸治疗对 HHcy 的疗效。对 638 名 HHcy 患者进行了前瞻性队列研究。患者口服叶酸（5 毫克/天）治疗 90 天。我们使用条件推理树模型对叶酸治疗的失败风险进行分层，综合来自加权遗传风险评分 (wGRS) 和环境暴露的信息，同时解释基因-环境相互作用网络以预测 HHcy 的功效。我们检测到中风病史、冠心病 (CHD)、wGRS、和基线总同型半胱氨酸 (tHcy) 对叶酸治疗失败风险的影响。第四四分位数的 wGRS 使叶酸治疗失败的风险增加了 3.73 倍（优势比 = 3.73，95% 置信区间：1.47-9.45）。中风被确定为检查的变量中的关键鉴别器。失败组共有 3.3% 的参与者处于叶酸治疗失败风险最低（非卒中、非 CHD、基线 tHcy ≤ 31.1 μmol/L、wGRS ≤ 1.05）。中风但 wGRS > 1.05 的个体叶酸治疗失败的风险最高（失败组参与者的 91.0%）。中风病史、冠心病、wGRS 和基线 tHcy 一直被认为是叶酸治疗失败风险的重要危险因素。