Ren Bingnan, Tian Dandan, Wang Lianke, Han Han, Wang Wenhua, Tian Huizi, Yue Limin, Zhang Weidong
Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou, Henan, China.
People's Hospital of Henan Province, Zhengzhou, Henan, China.
Ann Hum Genet. 2019 Nov;83(6):434-444. doi: 10.1111/ahg.12326. Epub 2019 May 20.
Oral folate is currently the most common treatment for hyperhomocysteinemia (HHcy), which seriously threatens human health, but its efficacy is unsatisfactory. Betaine-homocysteine methyltransferase (BHMT) is a key enzyme that regulates Hcy metabolism. We investigated the association between the BHMT rs3733890 and the efficacy of oral folate therapy for HHcy in the Chinese Han population and analysed the effects of gene-environmental interactions on the efficacy. Blood samples were collected from 1071 eligible patients at baseline, and these individuals received subsequent folate treatment for 90 days. A total of 638 patients included in the final analysis were grouped into the treatment success group or the treatment failure group based on posttreatment Hcy levels. Hcy concentrations were measured by fluorescence polarization immunoassay. Time-of-flight mass spectrometry (MassArray system) was used to assess the genotype of BHMT rs3733890. Stratified analyses based on additive models and generalized multifactor dimensionality reduction were used to explore gene-environmental interactions. The genotype distribution presented distinct differences in the two groups. The mutant genotype and allele had significantly increased risk of treatment failure (p < 0.05). Furthermore, synergistic effects of the BHMT rs3733890 polymorphism with environmental risk factors (smoking, drinking, past history) on the efficacy of therapy were also found. However, future, large well-designed studies, as well as mechanistic studies, are still needed to validate our findings.
口服叶酸是目前治疗高同型半胱氨酸血症（HHcy）最常用的方法，HHcy严重威胁人类健康，但其疗效并不理想。甜菜碱-同型半胱氨酸甲基转移酶（BHMT）是调节同型半胱氨酸（Hcy）代谢的关键酶。我们研究了中国汉族人群中BHMT rs3733890与口服叶酸治疗HHcy疗效之间的关联，并分析了基因-环境相互作用对疗效的影响。在基线时从1071名符合条件的患者中采集血样，这些个体随后接受了90天的叶酸治疗。根据治疗后Hcy水平，将最终分析中纳入的638名患者分为治疗成功组或治疗失败组。采用荧光偏振免疫分析法测定Hcy浓度。采用飞行时间质谱法（MassArray系统）评估BHMT rs3733890的基因型。基于加性模型和广义多因素降维的分层分析用于探索基因-环境相互作用。两组的基因型分布存在明显差异。突变基因型和等位基因显著增加了治疗失败的风险（p<0.05）。此外，还发现BHMT rs3733890多态性与环境危险因素（吸烟、饮酒、既往史）对治疗疗效具有协同作用。然而，仍需要未来大规模精心设计的研究以及机制研究来验证我们的发现。
