Choi Chang Kyun, Kweon Sun-Seog, Lee Young-Hoon, Nam Hae-Sung, Choi Seong-Woo, Kim Hye-Yeon, Shin Min-Ho
Division of Cancer Registration and Surveillance, National Cancer Control Institute, National Cancer Center, Goyang, Korea.
Department of Preventive Medicine, Chonnam National University Medical School, Hwasun, Korea.
Korean Circ J. 2023 Oct;53(10):710-719. doi: 10.4070/kcj.2023.0089. Epub 2023 Jul 21.
In previous studies, high homocysteine levels were associated with high cardiovascular mortality. However, these results were inconsistent with those of randomized controlled trials. We aimed to evaluate the causal role of homocysteine on all-cause and cardiovascular mortality using Mendelian randomization (MR) analysis.
This study included the 10,005 participants in the Namwon Study. In conventional observational analysis, age, sex, survey years, lifestyles, body mass index, comorbidities, and serum folate level were adjusted using multivariate Cox proportional regression. MR using 2-stage least squares regression was used to evaluate the association between genetically predicted plasma homocysteine levels and mortality. Age, sex, and survey years were adjusted for each stage. The methylenetetrahydrofolate reductase (MTHFR) polymorphism was used as an instrumental variable for predicting plasma homocysteine levels.
Observed homocysteine levels were positively associated with all-cause (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.26-1.54) and cardiovascular (HR, 1.62; 95% CI, 1.28-2.06) mortality when plasma homocysteine levels doubled. However, these associations were not significant in MR analysis. The HRs of doubling genetically predicted plasma homocysteine levels for all-cause and cardiovascular mortality were 0.99 (95% CI, 0.62-1.57) and 1.76 (95% CI, 0.54-5.77), respectively.
This MR analysis did not support a causal role for elevated plasma homocysteine concentrations in premature deaths.
在以往的研究中，高同型半胱氨酸水平与高心血管死亡率相关。然而，这些结果与随机对照试验的结果不一致。我们旨在使用孟德尔随机化（MR）分析评估同型半胱氨酸对全因死亡率和心血管死亡率的因果作用。
本研究纳入了南原研究中的10005名参与者。在传统的观察性分析中，使用多变量Cox比例回归对年龄、性别、调查年份、生活方式、体重指数、合并症和血清叶酸水平进行了调整。使用两阶段最小二乘回归的MR分析来评估基因预测的血浆同型半胱氨酸水平与死亡率之间的关联。每个阶段都对年龄、性别和调查年份进行了调整。亚甲基四氢叶酸还原酶（MTHFR）多态性被用作预测血浆同型半胱氨酸水平的工具变量。
当血浆同型半胱氨酸水平翻倍时，观察到的同型半胱氨酸水平与全因死亡率（风险比[HR]，1.40；95%置信区间[CI]，1.26 - 1.54）和心血管死亡率（HR，1.62；95%CI，1.28 - 2.06）呈正相关。然而，这些关联在MR分析中并不显著。基因预测的血浆同型半胱氨酸水平翻倍对全因死亡率和心血管死亡率的HR分别为0.99（95%CI，0.62 - 1.57）和1.76（95%CI，0.54 - 5.77）。
这项MR分析不支持血浆同型半胱氨酸浓度升高在过早死亡中起因果作用。
