The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China; Clinical Medical School, Jilin University, Changchun, Jilin 130021, China.
The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China; Department of Pathology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China.
Epilepsy Res. 2019 Aug;154:139-143. doi: 10.1016/j.eplepsyres.2019.05.010. Epub 2019 May 20.
Valproic acid (VPA) is frequently used in the treatment of epilepsy. The adverse effects of VPA include hyperammonemia (HA) which is characterized by abnormally elevated blood ammonia level. Carbamoyl-Phosphate Synthase 1 (CPS1) is an enzyme catalyzing the initial step of removing ammonia from blood. Studies have demonstrated that the CPS1 polymorphism rs1047891-A allele carriers were susceptible to VPA-induced HA. However, the evidences remained controversial. In this study, we sought to validate the association between rs1047891 and VPA-induced HA by combining the association results from previous studies together.
We first conducted a systematic meta-analysis to determine whether rs1047891 was statistically significant. Then, we further evaluated the pleiotropic effects of rs1047891 using published genome-wide association studies (GWAS) and UKBB results. A conditional analysis was conducted to investigate whether the association between rs1047891 and VPA-induced HA was mediated by cardiovascular or renal disease risk factors or vice versa.
The allelic, dominant and recessive ORs of rs1047891-A were all significant in our fixed-effect meta-analysis. In GWAS catalog and UKBB data, rs1047891 was associated with basal metabolic rate, adiposity and hematology traits, cardiovascular and renal disease risk factors. We further proved that plasma HDL cholesterol and homocysteine level, in addition to eGFR by serum creatinine, were associated with VPA-induced HA risk independently from rs1047891 polymorphism.
In conclusion, the SNP rs1047891 was associated with VPA-induce HA among epilepsy patients. Meanwhile, plasma HDL cholesterol and homocysteine level had independent effects from it.
丙戊酸（VPA）常用于治疗癫痫。VPA 的不良反应包括高氨血症（HA），其特征为血液中氨水平异常升高。氨基甲酰磷酸合成酶 1（CPS1）是一种酶，可催化从血液中去除氨的初始步骤。研究表明，CPS1 多态性 rs1047891-A 等位基因携带者易发生 VPA 诱导的 HA。然而，证据仍然存在争议。在这项研究中，我们通过结合以前研究的关联结果，试图通过系统的荟萃分析来验证 rs1047891 与 VPA 诱导的 HA 之间的关联。
我们首先进行了系统的荟萃分析，以确定 rs1047891 是否具有统计学意义。然后，我们使用已发表的全基因组关联研究（GWAS）和 UKBB 结果进一步评估了 rs1047891 的多效性效应。进行条件分析以调查 rs1047891 与 VPA 诱导的 HA 之间的关联是否受心血管或肾脏疾病风险因素的介导或反之亦然。
我们的固定效应荟萃分析中，rs1047891 的等位基因、显性和隐性 OR 均具有统计学意义。在 GWAS 目录和 UKBB 数据中，rs1047891 与基础代谢率、肥胖和血液学特征、心血管和肾脏疾病风险因素相关。我们进一步证明，除了血清肌酐外，血浆高密度脂蛋白胆固醇和同型半胱氨酸水平以及 eGFR 与 VPA 诱导的 HA 风险独立相关，与 rs1047891 多态性无关。
总之，SNP rs1047891 与癫痫患者的 VPA 诱导 HA 相关。同时，血浆高密度脂蛋白胆固醇和同型半胱氨酸水平对其具有独立作用。
