CPS1 T1405N polymorphism, HDL cholesterol, homocysteine and renal function are risk factors of VPA induced hyperammonemia among epilepsy patients.

Lanlan Chen, Qiuxiang Tian, Miaoran Zhang, Deyu Chen, Xue Gao, Hongqun Yang, Haitao Li, Chengnan Li, Jianping Wen, Yulin Li, Xin Tian, Peng Chen

Journal: Epilepsy research 2020;154():139-143

PMID: 31151073

Full Text on Elsevier Science View on PubMed

Abstract

PURPOSE

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.

Address: 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.; Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China.; Clinical Medical School, Jilin University, Changchun, Jilin 130021, China.; Department of Pediatrics, The Second Hospital of Jilin University, Changchun, Jilin 130021, China. Electronic address: [email protected].; The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China; Department of Genetics, 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. Electronic address: [email protected].

DOI: 10.1016/j.eplepsyres.2019.05.010

Link outs

Free resources

Medical:

Miscellaneous:

https://assays.cancer.gov/CPTAC-802

Research Materials:

https://antibodies.cancer.gov/detail/CPTC-EGFR-8

Subscription / membership required

Full Text Sources:

MeSH Terms: Anticonvulsants, Carbamoyl-Phosphate Synthase (Ammonia), Case-Control Studies, Cholesterol, HDL, Epilepsy, Homocysteine, Humans, Hyperammonemia, Kidney, Polymorphism, Genetic, Risk Factors, Valproic Acid