Association of LEPR and ANKK1 Gene Polymorphisms with Weight Gain in Epilepsy Patients Receiving Valproic Acid.
BACKGROUND
Weight gain is the most frequent adverse effect of valproic acid (VPA) treatment, resulting in poor compliance and many endocrine disturbances. Similarities in the weight change of monozygotic twins receiving VPA strongly suggests that genetic factors are involved in this effect. However, few studies have been conducted to identify the relevant genetic polymorphisms. Additionally, the causal relationship between the VPA concentration and weight gain has been controversial. Thus, we investigated the effects of single nucleotide polymorphisms (SNPs) in several appetite stimulation and energy homeostasis genes and the steady state plasma concentrations (Css) of VPA on the occurrence of weight gain in patients.


METHODS
A total of 212 epilepsy patients receiving VPA were enrolled. Nineteen SNPs in 11 genes were detected using the Sequenom MassArray iPlex platform, and VPA Css was determined by high-performance liquid chromatography (HPLC).


RESULTS
After 6 months of treatment, 20.28% of patients were found to gain a significant amount of weight (weight gained ≥7%). Three SNPs in the leptin receptor (LEPR), ankyrin repeat kinase domain containing 1 (ANKK1), and α catalytic subunit of adenosine monophosphate-activated protein kinase (AMPK) showed significant associations with VPA-induced weight gain (p < 0.001, p = 0.017 and p = 0.020, respectively). After Bonferroni correction for multiple tests, the genotypic association of LEPR rs1137101, the allelic association of LEPR rs1137101, and ANKK1 rs1800497 with weight gain remained significant. However, the VPA Css in patents who gained weight were not significantly different from those who did not gain weight (p = 0.121).


CONCLUSIONS
LEPR and ANKK1 genetic polymorphisms may have value in predicting VPA-induced weight gain.
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (Drs H Li, Wang, Y Zhou; Zhuojia Chen, J Li, X Chen, Hou, Xin, and Huang); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Drs Ni, Ziyi Chen, and L Zhou); Guangdong Pharmaceutical University, Guangzhou, China (Dr Su); Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Xie).
Hongliang
H
Li
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (Drs H Li, Wang, Y Zhou; Zhuojia Chen, J Li, X Chen, Hou, Xin, and Huang); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Drs Ni, Ziyi Chen, and L Zhou); Guangdong Pharmaceutical University, Guangzhou, China (Dr Su); Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Xie).
Xueding
X
Wang
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (Drs H Li, Wang, Y Zhou; Zhuojia Chen, J Li, X Chen, Hou, Xin, and Huang); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Drs Ni, Ziyi Chen, and L Zhou); Guangdong Pharmaceutical University, Guangzhou, China (Dr Su); Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Xie).
Yafang
Y
Zhou
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (Drs H Li, Wang, Y Zhou; Zhuojia Chen, J Li, X Chen, Hou, Xin, and Huang); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Drs Ni, Ziyi Chen, and L Zhou); Guangdong Pharmaceutical University, Guangzhou, China (Dr Su); Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Xie).
Guanzhong
G
Ni
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (Drs H Li, Wang, Y Zhou; Zhuojia Chen, J Li, X Chen, Hou, Xin, and Huang); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Drs Ni, Ziyi Chen, and L Zhou); Guangdong Pharmaceutical University, Guangzhou, China (Dr Su); Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Xie).
Qibiao
Q
Su
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (Drs H Li, Wang, Y Zhou; Zhuojia Chen, J Li, X Chen, Hou, Xin, and Huang); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Drs Ni, Ziyi Chen, and L Zhou); Guangdong Pharmaceutical University, Guangzhou, China (Dr Su); Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Xie).
Ziyi
Z
Chen
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (Drs H Li, Wang, Y Zhou; Zhuojia Chen, J Li, X Chen, Hou, Xin, and Huang); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Drs Ni, Ziyi Chen, and L Zhou); Guangdong Pharmaceutical University, Guangzhou, China (Dr Su); Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Xie).
Zhuojia
Z
Chen
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (Drs H Li, Wang, Y Zhou; Zhuojia Chen, J Li, X Chen, Hou, Xin, and Huang); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Drs Ni, Ziyi Chen, and L Zhou); Guangdong Pharmaceutical University, Guangzhou, China (Dr Su); Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Xie).
Jiali
J
Li
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (Drs H Li, Wang, Y Zhou; Zhuojia Chen, J Li, X Chen, Hou, Xin, and Huang); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Drs Ni, Ziyi Chen, and L Zhou); Guangdong Pharmaceutical University, Guangzhou, China (Dr Su); Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Xie).
Xinmeng
X
Chen
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (Drs H Li, Wang, Y Zhou; Zhuojia Chen, J Li, X Chen, Hou, Xin, and Huang); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Drs Ni, Ziyi Chen, and L Zhou); Guangdong Pharmaceutical University, Guangzhou, China (Dr Su); Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Xie).
Xiangyu
X
Hou
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (Drs H Li, Wang, Y Zhou; Zhuojia Chen, J Li, X Chen, Hou, Xin, and Huang); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Drs Ni, Ziyi Chen, and L Zhou); Guangdong Pharmaceutical University, Guangzhou, China (Dr Su); Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Xie).
Wen
W
Xie
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (Drs H Li, Wang, Y Zhou; Zhuojia Chen, J Li, X Chen, Hou, Xin, and Huang); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Drs Ni, Ziyi Chen, and L Zhou); Guangdong Pharmaceutical University, Guangzhou, China (Dr Su); Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Xie).
Shuang
S
Xin
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (Drs H Li, Wang, Y Zhou; Zhuojia Chen, J Li, X Chen, Hou, Xin, and Huang); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Drs Ni, Ziyi Chen, and L Zhou); Guangdong Pharmaceutical University, Guangzhou, China (Dr Su); Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Xie).
Liemin
L
Zhou
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (Drs H Li, Wang, Y Zhou; Zhuojia Chen, J Li, X Chen, Hou, Xin, and Huang); The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Drs Ni, Ziyi Chen, and L Zhou); Guangdong Pharmaceutical University, Guangzhou, China (Dr Su); Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Xie). huangmin@mail.sysu.edu.cn lmzhou56@163.com.
Min
M
Huang
D055372:AMP-Activated Protein Kinases / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D054411:Receptors, Leptin / Q000235:genetics*; D014635:Valproic Acid / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D015430:Weight Gain / Q000187:drug effects / Q000235:genetics*; D055815:Young Adult
D000927:Anticonvulsants; C515448:LEPR protein, human; D054411:Receptors, Leptin; D014635:Valproic Acid; C489948:ANKK1 protein, human; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
concentration; polymorphism; valproic acid; weight gain