Polymorphisms of peroxisome proliferator-activated receptor γ (PPARγ) and cluster of differentiation 36 (CD36) associated with valproate-induced obesity in epileptic patients
- 127 Downloads
Valproate (VPA) is a choice for the treatment of primary generalized epilepsies and partial epilepsies. Unfortunately, weight gain or obesity is one of the most frequent adverse effects of VPA treatment. Genetic factors were shown to be involved in the effect.
The aim of this study was to investigate the association of selected single nucleotide polymorphisms (SNPs) of cluster of differentiation 36 (CD36) and peroxisome proliferator-activated receptor γ (PPARγ) with VPA-induced weight gain and obesity in epileptic patients.
A total of 225 Chinese Han epilepsy patients receiving VPA treatment were recruited in the study. Height and weight for the calculation of body mass index (BMI) were measured at the initiation of VPA therapy and in the follow-up examination. A BMI of 25 kg/m2 or higher was defined as obesity on the basis of the World Health Organization (WHO) criteria for Asian populations. Four SNPs in CD36 (rs1194197, rs7807607) and PPARγ (rs10865710, rs2920502) were genotyped using the Sequenom® MassArray iPlex platform.
About 19.6% of epileptic patients receiving VPA therapy were found to become obese. After covariate analysis of age, gender, sex, height, initial BMI, and VPA dosage, the CD36 rs1194197 C allele and rs7807607 T allele (OR, 0.31; 95%CI, 0.13–0.72; P = 0.009 and OR, 0.38; 95%CI; 0.18–0.83; P = 0.02, respectively) were identified as protective factors for VPA-induced obesity. The PPARγ rs10865710 C allele carriers were found to be less likely to suffer from VPA-induced obesity compared with GG genotype carriers (OR, 0.04; 95%CI, 0.01–0.12; P < 0.001). After a Bonferroni correction for multiple comparisons, the genotypic associations of CD36 rs1194197 and PPARγ rs10865710 and the allelic association of CD36 rs7807607 with obesity remained statistically significant.
Our data first indicated that CD36 and PPARγ polymorphisms may be associated with VPA-induced obesity and weight gain, suggesting that CD36 and PPARγ may have potential value in predicting VPA-induced obesity in Chinese Han epileptic patients.
KeywordsVPA Epileptic Obesity PPARγ CD36 Genetic polymorphisms
Prof. Min Huang and Prof. Jing Jin designed the research; Xupeng Bai and Dingsheng Wen performed the research; Chuncao Xu, Hongliang Li, and Yibei Chen assisted with the research; Prof. Min Huang, Prof. Prof. Xueding Wang, and Lie-min Zhou provided appreciated support for the acquisition of subjects. Xupeng Bai and Dingsheng Wen analyzed the data; Xupeng Bai and Prof. Jing Jin wrote the paper.
This work was supported by the National Key Research and Development Program (2017YFC0909303), National Natural Science Foundations of China [81730103 and 81573658], Guangdong Provincial Key Laboratory of Construction Foundation [2017B030314030], and the Science and Technology Planning Project of Guangdong Province (2017A020215147).
Compliance with ethical standards
This study was approved by the Human Investigation Ethics Committee of the School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (Clinicaltrials.gov Identifier No. NCT01172626). It was conducted in accordance with the Declaration of Helsinki and was consistent with applicable guidelines of good clinical practice.
- Bokor S, Legry V, Meirhaeghe A, Ruiz JR, Mauro B, Widhalm K, Manios Y, Amouyel P, Moreno LA, Molnàr D, Dallongeville J, HELENA Study group (2010) Single-nucleotide polymorphism of CD36 locus and obesity in European adolescents. Obesity (Silver Spring) 18:1398–1403. https://doi.org/10.1038/oby.2009.412 CrossRefGoogle Scholar
- Brandl EJ, Tiwari AK, Zai CC, Chowdhury NI, Lieberman JA, Meltzer HY, Kennedy JL, Müller DJ (2014) No evidence for a role of the peroxisome proliferator-activated receptor gamma (PPARG) and adiponectin (ADIPOQ) genes in antipsychotic-induced weight gain. Psychiatry Res 219:255–260. https://doi.org/10.1016/j.psychres.2014.05.031 CrossRefGoogle Scholar
- Carmona-Vazquez CR, Ruiz-Garcia M, Pena-Landin DM, Diaz-Garcia L, Greenawalt SR (2015) The prevalence of obesity and metabolic syndrome in paediatric patients with epilepsy treated in monotherapy with valproic acid. Rev Neurol 61:193–201. https://doi.org/10.1016/j.jsbmb.2014.02.009 CrossRefGoogle Scholar
- Farook VS, Puppala S, Schneider J, Fowler SP, Chittoor G, Dyer TD, Allayee H, Cole SA, Arya R, Black MH, Curran JE, Almasy L, Buchanan TA, Jenkinson CP, Lehman DM, Watanabe RM, Blangero J, Duggirala R (2012) Metabolic syndrome is linked to chromosome 7q21 and associated with genetic variants in CD36 and GNAT3 in Mexican Americans. Obesity (Silver Spring) 20:2083–2092. https://doi.org/10.1038/oby.2012.74 CrossRefPubMedPubMedCentralGoogle Scholar
- Heni M, Müssig K, Machicao F, Machann J, Schick F, Claussen CD, Stefan N, Fritsche A, Häring HU, Staiger H (2011) Variants in the CD36 gene locus determine whole-body adiposity, but have no independent effect on insulin sensitivity. Obesity (Silver Spring) 19:1004–1009. https://doi.org/10.1038/oby.2010.251 CrossRefGoogle Scholar
- Keller KL, Liang LCH, Sakimura J, May D, van Belle C, Breen C, Driggin E, Tepper BJ, Lanzano PC, Deng L, Chung WK (2012) Common variants in the CD36 gene are associated with oral fat perception, fat preferences, and obesity in African Americans. Obesity (Silver Spring) 20:1066–1073. https://doi.org/10.1038/oby.2011.374 CrossRefGoogle Scholar
- Laugerette F, Passilly-Degrace P, Patris B, Niot I, Febbraio M, Montmayeur JP, Besnard P (2005) CD36 involvement in orosensory detection of dietary lipids, spontaneous fat preference, and digestive secretions. J Clin Invest 115:3177–3184. https://doi.org/10.1172/JCI25299 CrossRefPubMedPubMedCentralGoogle Scholar
- Li H, Wang X, Zhou Y, Ni G, Su Q, Chen Z, Chen Z, Li J, Chen X, Hou X, Xie W, Xin S, Zhou L, Huang M (2015) Association of LEPR and ANKK1 gene polymorphisms with weight gain in epilepsy patients receiving valproic acid. Int J Neuropsychopharmacol 18:pyv021. https://doi.org/10.1093/ijnp/pyv021 CrossRefPubMedPubMedCentralGoogle Scholar
- Luo W, Guo Z, Wu M, Hao C, Hu X, Zhou Z, Zhou Z, Yao X, Zhang L, Liu J (2013) Association of peroxisome proliferator-activated receptor α/δ/γ with obesity, and gene–gene interaction, in the Chinese Han population. J Epidemiol 23:187–194. https://doi.org/10.2188/jea.JE20120110 CrossRefPubMedPubMedCentralGoogle Scholar
- Ma X, Bacci S, Mlynarski W, Gottardo L, Soccio T, Menzaghi C, Iori E, Lager RA, Shroff AR, Gervino EV, Nesto RW, Johnstone MT, Abumrad NA, Avogaro A, Trischitta V, Doria A (2004) A common haplotype at the CD36 locus is associated with high free fatty acid levels and increased cardiovascular risk in Caucasians. Hum Mol Genet 13:2197–2205. https://doi.org/10.1093/hmg/ddh233 CrossRefGoogle Scholar
- Noel SE, Lai CQ, Mattei J, Parnell LD, Ordovas JM, Tucker KL (2010) Variants of the CD36 gene and metabolic syndrome in Boston Puerto Rican adults. Atherosclerosis 211:210–215. https://doi.org/10.1016/j.atherosclerosis.2010.02.009 CrossRefPubMedPubMedCentralGoogle Scholar
- Petty SJ, Kantor S, Lawrence KM, Berkovic SF, Collins M, Hill KD, Makovey J, Sambrook PN, O'Brien TJ, Wark JD (2014) Weight and fat distribution in patients taking valproate: a valproate-discordant gender-matched twin and sibling pair study. Epilepsia 55:1551–1557. https://doi.org/10.1111/epi.12745 CrossRefGoogle Scholar
- Tiwari HK, Patki A, Lieberman J, Stroup TS, Allison DB, Leibel RL, Chung WK (2011) Association of allelic variation in genes mediating aspects of energy homeostasis with weight gain during administration of antipsychotic drugs (CATIE study). Front Genet 2:56. https://doi.org/10.3389/fgene.2011.00056 CrossRefPubMedPubMedCentralGoogle Scholar
- Tiwari AK, Brandl EJ, Weber C, Likhodi O, Zai CC, Hahn MK, Lieberman JA, Meltzer HY, Kennedy JL, Müller DJ (2013) Association of a functional polymorphism in neuropeptide Y with antipsychotic-induced weight gain in schizophrenia patients. J Clin Psychopharmacol 33:11–17. https://doi.org/10.1097/JCP.0b013e31827d145a CrossRefGoogle Scholar
- Zhou J, Febbraio M, Wada T, Zhai Y, Kuruba R, He J, Lee JH, Khadem S, Ren S, Li S, Silverstein RL, Xie W (2008) Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARγ in promoting steatosis. Gastroenterology 134:556–567. https://doi.org/10.1053/j.gastro.2007.11.037 CrossRefGoogle Scholar