Pharmacogenetics of Risperidone-Induced Insulin Resistance in Children and Adolescents with Autism Spectrum Disorder.

Abstract

The purpose of this study was to explore the association of genetic polymorphism of genes related to pharmacokinetics or pharmacodynamics with insulin resistance in children and adolescents with autism spectrum disorder (ASD) and treated with risperidone. All 89 subjects underwent measurement of fasting blood glucose and insulin levels, body-weight and height. Genotyping was performed by TaqMan real-time polymerase chain reaction (PCR) (pharmacokinetics genes: cytochrome P450 2D6 (CYP2D6) *4 (rs3892097), *5 (gene deletion), *10 (rs1065852) and *41 (rs28371725), ATP-binding cassette transporter B1 (ABCB1) 2677 G>T/A (rs2032582) and 3435C>T (rs1045642) and pharmacodynamics genes: dopamine receptor D2 (DRD2) Tag-SNP (C>T) (rs4436578), DRD2 Tag1A (C>T) (rs1800497), leptin gene (LEP) -2548G>A (rs7799039), ghrelin gene (GHRL) -604G>A (rs27647) and brain-derived neurotrophic factor (BDNF) 196G>A (rs6265)). Drug levels were analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results revealed that 5 (5.62%) patients presented with hyperglycaemia. Insulin resistance was detected in 15 (16.85%) patients. Insulin resistance was associated with LEP 2548 G>A and BDNF 196 G>A polymorphism (p = 0.051 and p = 0.03). There was no association of pharmacokinetic gene polymorphisms (CYP2D6 and ABCB1) and risperidone levels with insulin resistance. Multiple regression analysis indicated that BDNF 196 G>A polymorphism was significantly associated with insulin resistance (p = 0.025). This finding suggested that BDNF 196 G>A polymorphism may be a genetic marker for predicting insulin resistance before initiating treatment in patients treated with risperidone. Because of the small sample size, further studies are needed to confirm these results.

• Authors: Chonlaphat Sukasem, Natchaya Vanwong, Pornpen Srisawasdi, Nattawat Ngamsamut, Nopphadol Nuntamool, Yaowaluck Hongkaew, Apichaya Puangpetch, Bhunnada Chamkrachangpada, Penkhae Limsila
• Journal: Basic & clinical pharmacology & toxicology (Basic Clin Pharmacol Toxicol) Vol. 123 Issue 1 Pg. 42-50 (Jul 2018) ISSN: 1742-7843 [Electronic] England
• PMID: 29369497 (Publication Type: Journal Article)
• Copyright: © 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• Antipsychotic Agents
• Blood Glucose
• Brain-Derived Neurotrophic Factor
• Insulin
• BDNF protein, human
• Cytochrome P-450 CYP2D6
• Risperidone

Topics

• ATP Binding Cassette Transporter, Subfamily B (genetics)
• Adolescent
• Adult
• Antipsychotic Agents (adverse effects, pharmacokinetics)
• Autism Spectrum Disorder (drug therapy, genetics)
• Blood Glucose
• Brain-Derived Neurotrophic Factor (genetics)
• Child
• Child, Preschool
• Cytochrome P-450 CYP2D6 (genetics)
• Female
• Genotype
• Humans
• Hyperglycemia (blood, chemically induced, genetics)
• Insulin (blood)
• Insulin Resistance (genetics)
• Male
• Pharmacogenomic Variants (genetics)
• Risperidone (adverse effects, pharmacokinetics)
• Young Adult