Association between polymorphisms of LEP, LEPR, DRD2, HTR2A and HTR2C genes and risperidone- or clozapine-induced hyperglycemia

Apichaya Puangpetch; Pornpen Srisawasdi; Weerapon Unaharassamee; Napa Jiratjintana; Somlak Vanavanan; Suweejuk Punprasit; Chalitpon Na Nakorn; Chonlaphat Sukasem; Martin H Kroll

doi:10.2147/PGPM.S210770

Association between polymorphisms of LEP, LEPR, DRD2, HTR2A and HTR2C genes and risperidone- or clozapine-induced hyperglycemia

Pharmgenomics Pers Med. 2019 Aug 6:12:155-166. doi: 10.2147/PGPM.S210770. eCollection 2019.

Authors

Apichaya Puangpetch¹, Pornpen Srisawasdi², Weerapon Unaharassamee³, Napa Jiratjintana³, Somlak Vanavanan², Suweejuk Punprasit², Chalitpon Na Nakorn¹, Chonlaphat Sukasem¹, Martin H Kroll⁴

Affiliations

¹ Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
² Division of Clinical Chemistry, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
³ Department of Psychiatry, Somdet Chaopraya Institute of Psychiatry, Bangkok, Thailand.
⁴ Quest Diagnostics, Secaucus, NJ 07094, USA.

Abstract

Objective: To determine whether genetic polymorphisms related to pharmacodynamics with metabolic adverse effects, namely leptin promoter (LEP) rs7799039, leptin receptor rs1137101, dopamine D2 rs4436578, serotonin 5-HT2A rs6313, and serotonin 5-HT2C rs518147 and rs12836771, are associated with hyperglycemia induced by risperidone or clozapine in adult Thai patients with psychosis.

Methods: A total of 180 patients treated with risperidone-based (n=130) or clozapine-based (n=50) regimens were included in this study. Blood samples were analyzed for genotyping of the candidate genes and biochemical testing. Genotyping was performed by conducting a TaqMan real-time polymerase chain reaction-based analysis.

Results: The prevalence of hyperglycemia was higher in patients receiving clozapine (64.0%) than in those receiving risperidone (30.8%). Among the candidate genes, only the LEP rs7799039 polymorphism demonstrated a significant association with hyperglycemia (χ²=9.879, P=0.008) in patients treated with risperidone; patients with the AA genotype had the highest risk (41.1%), followed by those with AG (20.8%) and GG (0%) genotypes. Using the recessive genetic model (AA vs AG + GG), the odds ratio and 95% CI were 3.28 and 1.44 -7.50, respectively. None of the genes were associated with hyperglycemia in patients treated with clozapine. A binary logistic regression revealed that the LEP rs7799039 polymorphism demonstrated a significant association with hyperglycemia, independent of body-mass index (BMI) in patients receiving risperidone; the odds ratio (95% CI) was 3.188 (1.399-7.262), P=0.006. By contrast, none of the pharmacodynamic genetic factors, except for BMI, were significantly associated with hyperglycemia in patients receiving clozapine.

Conclusion: The risk of type 2 diabetes mellitus is associated with the LEP rs7799039 polymorphism in Thai adults receiving risperidone but not in those receiving clozapine. Clarifying underlying mechanisms and risk of hyperglycemia provides an opportunity to prevent impaired glucose metabolism in patients receiving risperidone or clozapine.

Keywords: atypical antipsychotics; diabetes mellitus; dopamine D2; leptin promoter; leptin receptor; serotonin 5-HT2A; serotonin 5-HT2C.