<p>Association between polymorphisms of <em>LEP</em>,<em> LEPR</em>, <em>DRD2</em>, <em>HTR2A</em> and<em> HTR2C</em> genes and risperidone- or clozapine-induced hyperglycemia</p>

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 (χ 2 =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.

Impact of study design and statistical model in pharmacogenetic studies with gene‐treatment interaction

“…CROSSOVER STUDIES FOR GENE-TREATMENT INTERACTION the gene effect size has little influence but on the standard error. Indeed, in agreement with our study, the sample size simulation studies by Cardon et al 25 and Puangpetch et al 26 highlighted the association between sample size ratios and the genetic model, frequency, and effect size. In a crossover design, baseline covariates not impacting the within-subject variability, have limited impact on the power to detect a treatment effect.…”

“…Whereas the gene effect size applies whatever the given treatment (reference or new). 25,26 This work has limitations. Our example mimics symptoms modifying drugs for a chronic disease enabling us to assume no sequence or carry-over effects.…”

Association of CETP Gene Variants with Atherogenic Dyslipidemia Among Thai Patients Treated with Statin

“…The protocol for DNA extraction has been described in our previous study. 35 Genotyping of the CETP polymorphisms was performed by conducting a TaqMan SNP genotyping assay on an Applied Biosystems ® ViiA™7 Real-Time polymerase chain reaction (PCR) System (ABI, Foster City, CA, USA). The extracted DNA was amplified through PCR by using the primers of CETP c.2490C>A, rs3764261; c.5454G>A, rs708272; and c.2327G>A, rs12149545.…”

Personalized approach to antipsychotic-induced weight gain prognosis

“…In a recent study, the association between to carriage of the allele A SNV rs3828942 of LEP gene and disorders of carbohydrate metabolism development (an increase of the glucose concentration in a blood plasma for an empty stomach to a value above 6.1 mmol / L) in patients taking APs has also been presented [46]. Puangpetch A. et al (2019) investigated association between SNVs of candidate genes, in particular the SNVs rs7799039 of LEP gene and rs1137101 of LEPR gene, with metabolic disorders development in Thai schizophrenic patients receiving risperidone or clozapine. The authors discover that the prevalence of hyperglycemia is higher among patients treated with clozapine (64.0%) than among patients treated with risperidone (30.8%).…”

“…SNV (rs7799039) of LEP gene demonstrated a significant association with hyperglycemia development (χ2 = 9.879, p = 0.008) among patients receiving risperidone; patients with genotype AA have the highest risk of hyperglycemia developing (41.1%), and genotypes AG and GG -20.8% and 0%, respectively. None of SNV researched genes is associated with the risk of hyperglycemia developing in patients taking clozapine [47]. Klemettilä J.P. et al (2015) studied the role of leptin, adiponectin, and inflammatory cytokine levels in serum as possible biochemical markers of APs-induce weight gain.…”