Association of genetic variants of the histamine H1 and muscarinic M3 receptors with BMI and HbA1c values in patients on antipsychotic medication

Abstract

RationaleAntipsychotic affinity for the histamine H1 receptor and the muscarinic M3 receptor have been associated with the side effects weight gain, and development of diabetes, respectively.ObjectivesWe investigated polymorphisms of the histamine H1 (HRH1) and muscarinic acetylcholine receptor M3 (CHRM3) receptor genes for an association with body mass index (BMI) and glycated hemoglobin (HbA1c).MethodsWe included 430 Caucasian patients with a non-affective psychotic disorder using antipsychotics for at least 3 months. Primary endpoints of the study were cross-sectionally measured BMI and HbA1c; secondary endpoints were obesity and hyperglycaemia. Two single-nucleotide polymorphisms (SNPs) in the HRH1 gene, rs346074 and rs346070, and one SNP in the CHRM3 gene, rs3738435, were genotyped. Our primary hypothesis in this study was an interaction between genotype on BMI and antipsychotic affinity for the H1 and M3 receptor.ResultsA significant association of interaction between haplotype rs346074–rs346070 and BMI (p value 0.025) and obesity (p value 0.005) in patients using high-H1 affinity antipsychotics versus patients using low-H1 affinity antipsychotics was found. There was no association of CHRM3 gene variant rs3738435 with BMI, and we observed no association with HbA1c or hyperglycaemia in any of the variants.ConclusionsThis study, for the first time, demonstrates a significant association between HRH1 variants and BMI in patients with a psychotic disorder using antipsychotics. In future, genotyping of HRH1 variants may help predicting weight gain in patients using antipsychotics.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-011-2211-x) contains supplementary material, which is available to authorized users.

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

“…Olanzapine treatment upregulated mRNA expression and protein levels of hypothalamic H 1 R, which was correlated with hyperphagia and weight gain induced by olanzapine [56,64,65]. Similarly, clinical studies demonstrated patients treated with antipsychotics showed a significant correlation between the genetic variants of H 1 R (rs346074 -rs346070), BMI (body mass index) and obesity [66,67].…”

The Role of Hypothalamic H1 Receptor Antagonism in Antipsychotic-Induced Weight Gain

“…[8] Recently, studies in patients treated with antipsychotics showed a significant association of interaction between the genetic variants of H1 receptors (rs346074-rs346070) and BMI and obesity when comparing patients treated with high H1 receptor affinity antipsychotics (olanzapine, clozapine and quetiapine) with those treated with lower H1 receptor affinity antipsychotics (such as aripiprazole). [59] However, earlier studies also reported no relationship between other H1 receptor variants and clozapine-induced weight gain. [60][61] Additionally, in a rat model, both short-(1 week) and long-term (12 weeks) treatment of olanzapine (1.5mg/kg/day, oral), but not haloperidol (0.3mg/kg/day, oral) or aripiprazole (2.25 mg/kg/day, oral), reduced H1 receptor expression in the hypothalamic ARC and VMH, in which the mRNA expression of ARC H1 receptor is significantly correlated with body weight gain and feeding efficiency.…”

Mechanisms of development of antipsychotic-induced metabolic disorders: pharmacogenetic aspect

“…По актуальным данным, обнаружено, что 20 белковых вариантов CYP3A4, *6, *17, *20 обладают пониженной активностью. Это подтверждается исследованием, в котором добровольцы принимали кветипин, при ýтом носители мутации в промоторном регионе гена CYP3A4*1B (-392 G>A) имели значительно более низкую активность фермента [45].…”

“…Немногочисленны и противоречивы исследова-ния полиморфизмов генов гистаминовой систе-мы. Найдена связь ОНП rs346074 и rs346070 гена Н 1 -рецептора H1R с набором веса [85]. В то же время существует ряд работ, опровергающих связь полиморфизмов генов рецепторов гистами-на H1R/H2R/H3R с прибавкой массы тела при приеме нейролептиков [86].…”

“…По актуальным данным, обнаружено, что 20 белковых вариантов CYP3A4, *6, *17, *20 обладают пониженной активностью. Это подтверждается исследованием, в котором добровольцы принимали кветипин, при ýтом носители мутации в промоторном регионе гена CYP3A4*1B (-392 G>A) имели значительно более низкую активность фермента [45].АТФ-связывающие переносчики ýкспрессиру-ются во внутренних органах, являются частью гематоýнцефалического барьера, в почках они вовлечены в абсорбцию и ýкскрецию лекарствен-ных средств, при ýтом большая часть антипсихо-тиков является их субстратами [46]. Большинство фармакогенетических исследований направлены Бюллетень сибирской медицины.…”