Polymorphisms of the LEP- and LEPR Gene and Obesity in Patients Using Antipsychotic Medication

Abstract

Weight gain is one of the most serious adverse effects of atypical antipsychotic agents. Genetic factors influence the risk of an individual to gain weight. The objective of our study was to determine whether the LEPR Q223R polymorphism and the LEP promoter 2548G/A polymorphism are associated with obesity in a group of male and female patients using atypical antipsychotic drugs. A cross-sectional study design was used. The study population consisted of 200 patients aged between 18 and 65 years, diagnosed with a psychotic disorder, all of whom had been using an atypical antipsychotic for at least 3 months. The primary outcome measure was the presence of obesity. Determinants were the LEPR Q223R (rs1137101) polymorphism and the LEP promoter 2548G/A single nucleotide polymorphism ([SNP] rs7799039). Of the 200 included patients, 61 (31%) were obese. In females, the LEPR 223QR (adjusted odds ratio, 0.11; 95% confidence interval [CI], 0.02-0.54) and LEPR 223RR (adjusted odds ratio, 0.07; 95% CI, 0.01-0.63) genotypes were associated with a lower risk of obesity. In males, this association was not found. In females, the average body weight was 13.6 kg more (95% CI, 1.11-26.1) in the LEPR 223QQ group compared with the LEPR 223RR group. No significant association was found between the LEP promoter 2548G/A polymorphism and obesity. Taken together, the results of our study show that the LEPR Q223R polymorphism may be associated with obesity in women with a psychotic disorder treated with atypical antipsychotic drugs and stress the importance of stratification for gender when investigating the role of variations of the LEP- and LEPR genes on the metabolic side effects of antipsychotic medications.

Genetics of Common Antipsychotic-Induced Adverse Effects

“…Another study by Gregoor et al [52] found that baseline obesity risk was significantly greater for females carrying the LEPR 223R allele. This result runs contrary to the finding from their 2009 study which instead reported that the 223R allele was associated with lower baseline risk for female obesity [78]. …”

Weight gain related to treatment with atypical antipsychotics is due to activation of PKC-β

“…8,[19][20][21][22][23][24][25][26][27][28] Evidence from large clinical samples indicates a high prevalence of metabolic dysfunction in people with serious mental illness, particularly in schizophrenic patients with nearly twice the normal risk of dying from cardiovascular disease. 29 High levels of medication non-compliance are present in a variety of psychiatric disorders, and metabolic side effects, in particular weight gain, could contribute in discontinuing antipsychotic treatment.…”

Associations between the <b><i>LEP</i></b> -2548G/A Promoter and Baseline Weight and between <b><i>LEPR</i></b> Gln223Arg and Lys656Asn Variants and Change in BMI <b><i>z</i></b> Scores in Arab Children and Adolescents Treated with Risperidone

“…We included children treated with only one antipsychotic medication (risperidone), all of whom were antipsychotic-naïve at baseline, unlike other studies in which adults treated with a variety of antipsychotics were pooled into a single analysis [26,27,35,36]. This is the first report of associations of genetic markers with weight gain in Arab children and adolescents treated with risperidone.…”

“…This marker has also been associated with a measure of metabolic dysfunction, cholesterol/high density cholesterol ratio, in adult male patients using atypical antipsychotics who were at a relatively early phase (<1 year) of treatment [24]. Other studies in adults did not find any association between rs7799309 and obesity after 3 months of using antipsychotics [27], or weight gain after being on antipsychotics [28]. To our knowledge, only one study has examined rs7799309 and antipsychotic related weight gain in children and adolescents, and it reported that A allele carriers had steeper weight gain [17].…”

“…The LEPR rs1137101 and rs1805094 (into which rs8179183 has been merged) are functional variants encoding amino acid changes: the former (c.668A>G) encodes a glutamine to arginine substitution at amino acid 223 (Q223R), and the latter (c.1968G>C) encodes a lysine to asparagine substitution at amino acid 656 (K656N). In a study of LEPR Q223R in 200 adult patients treated for a psychotic disorder with antipsychotics, in females, the average body weight was 13.6 kg more (95% CI 1.11-26.1) in the LEPR 223QQ group than in the LEPR 223RR group [27]. In a previous study of 13 SNPs and weight profile in olanzapine-and risperidone-treated patients [26], the strongest genetic association for the risperidone-treated group was found with rs8179183 (the minor allele C being protective against weight with a frequency of 20% in those with a weight of 40-60 kg and approaching 0% for those weighing > 100 kg).…”