Genetic interactions in the adrenergic system genes: analysis of antipsychotic-induced weight gain.

UNLABELLED: Atypical antipsychotics (AP) have high affinity for many neurotransmitter receptors. Among these receptors, APs are antagonist at α-adrenergic and ß-adrenergic receptors, and this pharmacological property has been postulated to be involved in the mechanism of action of these drugs with respect to both clinical response and adverse effects. OBJECTIVE: We tested the hypotheses that AP-induced weight gain is associated with genetic variation in adrenergic receptors and pathway enzymes. We analyzed nine genetic polymorphisms across seven adrenergic genes (ADRA1A, ADRA2A, ADRA2C, ADRB3, DBH, MAOA and COMT). METHODS: One hundred thirty-nine patients with schizophrenia were prospectively assessed for AP-induced weight gain. The HelixTree software (Golden Helix, Bozeman, MT, USA) was employed to detect differences in genotypic distribution between weight gainer and non-weight gainer groups. Furthermore, for the dopamine ß-hydroxylase haplotype, we were able to obtain both the molecular and the statistical phases, analyzing the phenotype considering both phases. RESULTS: Weight gain was not associated with any adrenergic gene. CONCLUSIONS: Our results suggest that genetic polymorphisms in the adrenergic system may not play a major role in AP-induced weight gain; however, adrenergic 2A receptor gene that produced previously the most consistent associations with this phenotype showed a significant interaction with the monoamine oxidase A in weight gainers.

Association of the alpha 2A adrenergic receptor -1291C/G polymorphism and antipsychotic-induced weight gain in European-Americans.

AIMS: To investigate the -1291 C/G promoter polymorphism (rs1800544) of the adrenergic alpha-2A receptor (ADRA2A) with clozapine-/olanzapine-induced weight gain in European-Americans and African-Americans. The alpha-adrenergic receptors inhibit lipolysis in the adipose tissue and are involved in weight gain regulation. Moreover, two previous studies indicated an association with antipsychotic-induced weight gain with the same polymorphism in Asian populations. MATERIALS & METHODS: We analyzed a relatively large (n=129) and well-characterized group of patients and monitored them for a period of 6-14 weeks. Our refined sample consisted of 60 European-Americans and 39 African-Americans on clozapine or olanzapine, prospectively. RESULTS: In European-Americans, we observed a significant difference in weight gain across the genotypic categories (p=0.046). The carriers of the C allele gained more weight compared with the subjects homozygous for the GG allele (CC + CG vs GG; 3.73 +/- 4.13 kg vs 0.23 +/- 2.92 kg; p=0.013). We did not find a significant association in African-Americans, although the sample size was probably too small. CONCLUSION: Our observations suggest a possible role of ADRA2A polymorphisms in clozapine-/olanzpaine-induced weight gain in subjects of European descent.