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Association of ANKK1 polymorphism with antipsychotic-induced hyperprolactinemia.

ABSTRACT: OBJECTIVE:Schizophrenia is a severe highly heritable mental disorder. Genetic polymorphisms of dopaminergic pathways are related to pathogenesis of drug response. Hyperprolactinemia (HPRL), a common adverse effect of antipsychotics, is attributed to blockade of dopamine D2 receptors. Ankyrin Repeat and Kinase Domain containing 1 (ANKK1) gene is closely related to Dopamine Receptor D2 type (DRD2) gene functioning. We examined whether the functional polymorphism rs2734849 in the ANKK1 gene is associated with antipsychotic-induced HPRL. METHODS:We recruited 446 patients with schizophrenia from among the Russian population of the Siberian region. The polymorphism rs2734849 in the ANKK1 gene was genotyped with The MassARRAY® Analyzer 4 by Agena Bioscience™, using the kit SEQUENOM Consumables iPLEXGold 384. Genotype and allele frequencies were compared between groups of schizophrenia patients with and without HPRL using the ?2 test. RESULTS:A comparison between schizophrenia patients with and without HPRL revealed significantly higher frequency of the C allele of the polymorphic variant rs2734849 in the ANKK1 gene in patients with HPRL as compared to the patients without it (?2 = 3.70; p = .05; odds ratio [OR] = 1.30 [0.99-1.69]). CONCLUSION:The functional polymorphism rs2734849 in the ANKK1 gene was associated with HPRL in patients with schizophrenia.

SUBMITTER: Fedorenko OY

PROVIDER: S-EPMC7507142 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Association of ANKK1 polymorphism with antipsychotic-induced hyperprolactinemia.

Fedorenko Olga Yu OY Paderina Diana Z DZ Loonen Anton J M AJM Pozhidaev Ivan V IV Boiko Anastasiia S AS Kornetova Elena G EG Bokhan Nikolay A NA Wilffert Bob B Ivanova Svetlana A SA

Human psychopharmacology 20200508 4

<h4>Objective</h4>Schizophrenia is a severe highly heritable mental disorder. Genetic polymorphisms of dopaminergic pathways are related to pathogenesis of drug response. Hyperprolactinemia (HPRL), a common adverse effect of antipsychotics, is attributed to blockade of dopamine D2 receptors. Ankyrin Repeat and Kinase Domain containing 1 (ANKK1) gene is closely related to Dopamine Receptor D2 type (DRD2) gene functioning. We examined whether the functional polymorphism rs2734849 in the ANKK1 gene ...[more]

PMID: 32383805

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Project description:RationaleWeight gain is a frequent side effect of treatment with SGAs (second-generation antipsychotics) and a leading cause for nonadherence. Several candidate genes have been identified that could influence the amount of AIWG (antipsychotic-induced weight gain). The polymorphism rs17782313 near the MC4R (human melanocortin 4 receptor gene) was strongly associated with obesity in a large scale GWAS (genome wide association study), yet previous studies investigating its impact on AIWG did not lead to a definite conclusion regarding its effect. In particular, they were all relatively short and had a naturalistic design.ObjectiveWe therefore examined the influence of the rs17782313 polymorphism on SGA-related weight gain.MethodsParticipants of a multicenter randomized, controlled, double-blind study comparing two treatment strategies in individuals with schizophrenia or schizoaffective disorder were genotyped using a rapid-cycle polymerase chain reaction. Up to 252 individuals completed the first 2 weeks (phase I), 212 the entire 8 weeks (hence 'completers'). Patients received either amisulpride or olanzapine or both consecutively. Thirty-seven had their first episode. Weight gain occurring in different genotypes was statistically compared and confounding factors were adjusted by stepwise multiple linear regression. A correction for multiple testing was included.ResultsWithin 212 'completers', carriers of the C allele had a higher absolute weight gain than those homozygous for the T allele (2.6 kg vs. 1.2 kg), though this observation was not significant (P = 0.063). In the amisulpride subpopulation, this association appeared stronger and reached significance (2.5 kg vs. 0.7 kg, P = 0.043), though failed to remain significant after correction for multiple testing. A stepwise multiple linear regression showed a significant association in both the whole study population (P < 0.001) and the amisulpride subpopulation (P < 0.001).ConclusionOur results indicate that the rs17782313 polymorphism might influence antipsychotic-induced weight gain and therefore confirm some of the earlier conclusions.

Project description:BackgroundAntipsychotic-induced weight gain (AIWG) is a crucial factor for the medication cessation of patients with schizophrenia. Multiple studies have shown that the functional polymorphism -759 C/T (rs3813929) in the HTR2C promoter region could possibly be correlated with AIWG.AimTo evaluate the genetic association of the HTR2C-759C/T polymorphism and AIWG in patients with schizophrenia with antipsychotic drugs (APDs) administration.MethodsEligible studies were identified by searching the following databases: PubMed, Embase, Web of Science, China Nation Knowledge Infrastructure (CNKI), VIP, Wanfang Data, Chinese Biomedical Literature Database (CBM) and the Airiti Library. The quality of studies was evaluated based on the Newcastle-Ottawa Scale. The pooled OR and 95% CI were calculated for the dominant (CT/TT/T vs CC/C) mode, and subgroup analyses were performed based on ethnicity, antipsychotic medication and gender; all statistical analyses were performed using the statistical software STATA V.12.0.ResultA total of 17 studies with 3170 patients with schizophrenia were included in our meta-analysis. The result of the meta-analysis has shown that the association between the -759 C/T polymorphism and AIWG is statistically significant (OR 0.34, 95% CI: 0.20 to 0.57, z=4.11, p<0.001). The subgroup analyses revealed significant correlations between the -759 C/T polymorphism and AIWG in the Caucasian population (OR 0.33, 95% CI: 0.14 to 0.77, z=2.55, p=0.011), the Asian population (OR 0.31, 95% CI: 0.18 to 0.52, z=4.46, p<0.001), the patients with APDs administration (CT/TT/T vs CC/C: OR 0.63, 95% CI: 0.40 to 1.00, z=1.97, p=0.049) and the patients with atypical antipsychotic drug administration (CT/TT/T vs CC/C: OR 0.21, 95% CI: 0.09 to 0.47, z=3.83, p<0.001). The sensitivity analysis showed that the results were stable. Begg's test (after correction z=1.07, p=0.287) and Egger's test (t=-2.41, p=0.029) show that the included articles have no significant publication bias.ConclusionThere is a significant genetic association between HTR2C-759C/T and AIWG, and patients with T allele are less likely to have AIWG.

Project description:BackgroundGenetic factors are important in the pathogenesis of Tourette syndrome (TS). Notably, Dopamine receptor D2 (DRD2) gene has been suggested as a possible candidate gene for this disorder. Several studies have demonstrated that DRD2/ANKK1 TaqIA polymorphism is associated with an increased risk of developing TS. However, past results remain conflicting. We addressed this controversy by performing a meta-analysis of the relationship between DRD2/ANKK1 TaqIA polymorphism and TS.MethodsLiterature was searched in multiple databases including PUBMED, COCHRANE and WEB OF SCIENCE up to July 2014. The number of the genotypes for DRD2/ANKK1 TaqIA in the TS and control subjects was extracted and statistical analysis was performed using Review Manager 5.0.16 and Stata 12.0 software. Summary odds ratios (ORs) and 95% confidence intervals (95%CIs) were utilized to calculate the risk of TS with DRD2/ANKK1 TaqIA. Stratified analysis based on ethnicity was also conducted.Results523 patients with TS, 564 controls and 87 probands plus 152 relatives from five published studies were finally involved in this meta-analysis. Combined analysis revealed that the overall ORs for the DRD2/ANKK1 TaqIA A1 allele were 1.69 (95%CIs = 1.42-2.00) in the fixed-effect model and 1.66 (95%CIs = 1.33-2.08) in the random-effects model. Stratification by ethnicity indicated the TaqIA A1 allele was significantly associated with TS in Caucasians (fixed-effect model: OR=1.75, 95%CI = 1.43-2.16; random-effect model: OR=1.69, 95%CI = 1.25-2.28) and in Asians (OR=1.54, 95%CI = 1.12-2.10). Meta-analysis of the A1A1 vs. A2A2 (homozygous model), A1A2 vs. A2A2 (heterozygous model) and A1A1+A1A2 vs. A2A2 (dominant model) of this polymorphism revealed a significant association with TS in overall populations and Caucasians.ConclusionsThis meta-analysis suggested that the DRD2/ANKK1 TaqIA polymorphism might contribute to TS susceptibility, especially in Caucasian population. However, further investigation with a larger number of worldwide studies should be conducted to verify the association.

Project description:BackgroundHyperprolactinemia (HPRL) is a classical side effect of antipsychotic drugs primarily attributed to blockade of dopamine D2 receptors (DRD2s) on the membranes of lactotroph cells within the pituitary gland. Certain antipsychotic drugs, e.g. risperidone, are more likely to induce HPRL because of relative accumulation within the adenohypophysis. Nevertheless, due to competition for pituitary DRD2s by high dopamine levels may limit antipsychotic-induced HPRL. Moreover, the activity of prolactin-producing lactotrophs also depends on other hormones which are regulated by the extra-pituitary activity of dopamine receptors, dopamine transporters, enzymes of neurotransmitter metabolism and other factors. Polymorphic variants in the genes coding for these receptors and proteins can have functional significance and influence on the development of hyperprolactinemia.MethodsA set of 41 SNPs of genes for dopamine receptors DRD1, DRD2, DRD3, DRD4, the dopamine transporter SLC6A3 and dopamine catabolizing enzymes MAOA and MAOB was investigated in a population of 446 Caucasians (221 males/225 females) with a clinical diagnosis of schizophrenia (according to ICD-10: F20) with and without HPRL who were treated with classical and/or atypical antipsychotic drugs. Additive genetic model was tested and the analysis was carried out in the total group and in subgroup stratified by the use of risperidone/paliperidone.ResultsOne statistically significant association between polymorphic variant rs1799836 of MAOB gene and HPRL in men was found in the total group. Furthermore, the rs40184 and rs3863145 variants in SLC6A3 gene appeared to be associated with HPRL in the subgroup of patients using the risperidone/paliperidone, but not with HPRL induced by other antipsychotic drugs.ConclusionsOur results indicate that genetic variants of MAOB and SLC6A3 may have consequences on the modulation of prolactin secretion. A further search for genetic markers associated with the development of antipsychotic-related hyperprolactinemia in schizophrenic patients is needed.

Project description:Aripiprazole, metformin, and paeoniae-glycyrrhiza decoction (PGD) have been widely used as adjunctive treatments to reduce antipsychotic (AP)-induced hyperprolactinemia in patients with schizophrenia. However, the comparative efficacy and safety of these medications have not been previously studied. A network meta-analysis of randomized controlled trials (RCTs) was conducted to compare the efficacy and safety between aripiprazole, metformin, and PGD as adjunctive medications in reducing AP-induced hyperprolactinemia in schizophrenia. Both international (PubMed, PsycINFO, EMBASE, and Cochrane Library databases) and Chinese (WanFang, Chinese Biomedical, and Chinese National Knowledge infrastructure) databases were searched from their inception until January 3, 2019. Data were analyzed using the Bayesian Markov Chain Monte Carlo simulations with the WinBUGS software. A total of 62 RCTs with 5,550 participants were included in the meta-analysis. Of the nine groups of treatments included, adjunctive aripiprazole (<5 mg/day) was associated with the most significant reduction in prolactin levels compared to placebo (posterior MD = -65.52, 95% CI = -104.91, -24.08) and the other eight treatment groups. Moreover, adjunctive PGD (>1:1) was associated with the lowest rate of all-cause discontinuation compared to placebo (posterior odds ratio = 0.45, 95% CI = 0.10, 3.13) and adjunctive aripiprazole (>10 mg/day) was associated with fewer total adverse drug events than placebo (posterior OR = 0.93, 95% CI = 0.65, 1.77) and other eight treatment groups. In addition, when risperidone, amisulpride, and olanzapine were the primary AP medications, adjunctive paeoniae/glycyrrhiza = 1:1, aripiprazole <5 mg/day, and aripiprazole >10 mg/day were the most effective treatments in reducing the prolactin levels, respectively. Adjunctive aripiprazole, metformin, and PGD showed beneficial effects in reducing AP-induced hyperprolactinemia in schizophrenia, with aripiprazole (<5 mg/day) being the most effective one.

Dataset Information

Association of ANKK1 polymorphism with antipsychotic-induced hyperprolactinemia.

Publications

Association of ANKK1 polymorphism with antipsychotic-induced hyperprolactinemia.

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