The –1438A/G polymorphism in the 5-hydroxytryptamine type 2A receptor gene affects promoter activity

Parsons, Michael; D’Souza, Ursula M.; Arranz, M J; Kerwin, Robert; Makoff, Andrew

doi:10.1016/j.biopsych.2004.06.020

Cited by 232 publications

(148 citation statements)

References 25 publications

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“…57,58 The antagonistic effect exerted by risperidone on these receptors will inhibit prolactin secretion, therefore counteracting the increase induced by risperidone binding to D2 receptors. The presence of a HTR2A-1438G allele leads to a lower density of these receptors, 37,38 resulting in higher prolactin secretion and increased levels of this hormone in patients homozygous for this allele, and also to a diminished therapy response (as described above). On the other hand, the lack of association with the DRD2 gene, in agreement with earlier studies, 33,59,60 reinforces the idea that the serotonin receptors have a more important function in regulating prolactin secretion induced by risperidone than by other drugs because of the differences in the pharmacodynamic profile between risperidone and other atypicals, such as clozapine and olanzapine.…”

Section: Pharmacogenetics Of Risperidone In Autismmentioning

confidence: 96%

“…35,36 A decrease in promoter activity of the -1438G allele relative to the A allele results in lower density of these receptors in the brain. 37,38 The poorer response to risperidone observed in patients homozygous for the low expression G allele may therefore be explained by a lower availability of the 5-HT2A receptors and consequent decreased effectiveness of the drug. Another polymorphism in this gene, HTR2A 102T4C, has been more extensively studied.…”

Section: Pharmacogenetics Of Risperidone In Autismmentioning

confidence: 99%

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Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions

Almeida²,

et al. 2009

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Little has been reported on the factors, genetic or other, that underlie the variability in individual response, particularly for autism. In this study we simultaneously explored the effects of multiple candidate genes on clinical improvement and occurrence of adverse drug reactions, in 45 autistic patients who received monotherapy with risperidone up to 1 year. Candidate genes involved in the pharmacokinetics (CYP2D6 and ABCB1) and pharmacodynamics (HTR2A, HTR2C, DRD2, DRD3, HTR6) of the drug, and the brain-derived neurotrophic factor (BDNF) gene, were analysed. Using the generalized estimating equation method these genes were tested for association with drug efficacy, assessed with the Autism Treatment Evaluation Checklist, and with safety and tolerability measures, such as prolactin levels, body mass index (BMI), waist circumference and neurological adverse effects, including extrapyramidal movements. Our results confirm that risperidone therapy was very effective in reducing some autism symptoms and caused few serious adverse effects. After adjusting for confounding factors, the HTR2A c.-1438G4A, DRD3 Ser9Gly, HTR2C c.995G4A and ABCB1 1236C4T polymorphisms were predictors for clinical improvement with risperidone therapy. The HTR2A c.-1438G4A, HTR2C c.68G4C (p.C33S), HTR6 c.7154-2542C4T and BDNF c.196G4A (p.V66M) polymorphisms influenced prolactin elevation. HTR2C c.68G4C and CYP2D6 polymorphisms were associated with risperidone-induced increase in BMI or waist circumference. We thus identified for the first time several genes implicated in risperidone efficacy and safety in autism patients. Although association results require replication, given the small sample size, the study makes a preliminary contribution to the personalized therapy of risperidone in autism.

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Section: Pharmacogenetics Of Risperidone In Autismmentioning

confidence: 96%

Section: Pharmacogenetics Of Risperidone In Autismmentioning

confidence: 99%

Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions

Almeida²,

et al. 2009

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“…116,121,[123][124][125] This polymorphism is in complete LD with a À1438-G/A promoter polymorphism in Caucasian populations (the extent of linkage may vary in different ethnic groups). The G allele of this last polymorphism shows a lower promoter activity than the A allele 171 and may partly explain the associations with response. 121,126,127 A second study did not find differences in expression between both alleles, but found that the À1438-G allele was associated with decreased promoter activity when expressed in combination with a À783-G variant in the same gene.…”

Section: Pharmacodynamic Factorsmentioning

confidence: 98%

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

2007

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The last decade of research into the pharmacogenetics of antipsychotics has seen the development of genetic tests to determine the patients' metabolic status and the first attempts at personalization of antipsychotic treatment. The most significant results are the association between drug metabolic polymorphisms, mainly in cytochrome P450 genes, with variations in drug metabolic rates and side effects. Patients with genetically determined CYP2D6 poor metabolizer (PMs) status may require lower doses of antipsychotic. Alternatively, CYP2D6 ultrarapid matabolizers (UMs) will need increased drug dosage to obtain therapeutic response. Additionally, polymorphisms in dopamine and serotonin receptor genes are repeatedly found associated with response phenotypes, probably reflecting the strong affinities that most antipsychotics display for these receptors. In particular, there is important evidence suggesting association between dopamine 2 receptor (D2) polymorphisms (Taq I and À141-C Ins/Del) and a dopamine 3 receptor (D3) polymorphism (Ser9Gly) with antipsychotic response and drug-induced tardive dyskinesia. Additionally, there is accumulating evidence indicating the influence of a 5-HT2C polymorphism (À759ÀT/C) in antipsychotic-induced weight gain. Application of this knowledge to clinical practice is slowly gathering pace, with pretreatment determination of individual's drug metabolic rates, via CYP genotyping, leading the field. Genetic determination of patients' metabolic status is expected to bring clinical benefits by helping to adjust therapeutic doses and reduce adverse reactions. Genetic tests for the pretreatment prediction of antipsychotic response, although still in its infancy, have obvious implications for the selection and improvement of antipsychotic treatment. These developments can be considered as successes, but the objectives of bringing pharmacogenetic and pharmacogenomic research in psychiatric clinical practice are far from being realized. Further development of genetic tests is required before the concept of tailored treatment can be applied to psychopharmatherapy. This review aims to summarize the key findings from the last decade of research in the field. Current knowledge on genetic prediction of drug metabolic status, general response and drug-induced side effects will be reviewed and future pharmacogenomic and epigenetic research will be discussed.

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“…Genetic variability in the 5HT2A promoter (À1438 G/A), as well as the beta subunit of its G-protein second messenger (GNB3 C825T) may have functional consequences that may affect serotonergic transmission through this receptor (Levine et al, 1990;Parsons et al, 2004). Recent analysis of the differential expression of the À1438 SNP has suggested that the AA genotype is associated with higher 5HT2A gene expression in cell lines also endogenously expressing 5HT2A (Parsons et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Recent analysis of the differential expression of the À1438 SNP has suggested that the AA genotype is associated with higher 5HT2A gene expression in cell lines also endogenously expressing 5HT2A (Parsons et al, 2004). Another investigation published by Murphy and colleagues (Murphy et al, 2003) showed that the silent 5HT2A (T102C) SNP in linkage disequilibrium with the À1438 polymorphism was significantly related to antidepressant intolerance in elderly subjects treated with paroxetine.…”

Section: Introductionmentioning

confidence: 99%

Serotonin 2A −1438 G/A and G-Protein Beta3 Subunit C825T Polymorphisms in Patients with Depression and SSRI-Associated Sexual Side-Effects

Bishop

Moline

Ellingrod

et al. 2006

Neuropsychopharmacol

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The occurrence of sexual side-effects from antidepressants is thought to be mediated through serotonin 2A (5HT2A) receptors. It is currently unknown if functional polymorphisms in the 5HT2A receptor or its G-protein second messenger complex are related to sexual dysfunction in patients taking an selective serotonin reuptake inhibitor (SSRI) for depression. The purpose of this study was to determine the relationship of the 5HT2A À1438 G/A and GNB3 C825T single nucleotide polymorphisms with overall sexual well-being and individual components of sexual health as measured by the Changes in Sexual Functioning Questionnaire (CSFQ). We evaluated 89 outpatients (18-40 years of age) at low risk for other causes of sexual dysfunction who were being treated for depression with an SSRI and did not have sexual difficulties before taking the antidepressant. Outcome measures were stratified by 5HT2A and GNB3 genotypes. After controlling for age, gender, anxiety scale scores, and depression scale scores, persons with a GG genotype of the 5HT2A À1438 single nucleotide polymorphisms (SNP) were significantly more likely to be categorized as having sexual dysfunction than persons with a GA or AA genotype (OR ¼ 3.6; 95% CI 1.03, 12.6; p ¼ 0.046). Furthermore, the 5HT2A À1438 GG genotype was a significant predictor of lower arousal scores (p ¼ 0.022) after accounting for other measures. There was no significant relationship between any outcome measure and GNB3 genotype.

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The –1438A/G polymorphism in the 5-hydroxytryptamine type 2A receptor gene affects promoter activity

Cited by 232 publications

References 25 publications

Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions

Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

Serotonin 2A −1438 G/A and G-Protein Beta3 Subunit C825T Polymorphisms in Patients with Depression and SSRI-Associated Sexual Side-Effects

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