Core promoter in TNBC is highly mutated with rich ethnic signature.

The core promoter plays an essential role in regulating transcription initiation by controlling the interaction between transcriptional factors and sequence motifs in the core promoter. Although mutation in core promoter sequences is expected to cause abnormal gene expression leading to pathogenic consequences, limited supporting evidence showed the involvement of core promoter mutation in diseases. Our previous study showed that the core promoter is highly polymorphic in worldwide human ethnic populations in reflecting human history and adaptation. Our recent characterization of the core promoter in triple-negative breast cancer (TNBC), a subtype of breast cancer, in a Chinese TNBC cohort revealed the wide presence of core promoter mutation in TNBC. In the current study, we analyzed the core promoter in a Thai TNBC cohort. We also observed rich core promoter mutation in the Thai TNBC patients. We compared the core promoter mutations between Chinese and Thai TNBC cohorts. We observed substantial differences of core promoter mutation in TNBC between the two cohorts, as reflected by the mutation spectrum, mutation-effected gene and functional category, and altered gene expression. Our study confirmed that the core promoter in TNBC is highly mutable, and is highly ethnic-specific.

Pharmacogenomics Factors Influencing the Effect of Risperidone on Prolactin Levels in Thai Pediatric Patients With Autism Spectrum Disorder.

We investigated the association between genetic variations in pharmacodynamic genes and risperidone-induced increased prolactin levels in children and adolescents with autism spectrum disorder (ASD). In a retrospective study, variants of pharmacodynamic genes were analyzed in 124 ASD patients treated with a risperidone regimen for at least 3 months. To simplify genotype interpretation, we created an algorithm to calculate the dopamine D2 receptor (DRD2) gene genetic risk score. There was no relationship between prolactin levels and single SNPs. However, the H1/H3 diplotype (A2/A2-Cin/Cin-A/G) of DRD2/ankyrin repeat and kinase domain containing 1 (ANKK1) Taq1A, DRD2 -141C indel, and DRD2 -141A>G, which had a genetic risk score of 5.5, was associated with the highest median prolactin levels (23 ng/ml). As the dose-corrected plasma levels of risperidone, 9-OH-risperidone, and the active moiety increased, prolactin levels in patients carrying the H1/H3 diplotype were significantly higher than those of the other diplotypes. DRD2 diplotypes showed significantly high prolactin levels as plasma risperidone levels increased. Lower levels of prolactin were detected in patients who responded to risperidone. This is the first system for describing DRD2 haplotypes using genetic risk scores based on their protein expression. Clinicians should consider using pharmacogenetic-based decision-making in clinical practice to prevent prolactin increase.

Relationship between CYP2D6 genotype, activity score and phenotype in a pediatric Thai population treated with risperidone.

Recently, the Clinical Pharmacogenetics Implementation Consortium (CPIC) have revised recommendations for the translation of CYP2D6 genotype to phenotype. Changes affect phenotype grouping, as well as the value used to calculate activity score for the CYP2D6*10 allele to better reflect the substantially decreased activity of this allele which is the most frequent allele found in Asian populations. This study aimed to evaluate whether the lower value for CYP2D6*10 as recommended, and the revised phenotype groupings improve the relationship between CYP2D6 genotype and risperidone measures. One hundred and ninety-nine children and adolescents with autism treated with a risperidone-based regimen for at least four weeks were included. CYP2D6 genotype was determined using the Luminex xTAG CYP2D6 Kit assay and translated into phenotype using different translation methods. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using LC/MS/MS. Plasma levels of risperidone, risperidone concentration/dose ratio, and risperidone/9-hydroxyrisperidone ratio in patients with an activity score < 1 were significantly higher than those ≥ 1 (P value < 0.001 for all three parameters). Plasma risperidone levels and risperidone concentration/dose ratios were significantly higher in intermediate metabolizers (defined as AS = 0.25-0.75) than normal metabolizer (defined as AS = 1-2) patients (1.44 vs. 0.23 ng/ml, P < 0.001 and 1.63 vs. 0.29 ng/ml/ng, P < 0.001, respectively) as well as risperidone/9-hydroxyrisperidone ratio (0.20 vs. 0.04, P < 0.001). This is the first study in an Asian population utilizing the revised CPIC-recommended method for translating the CYP2D6 genotype to phenotype. In addition to validating that CYP2D6 genetic variation significantly impacts risperidone metabolism, we demonstrated that revised value for the CYP2D6*10 was superior for genotype to phenotype translation. However, at least for risperidone, subjects with an activity score of 1 presented as phenotypic normal, and not intermediate metabolizers, suggesting that phenotype classification is substrate dependent.

Hyperuricemia in Children and Adolescents with Autism Spectrum Disorder Treated with Risperidone: The Risk Factors for Metabolic Adverse Effects.

Background: Atypical antipsychotics have been found to be associated with hyperuricemia. Risperidone, one of the atypical antipsychotics, might be related to the hyperuricemia among autism spectrum disorder (ASD) patients. The aims of this study were to determine the prevalence of hyperuricemia in ASD patients treated with risperidone and to determine associations between serum uric acid levels and risperidone dosage, treatment duration, and metabolic parameters. Methods: 127 children and adolescents with ASD treated with risperidone and 76 age-matched risperidone-naïve patients with ASD were recruited. The clinical data and laboratory data were analyzed. Hyperuricemia was defined as serum uric acid >5.5 mg/dl. Results: Hyperuricemia was present in 44.70% of risperidone-naïve patients with ASD and 57.50% of ASD patients treated with risperidone. The fasting uric acid levels were significantly higher in the risperidone group than in the risperidone-naïve group (5.70 vs. 5.35 mg/dl, P = 0.01). The increased uric acid concentrations were significantly associated with adolescent patients treated with risperidone. The higher dose of risperidone and/or the longer treatment time were associated with the increased uric acid levels. Uric acid levels significantly rose with body mass index (BMI), waist circumference (WC), triglyceride (TG) levels, triglycerides to high-density lipoprotein cholesterol ratio (TG/HDL-C), insulin levels, homeostatic model assessment index (HOMA-IR), high-sensitivity CRP (hs-CRP) levels, and leptin levels. Conversely, the levels of HDL-C and adiponectin were negatively correlated with uric acid levels. In multiple regression analysis, there were age, BMI, TG/HDL-C ratio, and adiponectin levels remained significantly associated with uric acid levels. Conclusion: Hyperuricemia may play a role in metabolic adverse effect in children and adolescents with ASDs receiving the high dose and/or the long-term treatment with risperidone.