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

Exome Sequencing Identifies Compound Heterozygous Mutations in SCN5A Associated with Congenital Complete Heart Block in the Thai Population

Background. Congenital heart block is characterized by blockage of electrical impulses from the atrioventricular node (AV node) to the ventricles. This blockage can be caused by ion channel impairment that is the result of genetic variation. This study aimed to investigate the possible causative variants in a Thai family with complete heart block by using whole exome sequencing. Methods. Genomic DNA was collected from a family consisting of five family members in three generations in which one of three children in generation III had complete heart block. Whole exome sequencing was performed on one complete heart block affected child and one unaffected sibling. Bioinformatics was used to identify annotated and filtered variants. Candidate variants were validated and the segregation analysis of other family members was performed. Results. This study identified compound heterozygous variants, c.101G>A and c.3832G>A, in the SCN5A gene and c.28730C>T in the TTN gene. Conclusions. Compound heterozygous variants in the SCN5A gene were found in the complete heart block affected child but these two variants were found only in the this affected sibling and were not found in other unaffected family members. Hence, these variants in the SCN5A gene were the most possible disease-causing variants in this family

Genetic Association of Co‐Trimoxazole‐Induced Severe Cutaneous Adverse Reactions Is Phenotype‐Specific: HLA Class I Genotypes and Haplotypes

Co‐trimoxazole (CTX) causes various forms of severe cutaneous adverse reactions (SCARs). This case‐control study was conducted to investigate the involvement between genetic variants of human leukocyte antigen (HLA) and CYP2C9 in CTX‐induced SCARs, including Stevens‐Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) in Thai patients. Thirty cases of CTX‐induced SCARs were enrolled and compared with 91 CTX‐tolerant controls and 150 people from the general Thai population. Cases comprised 18 SJS/TEN and 12 DRESS patients. This study demonstrated that genetic association of CTX‐induced SCARs was phenotype‐specific. HLA‐B*15:02 and HLA‐C*08:01 alleles were significantly associated with CTX‐induced SJS/TEN, whereas the HLA‐B*13:01 allele was significantly associated with CTX‐induced DRESS. In addition, a significant higher frequency of HLA‐A*11:01‐B*15:02 and HLA‐B*13:01‐C*03:04 haplotypes were detected in the group of CTX‐induced Stevens‐Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and DRESS cases, respectively. Genetic association of CTX‐induced SCARs is phenotype‐specific. Interestingly, these association was observed only in HIV‐infected patients but not in non‐HIV‐infected patients

Effects of Pitavastatin on Lipid Profiles in HIV-Infected Patients with Dyslipidemia and Receiving Atazanavir/Ritonavir: A Randomized, Double-Blind, Crossover Study.

BACKGROUND:Dyslipidemia as a risk factor of cardiovascular disease is common especially in HIV-infected patients who are using protease inhibitors (PIs) including atazanavir. Pitavastatin has less drug-drug interactions and demonstrable efficacy in decreasing lipid levels in non HIV-infected individuals. MATERIALS AND METHODS:This study was a randomized, double-blind, crossover study comparing the safety and efficacy of pitavastatin vs placebo in HIV-infected patients with dyslipidemia and receiving atazanavir/ritonavir (ATV/r). Patients were randomized to receive either placebo or pitavastatin for 12 weeks. The follow-up visits were every 4 weeks until the end of the study. RESULTS:A total of 12 HIV-infected patients were enrolled to each study group. Of all, 14 (58%) patients were men and mean (standard deviation, SD) age was 48.1 (1.8) years. At 12 weeks of treatment with pitavastatin compared to placebo; mean [95% confidence interval (CI)] total cholesterol (TC) was 207 (187.3, 226.8) mg/dL vs 246.3 (226.5, 266) mg/dL (p <0.001); mean (95% CI) triglyceride (TG) was 351.3 (193.2, 509.4) mg/dL vs 279.1 (121, 437.2) mg/dL (p = 0.269); mean (95% CI) high density lipoprotein (HDL) was 45.3 (40.4, 50.2) mg/dL vs 44.2 (39.3, 49.1) mg/dL (p = 0.354); and mean (95% CI) low density lipoprotein (LDL) was 113.2 (100.4, 126) mg/dL vs 145.6 (132.8, 158.4) mg/dL (p <0.001). Mean liver enzyme and median creatine phosphokinase levels were not statistically significant between patients receiving placebo and pitavastatin. CONCLUSIONS:Pitavastatin decreases TC and LDL level at 12 weeks significantly and shows indifferent in hepatotoxicity and creatine phosphokinase levels compared to those of placebo. Thus, pitavastatin can be a good option of lipid-lowering agent in HIV-infected patients who are receiving ATV/r. TRIAL REGISTRATION:ClinicalTrials.gov NCT02442700

Pharmacogenomic study reveals new variants of drug metabolizing enzyme and transporter genes associated with steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone in Thai autism spectrum disorder patients

The present study sought to investigate the genetic variants in drug metabolizing enzyme and transporter (DMET) genes associated with steady-state plasma concentrations of risperidone among Thai autism spectrum disorder (ASD) patients. ASD patients taking risperidone for at least one month were enrolled for this pharmacogenomic study. Genotyping profile was obtained using Affymetrix DMET Plus array interrogating 1931 variants in 231 genes. Steady-state plasma risperidone and 9-hydroxyrisperidone were measured using liquid chromatography/tandem mass spectrometry (LC-MS/MS) assay. The final analysis included 483 markers for 167 genes. Six variants, ABCB11 (c.3084A>G, c.*420A>G, c.*368G>A, and c.*236G>A) and ADH7 (c.690G>A and c.-5360G>A), were found to be associated with plasma concentrations of risperidone. 9-Hydroxyrisperidone and the total active-moiety levels were associated with six gene variants, SCLO1B1 (c.-11187G>A and c.521T>C), SLCO1B3 (c.334G>T, c.699A>G, and c.1557G>A), and SLC7A5 c.*438C>G. Polymorphisms in UGT2B4 c.*448A>G and CYP2D6 (c.1661G>C, c.4180G>C, and c.-2178G>A) showed considerable but not significant associations with metabolic ratio. This pharmacogenomic study identifies new genetic variants of DMET genes in monitoring risperidone therapy

Significant Association of HLA-B Alleles and Genotypes in Thai Children with Autism Spectrum Disorders: A Case-Control Study

Autism is a severe neurodevelopmental disorder. Many susceptible causative genes have been identified. Most of the previous reports showed the relationship between the Human Leukocyte Antigen (HLA) gene and etiology of autism. In order to identify HLA-B alleles associated with autism in Thai population, we compared the frequency of HLA-B allele in 364 autistic subjects with 952 normal subjects by using a two-stage sequence-specific oligonucleotide probe system (PCR-SSOP) method based on flow-cytometry technology. HLA-B⁎13:02 (P=0.019, OR = 2.229), HLA-B⁎38:02 (P=0.049, OR = 1.628), HLA-B⁎44:03 (P=0.016, OR = 1.645), and HLA-B⁎56:01 (P = 1.78 × 10−4, OR = 4.927) alleles were significantly increased in autistic subjects compared with normal subjects. Moreover, we found that the HLA-B⁎18:02 (P=0.016, OR = 0.375) and HLA-B⁎46:12 (P=0.008, OR = 0.147) alleles were negatively associated with autism when compared to normal controls. Both alleles might have a protective role in disease development. In addition, four HLA-B genotypes of autistic patients had statistically significant relationship with control groups, consisting of HLA-B⁎3905/⁎5801 (P=0.032, OR = 24.697), HLA-B⁎2704/⁎5801 (P=0.022, OR = 6.872), HLA-B⁎3501/⁎4403 (P=0.021, OR = 30.269), and HLA-B⁎1801/⁎4402 (P = 0.017, OR = 13.757). This is the first report on HLA-B associated with Thai autism and may serve as a marker for genetic susceptibility to autism in Thai population

Exome Sequencing Identifies Compound Heterozygous Mutations in SCN5A Associated with Congenital Complete Heart Block in the Thai Population

Background. Congenital heart block is characterized by blockage of electrical impulses from the atrioventricular node (AV node) to the ventricles. This blockage can be caused by ion channel impairment that is the result of genetic variation. This study aimed to investigate the possible causative variants in a Thai family with complete heart block by using whole exome sequencing. Methods. Genomic DNA was collected from a family consisting of five family members in three generations in which one of three children in generation III had complete heart block. Whole exome sequencing was performed on one complete heart block affected child and one unaffected sibling. Bioinformatics was used to identify annotated and filtered variants. Candidate variants were validated and the segregation analysis of other family members was performed. Results. This study identified compound heterozygous variants, c.101G>A and c.3832G>A, in the SCN5A gene and c.28730C>T in the TTN gene. Conclusions. Compound heterozygous variants in the SCN5A gene were found in the complete heart block affected child but these two variants were found only in the this affected sibling and were not found in other unaffected family members. Hence, these variants in the SCN5A gene were the most possible disease-causing variants in this family

Whole-Exome Sequencing Identifies One De Novo Variant in the FGD6 Gene in a Thai Family with Autism Spectrum Disorder

Autism spectrum disorder (ASD) has a strong genetic basis, although the genetics of autism is complex and it is unclear. Genetic testing such as microarray or sequencing was widely used to identify autism markers, but they are unsuccessful in several cases. The objective of this study is to identify causative variants of autism in two Thai families by using whole-exome sequencing technique. Whole-exome sequencing was performed with autism-affected children from two unrelated families. Each sample was sequenced on SOLiD 5500xl Genetic Analyzer system followed by combined bioinformatics pipeline including annotation and filtering process to identify candidate variants. Candidate variants were validated, and the segregation study with other family members was performed using Sanger sequencing. This study identified a possible causative variant for ASD, c.2951G>A, in the FGD6 gene. We demonstrated the potential for ASD genetic variants associated with ASD using whole-exome sequencing and a bioinformatics filtering procedure. These techniques could be useful in identifying possible causative ASD variants, especially in cases in which variants cannot be identified by other techniques