Browsing by Author "Higgins, Faatiemah"

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    Molecular genetic analyses of antipsychotic pharmacogenes in a South African first episode schizophrenia cohort
    (Stellenbosch : Stellenbosch University, 2015-12) Higgins, Faatiemah; Warnich, L. ; Emsley, R. A.; Niehaus, D. J. H.; Drogemoller, B. I.; Stellenbosch University. Faculty of Agrisciences. Dept. of Genetics.
    ENGLISH ABSTRACT: Antipsychotic treatment of schizophrenia is often accompanied by distressing adverse effects and a high relapse rate. Although pharmacogenetic research has identified some promising candidate pharmacogenes, these remain poorly characterized in South African (SA) populations. This study investigated whether polymorphisms in several candidate pharmacogenes (COMT, CYP1A2, CYP2D6, DRD2, DRD3, HTR2A and SOD2) were associated with antipsychotic treatment outcome in a SA schizophrenia cohort. The cohort utilized consisted of 103 first episode schizophrenia (FES) patients from SA Coloured, Caucasian and Xhosa populations, clinically well-characterized and treated with a first generation antipsychotic, flupenthixol decanoate, for at least twelve months. Previously generated exome sequencing data of eleven of the FES patients were used to identify known and novel functional variants within the seven pharmacogenes, and the predicted functional effect of novel variants were assessed with SIFT and PolyPhen-2 algorithms. Based on these analyses and mining of the literature, a total of 33 variants were prioritized for genotyping by PCR-RFLP, long-range and allele-specific PCR, and TaqMan® assays. Minor allele frequencies in our cohort were compared to populations from the 1000 Genomes Project or the Human CYP Allele Nomenclature databases to distinguish unique genetic variation in SA populations. A mixed model for repeated measures analysis was used to determine whether any of the polymorphisms identified were associated with antipsychotic treatment response, as measured by a change in PANSS scores over time from the twelve-month longitudinal PANSS scores adjusted at baseline. Inheritance models to estimate the effect size (ES) of significant associations were assessed using 95% confidence intervals (CI). Exome data revealed a total of eighteen functional variants in six of the genes, predominantly present in CYP2D6. Novel variants were identified in COMT (rs373611092) and SOD2 (rs372173830), where rs373611092 was predicted to “damage” the COMT protein function (SIFT score = 0.015). Of the 33 variants, only variants in COMT and DRD2 were significantly associated with changes in PANSS negative scores after twelve months of treatment. Associations with improved treatment outcomes included COMT rs4633 [P = 0.0080 (T allele), ES = -0.17 95% CI (-0.30 to -0.04)], and DRD2 rs1799732 [P = 0.0004 (-C vs CC), ES = -0.19 95% CI (-0.38 to 0.00)]. COMT haplotypes (rs2020917-rs737869-rs6269-rs4633-rs9332377) also showed an improved treatment outcome for negative symptoms. Undesirable treatment outcomes were associated with COMT rs9332377 [P = 0.0006 (T allele), ES = 0.25 95% CI (0.11 to 0.39)], and DRD2 variants rs1799732 [P = 0.0004 (-- vs CC), ES = 0.50 95% CI (0.15 to 0.86)] and rs1079597 [P = 0.0020 (AA vs AG+GG), ES = 0.93 95% CI (0.34 to 1.53)]. This study confirmed the presence of unique variation in a SA FES cohort associated with antipsychotic pharmacogenetic traits, highlighting the value of re-sequencing in SA individuals. Several SNPs in COMT and DRD2 were identified to be involved in treatment response, specifically influencing negative symptoms. These results serve as a platform for future antipsychotic pharmacogenetic studies within the SA context that could aid the optimization of antipsychotic treatment in the uniquely diverse, but understudied populations.
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    Molecular genetic analyses of antipsychotic pharmacogenes in a South African first episode schizophrenia cohort
    (Stellenbosch : Stellenbosch University, 2015-12) Higgins, Faatiemah; Warnich, L. ; Emsley, R. A.; Niehaus, D. J. A.; Drogemoller, B. I.; Stellenbosch University. Faculty of AgriSciences. Dept. of Genetics.
    ENGLISH ABSTRACT: Antipsychotic treatment of schizophrenia is often accompanied by distressing adverse effects and a high relapse rate. Although pharmacogenetic research has identified some promising candidate pharmacogenes, these remain poorly characterized in South African (SA) populations. This study investigated whether polymorphisms in several candidate pharmacogenes (COMT, CYP1A2, CYP2D6, DRD2, DRD3, HTR2A and SOD2) were associated with antipsychotic treatment outcome in a SA schizophrenia cohort. The cohort utilized consisted of 103 first episode schizophrenia (FES) patients from SA Coloured, Caucasian and Xhosa populations, clinically well-characterized and treated with a first generation antipsychotic, flupenthixol decanoate, for at least twelve months. Previously generated exome sequencing data of eleven of the FES patients were used to identify known and novel functional variants within the seven pharmacogenes, and the predicted functional effect of novel variants were assessed with SIFT and PolyPhen-2 algorithms. Based on these analyses and mining of the literature, a total of 33 variants were prioritized for genotyping by PCR-RFLP, long-range and allele-specific PCR, and TaqMan® assays. Minor allele frequencies in our cohort were compared to populations from the 1000 Genomes Project or the Human CYP Allele Nomenclature databases to distinguish unique genetic variation in SA populations. A mixed model for repeated measures analysis was used to determine whether any of the polymorphisms identified were associated with antipsychotic treatment response, as measured by a change in PANSS scores over time from the twelve-month longitudinal PANSS scores adjusted at baseline. Inheritance models to estimate the effect size (ES) of significant associations were assessed using 95% confidence intervals (CI). Exome data revealed a total of eighteen functional variants in six of the genes, predominantly present in CYP2D6. Novel variants were identified in COMT (rs373611092) and SOD2 (rs372173830), where rs373611092 was predicted to “damage” the COMT protein function (SIFT score = 0.015). Of the 33 variants, only variants in COMT and DRD2 were significantly associated with changes in PANSS negative scores after twelve months of treatment. Associations with improved treatment outcomes included COMT rs4633 [P = 0.0080 (T allele), ES = -0.17 95% CI (-0.30 to -0.04)], and DRD2 rs1799732 [P = 0.0004 (-C vs CC), ES = -0.19 95% CI (-0.38 to 0.00)]. COMT haplotypes (rs2020917-rs737869-rs6269-rs4633-rs9332377) also showed an improved treatment outcome for negative symptoms. Undesirable treatment outcomes were associated with COMT rs9332377 [P = 0.0006 (T allele), ES = 0.25 95% CI (0.11 to 0.39)], and DRD2 variants rs1799732 [P = 0.0004 (-- vs CC), ES = 0.50 95% CI (0.15 to 0.86)] and rs1079597 [P = 0.0020 (AA vs AG+GG), ES = 0.93 95% CI (0.34 to 1.53)]. This study confirmed the presence of unique variation in a SA FES cohort associated with antipsychotic pharmacogenetic traits, highlighting the value of re-sequencing in SA individuals. Several SNPs in COMT and DRD2 were identified to be involved in treatment response, specifically influencing negative symptoms. These results serve as a platform for future antipsychotic pharmacogenetic studies within the SA context that could aid the optimization of antipsychotic treatment in the uniquely diverse, but understudied populations.