Browsing by Subject "Pharmacogenetics"

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    Open Access
    A cost effective RFLP method to genotype Solute carrier organic anion 1B1 (SLCO1B1) c.1929A>C (p.Leu643Phe, rs34671512); a variant with potential effect on rosuvastatin pharmacokinetics
    (BioMed Central, 2018-06-14) Soko, Nyarai D; Masimirembwa, Collen; Dandara, Collet
    Objective: This study describes a restriction fragment polymorphism protocol for rapidly screening the polymorphism SLCO1B1 c.1929A>C in genomic DNA samples. The polymorphism SLCO1B1 c.1929A>C has been associated with increased activity resulting in increased hepatic uptake of drugs. Currently SLCO1B1 c.1929A>C is genotyped using direct sequencing techniques and 5′ nuclease based assays which can be cost prohibiting in resource limited settings. The aim of this study therefore was to design and validate a cost effective RFLP for genotyping the SLCO1B1 c.1929A>C polymorphism. This study was designed to investigate the effect of the polymorphism SLCO1B1 c.1929A>C on interindividual variability in rosuvastatin pharmacokinetics in healthy volunteers of African descent. Results We describe a restriction fragment length polymorphism method to genotype SLCO1B1 c.1929A>C polymorphism using the restriction enzyme Ase1. A student’s t test with Welch correction was used to establish association between the SLCO1B1 c.1929A>C variant and rosuvastatin exposure. The frequency of the SLCO1B1 c.1929C allele amongst Zimbabweans was 6%. The SLCO1B1 c.1929C allele was associated with a 75% reduction (P < 0.001) in rosuvastatin exposure when compared to individuals carrying the wild type SLCO1B1 c.1929A allele. Polymorphism c.1929A>C may therefore play a significant role in rosuvastatin response. The RFLP method is quick and cost effective.
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    Open Access
    An exploratory pharmacogenetic screening of SLC22A6, SLC22A8, ABCC4 and ABCC10 genes in a cohort of Ghanaian HBV patients
    (2023-07-27) Thomford, Nicholas E.; Adu, Faustina; Gavor-Kwashi, Cyril; Nyarko, Samuel B.; Nsiah, Paul; Ephraim, Richard D.; Adjei, George; Anyanful, Akwasi
    Abstract Background Organic anion transporters and efflux transporters are involved in the metabolism of drugs such as tenofovir disoproxil fumarate (TDF). Given the important role of organic anions and efflux transporters in drug disposition, genetic variations lead to interindividual differences in drug response. Variations in the SLC and ABC transporters have been associated with drug-induced renal dysfunction. Looking at the prevalence of HBV infection in our population and the use of drugs such as TDF in managing this condition, this study aimed to undertake an exploratory analysis of genetic variation in renal transporters SLC22A6, SLC22A8, ABCC10 and ABCC4 in a Ghanaian HBV infected cohort. Methods We genotyped 160 HBV infected patients for SNPs in SLC22A6 (rs12293966, rs4149170, rs6591722, rs955434), SLC22A8 (rs11568487), ABCC10 (rs700008, rs831311) and ABCC4 (rs9282570) genes. Clinicodemographic data was taken, and glomerular filtration rate (eGFR) was estimated using the CKD-EPI formula. Genotyping was undertaken using Iplex gold SNP genotyping protocol on the Agena MassARRAY® system. Statistical analysis was undertaken using packages in Stata SE (v17) and GraphPad prism. Hardy–Weinberg equilibrium, haplotype inference, and linkage disequilibrium (LD) were evaluated using web-based tools LDlink and Shesis. Results The average eGFR was 79.78 ± 33.08 mL/min/1.73 m2 with 31% classified as stage 1 with normal or high GFR (eGFR > 90 mL/min/1.73 m2) and 45% with stage 2 CKD (> 60–89.99 mL/min/1.73 m2). All variants were in HWE except rs4149170, rs9282570 and rs700008 where p < 0.05. Strong LD was observed in the variants rs6591722, rs4149170, rs12293966, rs955434 and rs11568487. There was significant association between rs12293966 and eGFR stage under crude dominant inheritance model (OR 0.27, 95% CI 0.08–0.81; p = 0.019). Under crude model (OR 0.21, 95% CI 0.07–0.66; p = 0.008), adjusted model 1 (OR 76, 95% CI 0.39–7.89; p = 0.014) and adjusted model 2 (OR 0.30, 95% CI 0.12–0.78; p = 0.013) there was significant association observed between rs12293966 and eGFR stage in a codominant inheritance. Conclusion The associations observed in this study point to the need for further evaluation with the population of HBV patients on TDF treatment in addition to other factors that would lead to unfavorable outcomes. This exploratory finding may require confirmation in a larger cohort with proper phenotyping to investigate the exact pharmacogenetic mechanisms.
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    Open Access
    Pharmacogenetics of resistant hypertension: evaluating the role of genetic variation in ABCB1, ADBR1, CES1, CYP3A4, CYP3A5, NEDD4L, NOS3, NR3C2 and SCNN1B among South African hypertensive patient
    (2024) Katsukunya, Jonathan Nyasha; Dandara, Collet
    Globally, it is estimated that over one billion individuals live with hypertension. The prevalence of resistant hypertension can be as high as 19% among African populations. Genetic variation in genes that affect the metabolism and transport of antihypertensive drugs has been reported to influence treatment outcome in patients with hypertension. However, there is substantial lack of data on which genetic variants are important in influencing how African patients with hypertension respond to treatment. We hypothesise that genetic variants previously reported to influence treatment outcome in hypertensive patients, may play a role in the development of resistant hypertension in Africans, as well as other novel variants. Therefore, this study set out to investigate the role of genetic variation in nine genes, namely, ABCB1, ADBR1, CES1, CYP3A4, CYP3A5, NEDD4L, NOS3, NR3C2 and SCNN1B, in the development of resistant hypertension in South African patients. Knowledge of pharmacogenetic variants that play a role in resistant hypertension may potentially improve treatment and management of hypertension in our populations. Materials and Method This was a retrospective matched case-control study. The study was conducted at the Hypertension Clinic at Groote Schuur Hospital, Cape Town, South Africa. The study was approved by the Human Research Ethics Committee (HREC) of the University of Cape Town (HREC 141/2022) and all patients had consented to be included in pharmacogenetic studies. Demographic and clinical variables were extracted from the patients' medical records. Patients with BP ≥ 140/90 mmHg on 3 or more antihypertensive drugs or BP < 140/90 mmHg on more than 3 antihypertensive drugs, were classified into the resistant hypertension group (i.e., the case group). Patients on less than 3 antihypertensive drugs were classified into the non-resistant hypertension group (i.e., the control group). Twenty variants in the ABCB1, ADBR1, CES1, CYP3A4, CYP3A5, NEDD4L, NOS3, NR3C2 and SCNN1B genes were genotyped using either polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or quantitative PCR and subsequently validated using Sanger sequencing. Genetic models of inheritance were used to determine associations between genotypes and resistant hypertension. Multivariable logistic regression was performed to determine the association between genotypes and resistant hypertension while adjusting for potential confounding variables. Results A total of 379 participants (29% Black African and 71% Mixed Ancestry) were successfully recruited and genetically characterised for 19 SNPs and 1 copy number variant (CNV). The participants comprised 190 cases (resistant to hypertension treatment) and 189 controls (non resistant to hypertension treatment). In each group, 54% were female and the median age for cases and controls was 43.8 (20 - 54.2) and 42.2 (26 - 52.6) years, respectively. Most genotyping results were consistent with the Hardy-Weinberg equilibrium (P >0.05) except for ABCB1 rs2032582 (P = 0.01), CES1 copy number (P < 0.01), CYP3A4 rs2740574 (P = 0.01) and SCNN1B rs149868979 (P = 0.008) polymorphisms. Homozygosity for CYP3A5 rs776746C/C (P = 0.02; OR: 0.44; CI: 0.22 - 0.89) and NOS3 rs3918188A/A (P = 0.0003; OR: 0.21; CI: 0.08 - 0.49) was associated with protection against resistant hypertension. On the other hand, homozygosity for ADRB1 rs1801252G/G (P = 0.02; OR: 3.30; CI: 1.17 - 10.03) and NEDD4L rs4149601A/A (P = 0.001; OR: 3.82; CI: 1.67 - 9.07) was associated with increased risk of resistant hypertension. Carriers of the ADRB1 rs1801252 - rs1801253G-C haplotype were more likely to have resistant hypertension (P = 0.04; OR: 2.83; CI: 1.05 -8.20). Carriers of the NOS3 rs2070744 -rs1798883 - rs3918188G-T-A haplotype appeared to be protected against resistant hypertension (P = 0.006; OR: 0.47; CI: 0.27 - 0.80). There were no significant associations with resistant hypertension for selected polymorphisms in the ABCB1, CES1, CYP3A4, NR3C2 and SCNN1B genes (P > 0.05). Discussion The CYP3A5 rs776746C allele is functionally associated with reduced CYP3A5 expression. This may lead to reduced clearance of antihypertensive drugs such as amlodipine, enalapril or spironolactone, increasing their exposure and efficacy. NOS3 rs3918188A allele may affect NOS3 gene expression, or its effect may be due to variants in linkage disequilibrium with it, leading to increased efficacy of antihypertensives drugs such as enalapril. ADRB1 rs1801252G allele or ADRB1 rs1801252A>G - rs1801253G>C, G-C haplotype alters ADRB1 receptor function, leading to reduced sensitivity to beta-blockers such as atenolol and consequently reduced efficacy. The NEDD4L rs4149601A allele results in a non-functional NEDD4L, impacting antihypertensive drugs with renal mechanisms, such as hydrochlorothiazide and amiloride. Conclusion CYP3A5 rs776746T>C, NOS3 rs3918188C>A, ADRB1 rs1801252A>G and NEDD4L rs4149601G>A may be variants of pharmacogenomics importance in Africans with respect to response to hypertension treatment. They seem to play a role in either predisposition to resistant hypertension or the pharmacogenomics of antihypertensive drugs. Pre-emptive screening for these variants may be of potential clinical utility in prescribing antihypertensive drugs by influencing decisions on suitable drug types or optimal drug doses in patients with hypertension
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    Open Access
    PXR and CAR single nucleotide polymorphisms influence plasma efavirenz levels in South African HIV/AIDS patients
    (BioMed Central Ltd, 2012) Swart, Marelize; Whitehorn, Heather; Ren, Yuan; Smith, Peter; Ramesar, Rajkumar; Dandara, Collet
    BACKGROUND: This study investigated variation in NR1I2 and NR1I3 and its effect on plasma efavirenz levels in HIV/AIDS patients. Variability in plasma drug levels has largely led research on identifying causative variants in drug metabolising enzyme (DME) genes, with little focus on the nuclear receptor genes NR1I2 and NR1I3, coding for PXR and CAR, respectively, that are involved in regulating DMEs. METHODS: 464 Bantu-speaking South Africans comprising of HIV/AIDS patients on efavirenz-based treatment (n=301) and 163 healthy subjects were genotyped for 6 SNPs in NR1I2 and NR1I3. 32 of the 301 patients had their DNA binding domains (DBDs) in NR1I2 and NR1I3 sequenced. RESULTS: Significantly decreased efavirenz plasma concentrations were observed in patients carrying the NR1I3 rs3003596C/C and T/C genotypes (P=0.015 and P=0.010, respectively). Sequencing resulted in the discovery of a further 13 SNPs, 3 of which are novel variants in the DBD of NR1I2. There were significant differences in the distribution of NR1I2 and NR1I3 SNPs between South Africans when compared to Caucasian, Asian and Yoruba population groups. CONCLUSION: For the realisation of personalised medicine, PXR and CAR genetic variation should be taken into consideration because of their involvement in the regulation of DMEs.