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

Katsukunya, Jonathan Nyasha

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

Thesis / Dissertation

2024

Publisher

Unirvesity of Cape Town

Department

Department of Pathology

Faculty

Faculty of Health Sciences

Abstract

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