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The prevalence of 3-hydroxy-3-methylglutaryl-Coenzyme a reductase variants in hypercholesterolaemic patients with statin intolerance
Dissertation (MSc (Human Physiology))--University of Pretoria, 2024.
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University of Pretoria
2025
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| _version_ | 1867613489328029696 |
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| access_status_str | Open Access |
| author2 | Phulukdaree, Alisa |
| author_browse | Phulukdaree, Alisa |
| author_facet | Phulukdaree, Alisa |
| collection | Thesis |
| dc_rights_str_mv | © 2023 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. |
| description | Dissertation (MSc (Human Physiology))--University of Pretoria, 2024. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/100620 |
| institution | University of Pretoria (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:36:57.501Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2025 |
| publishDateRange | 2025 |
| publishDateSort | 2025 |
| publisher | University of Pretoria |
| publisherStr | University of Pretoria |
| record_format | dspace |
| source_str | UPSpace — University of Pretoria Institutional Repository |
| spelling | oai:repository.up.ac.za:2263/100620 The prevalence of 3-hydroxy-3-methylglutaryl-Coenzyme a reductase variants in hypercholesterolaemic patients with statin intolerance Phulukdaree, Alisa u23995158@tuks.co.za Alummoottil, Sajee Van den Bout, Jan Iman Gunas, Ashley UCTD Sustainable Development Goals (SDGs) Hypercholesterolaemia Statin intolerance Statins Creatine kinase Dissertation (MSc (Human Physiology))--University of Pretoria, 2024. Background: High cholesterol raises the risk of heart disease, the leading cause of death around the world. The World Health Organization (WHO), reports that elevated cholesterol levels contribute to more than 2.6 million deaths, representing 4.5% of all global fatalities. The advent of statins, known as HMG-CoA reductase inhibitors, has revolutionised the treatment of hypercholesterolaemia. These drugs function by blocking cholesterol production and by boosting the number of low-density lipoprotein (LDL) receptors in the liver, which leads to reduced cholesterol levels in the blood. In the South African public healthcare system, simvastatin and atorvastatin are the recommended treatments for hypercholesterolaemia. When combined with dietary and lifestyle modifications, these medications have shown great potential to reduce LDL levels. Although statins are typically safe, some individuals may encounter side effects such as muscle-related symptoms. These adverse effects can occur when the drug is not metabolised and cleared efficiently, leading to an accumulation of the drug, and its metabolites, or prolonged exposure. This altered metabolism may be due to variants of proteins involved in drug metabolism pathways, such as 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). Therefore, this study explored the prevalence of HMGCR variants (rs12916 and rs17244841) in healthy individuals compared to hypercholesterolaemic patients on statin treatment, as well as possible associations between intolerance and creatine kinase (CK) levels in patients diagnosed with hypercholesterolaemia and who are receiving statin therapy. Methodology: The study included 186 participants aged 19 to 75 for the rs12916 analysis. Among them, 100 were healthy volunteers serving as the control group, while 86 were hypercholesterolaemic patients constituting the test group. The patients were treated with either simvastatin (67%) or atorvastatin (33%). For the rs17244841 analysis, 192 participants aged 19 to 75 were studied, comprising 100 healthy volunteers as the control group and 92 hypercholesterolaemic patients as the test group. In this group, 72% received simvastatin and 28% were on atorvastatin. TaqMan® Polymerase Chain Reaction (PCR) genotyping assays were employed for the identification of single nucleotide variants (SNVs) rs12916 and rs17244841. The CKM Human SingleStep ELISA® Kit was used to assess CK levels, and to evaluate the likelihood of statin intolerance, a quantitative questionnaire was utilised. Results: Among the 86 samples analysed from individuals with diagnosed hypercholesterolaemia, 14% exhibited a high risk of statin intolerance, 48% demonstrated moderate risk, and 38% showed low risk based on the rs12916 variant. Similarly, among the 92 hypercholesterolemia samples analysed, 14% showed high risk, 48% moderate risk, and 38% low risk for statin intolerance associated with the rs17244841 variant. The genotype distribution for HMGCR rs12916 in the test group and for rs17244841 in both the test and control groups did not align with the Hardy-Weinberg equilibrium (HWE) (p<0.05). However, the genotype distribution for HMGCR rs12916 in the control group was consistent with the HWE. The rs12916 variant was significantly more common in the control group (42%) than in the test group (36%), (Odds ratio (OR)=0.5318; 95% confidence interval (CI)=0.3543 to 0.8081; p=0.0034). The frequency of rs17244841 was more common in the control group (61%) than in the test group (50%), (OR)=0.7846; 95% CI=0.5093 to 1.204; p=0.2774). No significant association was found between the risk levels (low, moderate, and high) and statin intolerance for the genotype frequencies for rs12916 (OR=0.5318, 95% CI=0.3543 to 0.8081, relative risk (RR)=0.7439, 95% CI=0.6066 to 0.9036, p=0.0034) or for rs17244841 (OR=0.7846, 95% CI=0.5093 to 1.204, RR=0.888, 95% CI=0.7103 to 1.091, p=0.2774) when based on calculated statin intolerance risk (low risk vs. moderate to high risk). Relative risk quantifies the likelihood of statin intolerance in individuals with these genetic variants compared to those without them. Although patients on simvastatin had higher mean CK levels (25041 pg/mL) compared to atorvastatin users (17650 pg/mL), this difference was not statistically significant (p=0.2111). There was no correlation found between the rs12916 variant and statin intolerance or CK levels (p=0.3658), a positive correlation was observed between the rs17244841 variant and both the severity of statin intolerance and elevated CK levels (p=0.2314). Conclusion: This study is the inaugural report on the occurrence of rs12916 and rs17244841 in the South African population. Consistent with earlier studies, this research suggests that patients treated with simvastatin experience statin intolerance than those treated with atorvastatin. From a clinical perspective, these findings contribute to the expanding field of pharmacogenomics and precision medicine. Identifying population-specific genetic risk factors for statin intolerance can facilitate more personalised treatment strategies, enabling healthcare practitioners to tailor statin prescriptions based on an individual’s genetic profile. This approach has the potential to improve patient adherence, reduce adverse effects, and ultimately enhance cardiovascular health outcomes. Physiology MSC (Human Physiology) Unrestricted Faculty of Health Sciences SDG-03: Good health and well-being 2025-02-07T10:30:47Z 2025-02-07T10:30:47Z 2025-04-22 2024-10-30 Dissertation * A2025 http://hdl.handle.net/2263/100620 10.25403/UPresearchdata.28367972 10.25403/UPresearchdata.28367972 en © 2023 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. application/pdf University of Pretoria |
| spellingShingle | UCTD Sustainable Development Goals (SDGs) Hypercholesterolaemia Statin intolerance Statins Creatine kinase The prevalence of 3-hydroxy-3-methylglutaryl-Coenzyme a reductase variants in hypercholesterolaemic patients with statin intolerance |
| title | The prevalence of 3-hydroxy-3-methylglutaryl-Coenzyme a reductase variants in hypercholesterolaemic patients with statin intolerance |
| title_full | The prevalence of 3-hydroxy-3-methylglutaryl-Coenzyme a reductase variants in hypercholesterolaemic patients with statin intolerance |
| title_fullStr | The prevalence of 3-hydroxy-3-methylglutaryl-Coenzyme a reductase variants in hypercholesterolaemic patients with statin intolerance |
| title_full_unstemmed | The prevalence of 3-hydroxy-3-methylglutaryl-Coenzyme a reductase variants in hypercholesterolaemic patients with statin intolerance |
| title_short | The prevalence of 3-hydroxy-3-methylglutaryl-Coenzyme a reductase variants in hypercholesterolaemic patients with statin intolerance |
| title_sort | prevalence of 3 hydroxy 3 methylglutaryl coenzyme a reductase variants in hypercholesterolaemic patients with statin intolerance |
| topic | UCTD Sustainable Development Goals (SDGs) Hypercholesterolaemia Statin intolerance Statins Creatine kinase |
| url | http://hdl.handle.net/2263/100620 |