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Document Type |
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Thesis |
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Document Title |
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THE IMPACT OF GENETIC POLYMORPHISM IN CYP3A4 AND CYP3A5 GENES ON THE CLINICAL OUTCOMES OF TACROLIMUS IN SAUDI KIDNEY TRANSPLANT PATIENTS تأثير تعدد الأشكال الجينية في الجينات CYP3A4 وCYP3A5 على النتائج السريرية لدواء التاكروليمس في مرضى زراعة الكلى السعوديين |
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Subject |
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Faculty of medicine |
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Document Language |
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Arabic |
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Abstract |
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Tacrolimus is the cornerstone of immunosuppressive therapy after solid organ transplantation. However, tacrolimus is known to exhibit a narrow therapeutic index and Pharmacokinetic (PK) variability that affects the dose required to achieve the target tacrolimus trough level (C0) among individuals. Despite the intensive therapeutic drug monitoring, considerable time can pass before the target tacrolimus C0 is obtained, which increases the risk of graft rejection or drug-related adverse effects. Single Nucleotide Polymorphisms (SNPs) in CYP3A4 and CYP3A5 are demonstrated to affect both tacrolimus metabolism and PK variability. In view of the non-availability of data from Saudi Arabia, the present study attempts to identify the frequencies of genetic polymorphisms in CYP3A4 and CYP3A5 genes in Saudi Kidney Transplant Patients (SKTPs) and its effects on tacrolimus dosage requirement and clinical outcomes. The current study is a retrospective cohort study design. The population of the research comprised of the SKTPs at the Armed Forces Hospital in the Southern Region. The sample of the research comprised of 129 SKTPs whose treatment with tacrolimus- based regimen during the period of five years (from 2012 – 2017) and for a follow-up period of a 24 month. In addition, 122 Saudi healthy volunteers subjects have participated. All participants were genotyped for CYP3A4 (CYP3A4*1B, CYP3A4*6, CYP3A4*18 and CYP3A4*22) and CYP3A5 (CYP3A5*2 , CYP3A5*3 and CYP3A5*4) genes polymorphisms using TaqMan allelic discrimination assay. The accuracy of our genotype calling approach was further validated by Sanger sequencing method. The association between major CYP3A4 and CYP3A5 genotypes in SKTPs and tacrolimus dose requirement as well as clinical outcomes were assessed at different post-transplantation times. The findings of this study showed that the following genes CYP3A5*2, CYP3A5*4, CYP3A4*6 and CYP3A4*18 had 100% wild allele genotype while wild alleles of CYP3A4*1B and CYP3A4*22 were found in higher frequency and the mutant allele of CYP3A5*3 was found in higher frequency in Saudis. The genetics polymorphism and its frequencies in Saudi healthy was similar to that in the SKTPs. The wild allele of CYP3A5*3 and mutant allele of CYP3A4*1B carriers required a higher initial dose while heterozygous allele of CYP3A4*22 required a lower initial dose. CYP3A5*3 and CYP3A4*1B genotypes had a strong correlation with the tacrolimus dose requirement and led to sub-therapeutic tacrolimus C0 consequently, higher renal rejection rates while CYP3A4*22 genotypes especially heterozygous allele exhibited a strong relationship with the tacrolimus dose requirement that led to higher tacrolimus C0, therefore, increased incidence of adverse effect and complications such as nephrotoxicity, diabetes and neurotoxicity. This study proposed initial dose (mg/kg/day) required to achieve target tacrolimus C0 according to CYP3A4/5 genotypes in SKTPs. The present study has used Artificial Intelligence (AI) application to predict the critical parameters that could affect initial tacrolimus dose among SKTPs. The findings demonstrated that the genotypes of CYP3A5*3, CYP3A4*22 and CYP3A4*1B were the most vital predictor parameters for initial tacrolimus dose in SKTPs. For future perspective, this study strongly recommends increasing use of AI application for kidney transplant patients and the medical field in general thus will allow clinicians to personalize the treatment by developing a predictive model that comprises both clinical and genetic factors. |
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Supervisor |
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Prof. Mai Abdul Alim Abdul Sattar |
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Thesis Type |
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Doctorate Thesis |
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Publishing Year |
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1441 AH
2020 AD |
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Co-Supervisor |
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Prof. Zoheir Abdullah Damanhouri |
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Added Date |
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Monday, June 29, 2020 |
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Researchers
| مرزوق سعيد آل ناصر | Al Nasser, Marzog Saeed | Researcher | Doctorate | |
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