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Current Drug Metabolism

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ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

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Research Article

The Impact of Certain Pharmacogenetic Differences on the Metabolism of Antiretroviral Drugs Used in A Black South African Population

Author(s): Riaan Reay, Michelle Viljoen and Malie Rheeders*

Volume 24, Issue 10, 2023

Published on: 24 November, 2023

Page: [700 - 708] Pages: 9

DOI: 10.2174/0113892002255240231117072211

Price: $65

Abstract

Background: Genetic polymorphism of drug-metabolising enzymes and transporters may influence the effect and toxicity of antiretroviral drugs.

Objectives: To determine and compare the minimum allele frequency of 20 single nucleotide polymorphisms (SNPs) with possible involvement in the metabolism of the antiretroviral drugs with other populations. To investigate the influence of these variants on Reverse transcriptase, Protease and Integrase strand transfer inhibitor drugs.

Method: DNA samples were collected from 1489 subjects. All SNPs with a gene call score of > 0.6 were selected for genotyping. The R package calculated call rates, MAF and Hardy-Weinberg equilibrium (HWE), test p-values, and Chi-squared analysis were performed on the data. The Fisher’s exact test compared the allele frequencies between the populations.

Results: The highest similarities in minimum allele frequency (MAF) were between the Prospective Urban and Rural Epidemiological group (PURE), a Black population in South Africa, and the Yoruba and Luhya populations in Africa.

The following SNPs were identified with a possible effect on metabolism: CYP2B6 rs28399494 (MAF 11%) is indicated in the toxicity of Efavirenz and Nevirapine. CYP3A5 rs776746 (MAF 17%) and CYP3A4 rs2749674 (MAF 23%) both cause an increase in the metabolism of the protease inhibitors. The very low MAF values for both SCL01B1 rs4149056 (MAF 0.6%) and ABCC rs717620 (MAF 2.8%) are indications that OATP1B1 transport function and glomerular filtration tempo will not be compromised. The high MAF value of 30% for UGTA1 rs10929302 can result in hyperbilirubinemia, which can decrease the clearance of Dolutegravir.

Conclusion: These results show a possibility of kidney protection and an increase in bilirubin in this population.

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[1]
Afsar, N.A.; Bruckmueller, H.; Werk, A.N.; Nisar, M.K.; Ahmad, H.R.; Cascorbi, I. Implications of genetic variation of common Drug Metabolizing Enzymes and ABC Transporters among the Pakistani Population. Sci. Rep., 2019, 9(1), 7323.
[http://dx.doi.org/10.1038/s41598-019-43736-z] [PMID: 31086207]
[2]
Böhm, R.; Cascorbi, I. Pharmacogenetics and predictive testing of drug hypersensitivity reactions. Front. Pharmacol., 2016, 7(396), 396.
[http://dx.doi.org/10.3389/fphar.2016.00396] [PMID: 27818635]
[3]
Dandara, C.; Masimirembwa, C.; Haffani, Y.Z.; Ogutu, B.; Mabuka, J.; Aklillu, E.; Bolaji, O. African Pharmacogenomics Consortium Consolidating pharmacogenomics knowledge, capacity development and translation in Africa. AAS Open Res., 2019, 2, 19.
[http://dx.doi.org/10.12688/aasopenres.12965.1] [PMID: 32382701]
[4]
Dandara, C.; Lombard, Z.; Du Plooy, I.; McLellan, T.; Norris, S.A.; Ramsay, M. Genetic variants in CYP (-1A2, -2C9, -2C19, -3A4 and -3A5), VKORC1 and ABCB1 genes in a black South African population: a window into diversity. Pharmacogenomics, 2011, 12(12), 1663-1670.
[http://dx.doi.org/10.2217/pgs.11.106] [PMID: 22118051]
[5]
Radouani, F.; Zass, L.; Hamdi, Y.; Rocha, J.; Sallam, R.; Abdelhak, S.; Ahmed, S.; Azzouzi, M.; Benamri, I.; Benkahla, A.; Bouhaouala-Zahar, B.; Chaouch, M.; Jmel, H.; Kefi, R.; Ksouri, A.; Kumuthini, J.; Masilela, P.; Masimirembwa, C.; Othman, H.; Panji, S.; Romdhane, L.; Samtal, C.; Sibira, R.; Ghedira, K.; Fadlelmola, F.; Kassim, S.K.; Mulder, N. A review of clinical pharmacogenetics studies in african populations. Per. Med., 2020, 17(2), 155-170.
[http://dx.doi.org/10.2217/pme-2019-0110] [PMID: 32125935]
[6]
Rajman, I.; Knapp, L.; Morgan, T.; Masimirembwa, C. African genetic diversity: Implications for cytochrome p450-mediated drug metabolism and drug development. EBioMedicine, 2017, 17, 67-74.
[http://dx.doi.org/10.1016/j.ebiom.2017.02.017] [PMID: 28237373]
[7]
Ikediobi, O.; Aouizerat, B.; Xiao, Y.; Gandhi, M.; Gebhardt, S.; Warnich, L. Analysis of pharmacogenetic traits in two distinct South African populations. Hum. Genomics, 2011, 5(4), 265-282.
[http://dx.doi.org/10.1186/1479-7364-5-4-265] [PMID: 21712189]
[8]
Wright, G.E.B.; Niehaus, D.J.H.; Drögemöller, B.I.; Koen, L.; Gaedigk, A.; Warnich, L. Elucidation of CYP2D6 genetic diversity in a unique African population: Implications for the future application of pharmacogenetics in the Xhosa population. Ann. Hum. Genet., 2010, 74(4), 340-350.
[http://dx.doi.org/10.1111/j.1469-1809.2010.00585.x] [PMID: 20597905]
[9]
Paganotti, G.M.; Russo, G.; Sobze, M.S.; Mayaka, G.B.; Muthoga, C.W.; Tawe, L.; Martinelli, A.; Romano, R.; Vullo, V. CYP2B6 poor metaboliser alleles involved in efavirenz and nevirapine metabolism: CYP2B6*9 and CYP2B6*18 distribution in HIV-exposed subjects from Dschang, Western Cameroon. Infect. Genet. Evol., 2015, 35, 122-126.
[http://dx.doi.org/10.1016/j.meegid.2015.08.003] [PMID: 26247717]
[10]
Yu, Z.J.; Mosher, E.P.; Bumpus, N.N. Pharmacogenomics of antiretroviral drug metabolism and transport. Annu. Rev. Pharmacol. Toxicol., 2021, 61(1), 565-585.
[http://dx.doi.org/10.1146/annurev-pharmtox-021320-111248] [PMID: 32960701]
[11]
Pallerla, S.R.; Elion Assiana, D.O.; Linh, L.T.K.; Cho, F.N.; Meyer, C.G.; Fagbemi, K.A.; Adegnika, A.A.; Beng, V.P.; Achidi, E.A.; Kahunu, G.M.; Bates, M.; Grobusch, M.P.; Kremsner, P.G.; Ntoumi, F.; Velavan, T.P. Pharmacogenetic considerations in the treatment of co-infections with HIV/AIDS, tuberculosis and malaria in Congolese populations of Central Africa. Int. J. Infect. Dis., 2021, 104, 207-213.
[http://dx.doi.org/10.1016/j.ijid.2020.12.009] [PMID: 33310105]
[12]
Aminkeng, F.; Ross, C.J.D.; Rassekh, S.R.; Brunham, L.R.; Sistonen, J.; Dube, M-P.; Ibrahim, M.; Nyambo, T.B.; Omar, S.A.; Froment, A.; Bodo, J-M.; Tishkoff, S.; Carleton, B.C.; Hayden, M.R. Higher frequency of genetic variants conferring increased risk for ADRs for commonly used drugs treating cancer, AIDS and tuberculosis in persons of African descent. Pharmacogenomics J., 2014, 14(2), 160-170.
[http://dx.doi.org/10.1038/tpj.2013.13] [PMID: 23588107]
[13]
Swart, M.; Skelton, M.; Ren, Y.; Smith, P.; Takuva, S.; Dandara, C. High predictive value of CYP2B6 SNPs for steady-state plasma efavirenz levels in South African HIV/AIDS patients. Pharmacogenet. Genomics, 2013, 23(8), 415-427.
[http://dx.doi.org/10.1097/FPC.0b013e328363176f] [PMID: 23778320]
[14]
O’Connell, K.S.; Swart, M.; McGregor, N.W.; Dandara, C.; Warnich, L. Pharmacogenetics of antiretroviral drug response and pharmacokinetic variations in indigenous south african populations. OMICS, 2018, 22(9), 589-597.
[http://dx.doi.org/10.1089/omi.2018.0117] [PMID: 30235109]
[15]
Tishkoff, S.A.; Williams, S.M. Genetic analysis of African populations: Human evolution and complex disease. Nat. Rev. Genet., 2002, 3(8), 611-621.
[http://dx.doi.org/10.1038/nrg865] [PMID: 12154384]
[16]
Dandara, C.; Mutowembwa Masimirembwa, C.; Magimba, A.; Sayi, J.; Kaaya, S.; Sommers, D.K.; Snyman, J.R.; Hasler, J.A. Genetic polymorphism of CYP2D6 and CYP2C19 in East- and Southern African populations including psychiatric patients. Eur. J. Clin. Pharmacol., 2001, 57(1), 11-17.
[http://dx.doi.org/10.1007/s002280100282] [PMID: 11372584]
[17]
Sim, S.C.; Kacevska, M.; Ingelman-Sundberg, M. Pharmacogenomics of drug-metabolizing enzymes: A recent update on clinical implications and endogenous effects. Pharmacogenomics J., 2013, 13(1), 1-11.
[http://dx.doi.org/10.1038/tpj.2012.45] [PMID: 23089672]
[18]
Zhou, Y.; Ingelman-Sundberg, M.; Lauschke, V.M. Worldwide distribution of cytochrome P450 alleles: A meta‐analysis of population‐scale sequencing projects. Clin. Pharmacol. Ther., 2017, 102(4), 688-700.
[http://dx.doi.org/10.1002/cpt.690] [PMID: 28378927]
[19]
Badary, O.A. Pharmacogenomics and COVID-19: Clinical implications of human genome interactions with repurposed drugs. Pharmacogenomics J., 2021, 21(3), 275-284.
[http://dx.doi.org/10.1038/s41397-021-00209-9] [PMID: 33542445]
[20]
Yagura, H.; Watanabe, D.; Kushida, H.; Tomishima, K.; Togami, H.; Hirano, A.; Takahashi, M.; Hirota, K.; Ikuma, M.; Kasai, D.; Nishida, Y.; Yoshino, M.; Yamazaki, K.; Uehira, T.; Shirasaka, T. Impact of UGT1A1 gene polymorphisms on plasma dolutegravir trough concentrations and neuropsychiatric adverse events in Japanese individuals infected with HIV-1. BMC Infect. Dis., 2017, 17(1), 622.
[http://dx.doi.org/10.1186/s12879-017-2717-x] [PMID: 28915895]
[21]
Collins, K.S.; Metzger, I.F.; Gufford, B.T.; Lu, J.B.; Medeiros, E.B.; Pratt, V.M.; Skaar, T.C.; Desta, Z. Influence of uridine diphosphate glucuronosyltransferase family 1 member A1 and solute carrier organic anion transporter family 1 member B1 polymorphisms and efavirenz on bilirubin disposition in healthy volunteers. Drug Metab. Dispos., 2020, 48(3), 169-175.
[http://dx.doi.org/10.1124/dmd.119.089052] [PMID: 31888882]
[22]
Zazuli, Z.; Duin, N.J.C.B.; Jansen, K.; Vijverberg, S.J.H.; Maitland-van der Zee, A.H.; Masereeuw, R. The impact of genetic polymorphisms in organic cation transporters on renal drug disposition. Int. J. Mol. Sci., 2020, 21(18), 6627.
[http://dx.doi.org/10.3390/ijms21186627] [PMID: 32927790]
[23]
Lade, J.M.; To, E.E.; Hendrix, C.W.; Bumpus, N.N. Discovery of genetic variants of the kinases that activate tenofovir in a compartment-specific manner. EBioMedicine, 2015, 2(9), 1145-1152.
[http://dx.doi.org/10.1016/j.ebiom.2015.07.008] [PMID: 26501112]
[24]
Hamlin, A.N.; Tillotson, J.; Bumpus, N.N. Genetic variation of kinases and activation of nucleotide analog reverse transcriptase inhibitor tenofovir. Pharmacogenomics, 2019, 20(2), 105-111.
[http://dx.doi.org/10.2217/pgs-2018-0140] [PMID: 30628547]
[25]
Figueroa, D.B.; Tillotson, J.; Li, M.; Piwowar-Manning, E.; Hendrix, C.W.; Holtz, T.H.; Bokoch, K.; Bekker, L.G.; van Griensven, F.; Mannheimer, S.; Hughes, J.P.; Grant, R.M.; Bumpus, N.N. Discovery of genetic variants of the kinases that activate tenofovir among individuals in the United States, Thailand, and South Africa: HPTN067. PLoS One, 2018, 13(4), e0195764.
[http://dx.doi.org/10.1371/journal.pone.0195764] [PMID: 29641561]
[26]
Izzedine, H.; Hulot, J.S.; Villard, E.; Goyenvalle, C.; Dominguez, S.; Ghosn, J.; Valantin, M.A.; Lechat, P.; Deray, G. Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy. J. Infect. Dis., 2006, 194(11), 1481-1491.
[http://dx.doi.org/10.1086/508546] [PMID: 17083032]
[27]
Chou, M.; Bertrand, J.; Segeral, O.; Verstuyft, C.; Borand, L.; Comets, E.; Le Tiec, C.; Becquemont, L.; Ouk, V.; Mentre, F.; Taburet, A.M. Population pharmacokinetic-pharmacogenetic study of nevirapine in HIV-infected Cambodian patients. Antimicrob. Agents Chemother., 2010, 54(10), 4432-4439.
[http://dx.doi.org/10.1128/AAC.00512-10] [PMID: 20696882]
[28]
Reay, R.; Dandara, C.; Viljoen, M.; Rheeders, M. CYP2B6 haplotype predicts efavirenz plasma concentration in black South African HIV-1-infected children: A longitudinal pediatric pharmacogenomic study. OMICS, 2017, 21(8), 465-473.
[http://dx.doi.org/10.1089/omi.2017.0078] [PMID: 28816644]
[29]
Swart, M.; Evans, J.; Skelton, M.; Castel, S.; Wiesner, L.; Smith, P.J.; Dandara, C. An expanded analysis of pharmacogenetics determinants of efavirenz response that includes 3′-UTR single nucleotide polymorphisms among Black South African HIV/AIDS patients. Front. Genet., 2016, 6, 356.
[http://dx.doi.org/10.3389/fgene.2015.00356] [PMID: 26779253]
[30]
Sinxadi, P.Z.; Leger, P.D.; McIlleron, H.M.; Smith, P.J.; Dave, J.A.; Levitt, N.S.; Maartens, G.; Haas, D.W. Pharmacogenetics of plasma efavirenz exposure in HIV‐infected adults and children in South Africa. Br. J. Clin. Pharmacol., 2015, 80(1), 146-156.
[http://dx.doi.org/10.1111/bcp.12590] [PMID: 25611810]
[31]
Relling, M.V.; Evans, W.E. Pharmacogenomics in the clinic. Nature, 2015, 526(7573), 343-350.
[http://dx.doi.org/10.1038/nature15817] [PMID: 26469045]
[32]
Drögemöller, B.I.; Wright, G.E.B.; Niehaus, D.J.H.; Koen, L.; Malan, S.; Da Silva, D.M.; Hillermann-Rebello, R.; La Grange, A.M.; Venter, M.; Warnich, L. Characterization of the genetic profile of CYP2C19 in two South African populations. Pharmacogenomics, 2010, 11(8), 1095-1103.
[http://dx.doi.org/10.2217/pgs.10.90] [PMID: 20712527]
[33]
Zhang, J.; Hayes, S.; Sadler, B.M.; Minto, I.; Brandt, J.; Piscitelli, S.; Min, S.; Song, I.H. Population pharmacokinetics of dolutegravir in HIV‐infected treatment‐naive patients. Br. J. Clin. Pharmacol., 2015, 80(3), 502-514.
[http://dx.doi.org/10.1111/bcp.12639] [PMID: 25819132]
[34]
Wentzel-Viljoen, E.; Lee, S.; Laubscher, R.; Vorster, H.H. Accelerated nutrition transition in the North West Province of South Africa: Results from the prospective Urban and Rural epidemiology (PURE-NWP-SA) cohort study, 2005 to 2010. Public Health Nutr., 2018, 21(14), 2630-2641.
[http://dx.doi.org/10.1017/S1368980018001118] [PMID: 29734966]
[35]
Mbongwa, HP; Pretorius, PJ; Kruger, A; Koekemoer, G; Reinecke, CJ Single nucleotide and copy number polymorphisms of the SULT1A1 gene in a South African Tswana population group., 2011.
[http://dx.doi.org/10.4102/sajs.v107i11/12.395]
[36]
Teo, K.; Chow, C.K.; Vaz, M.; Rangarajan, S.; Yusuf, S. The Prospective Urban Rural Epidemiology (PURE) study: Examining the impact of societal influences on chronic noncommunicable diseases in low-, middle-, and high-income countries. American heart journal., 2009, 158(1), 1-7.e1.
[37]
Jacobs, C.; Pearce, B.; Du Plessis, M.; Hoosain, N.; Benjeddou, M. Genetic polymorphisms and haplotypes of the organic cation transporter 1 gene (SLC22A1) in the Xhosa population of South Africa. Genet. Mol. Biol., 2014, 37(2), 350-359.
[http://dx.doi.org/10.1590/S1415-47572014005000002] [PMID: 25071399]
[38]
Rodríguez-Nóvoa, S.; Barreiro, P.; Jiménez-Nácher, I.; Soriano, V. Overview of the pharmacogenetics of HIV therapy. Pharmacogenomics J., 2006, 6(4), 234-245.
[http://dx.doi.org/10.1038/sj.tpj.6500374] [PMID: 16462814]
[39]
Wyen, C.; Hendra, H.; Vogel, M.; Hoffmann, C.; Knechten, H.; Brockmeyer, N.H.; Bogner, J.R.; Rockstroh, J.; Esser, S.; Jaeger, H.; Harrer, T.; Mauss, S.; van Lunzen, J.; Skoetz, N.; Jetter, A.; Groneuer, C.; Fätkenheuer, G.; Khoo, S.H.; Egan, D.; Back, D.J.; Owen, A. Impact of CYP2B6 983T>C polymorphism on non-nucleoside reverse transcriptase inhibitor plasma concentrations in HIV-infected patients. J. Antimicrob. Chemother., 2008, 61(4), 914-918.
[http://dx.doi.org/10.1093/jac/dkn029] [PMID: 18281305]
[40]
Aceti, A.; Gianserra, L.; Lambiase, L.; Pennica, A.; Teti, E. Pharmacogenetics as a tool to tailor antiretroviral therapy: A review. World J. Virol., 2015, 4(3), 198-208.
[http://dx.doi.org/10.5501/wjv.v4.i3.198] [PMID: 26279982]
[41]
Bertrand, J.; Treluyer, J.M.; Panhard, X.; Tran, A.; Auleley, S.; Rey, E.; Salmon-Céron, D.; Duval, X.; Mentré, F. Influence of pharmacogenetics on indinavir disposition and short-term response in HIV patients initiating HAART. Eur. J. Clin. Pharmacol., 2009, 65(7), 667-678.
[http://dx.doi.org/10.1007/s00228-009-0660-5] [PMID: 19440701]
[42]
da Rocha, I.M.; Gasparotto, A.S.; Lazzaretti, R.K.; Notti, R.K.; Sprinz, E.; Mattevi, V.S. Polymorphisms associated with renal adverse effects of antiretroviral therapy in a Southern Brazilian HIV cohort. Pharmacogenet. Genomics, 2015, 25(11), 541-547.
[http://dx.doi.org/10.1097/FPC.0000000000000169] [PMID: 26287941]
[43]
Zubiaur, P.; Benedicto, M.D.; Villapalos-García, G.; Navares-Gómez, M.; Mejía-Abril, G.; Román, M.; Martín-Vílchez, S.; Ochoa, D.; Abad-Santos, F. SLCO1B1 phenotype and CYP3A5 polymorphism significantly affect atorvastatin bioavailability. J. Pers. Med., 2021, 11(3), 204.
[http://dx.doi.org/10.3390/jpm11030204] [PMID: 33805706]
[44]
Park, S.; Lee, S.; Kim, Y.; Lee, Y.; Kang, M.W.; Kim, K.; Kim, Y.C.; Han, S.S.; Lee, H.; Lee, J.P.; Joo, K.W.; Lim, C.S.; Kim, Y.S.; Kim, D.K. Serum bilirubin and kidney function: A Mendelian randomization study. Clin. Kidney J., 2022, 15(9), 1755-1762.
[http://dx.doi.org/10.1093/ckj/sfac120] [PMID: 36003670]
[45]
Horsfall, L.J.; Zeitlyn, D.; Tarekegn, A.; Bekele, E.; Thomas, M.G.; Bradman, N.; Swallow, D.M. Prevalence of clinically relevant UGT1A alleles and haplotypes in African populations. Ann. Hum. Genet., 2011, 75(2), 236-246.
[http://dx.doi.org/10.1111/j.1469-1809.2010.00638.x] [PMID: 21309756]
[46]
Nishijima, T.; Tsuchiya, K.; Tanaka, N.; Joya, A.; Hamada, Y.; Mizushima, D.; Aoki, T.; Watanabe, K.; Kinai, E.; Honda, H.; Yazaki, H.; Tanuma, J.; Tsukada, K.; Teruya, K.; Kikuchi, Y.; Oka, S.; Gatanaga, H. Single-nucleotide polymorphisms in the UDP-glucuronosyltransferase 1A-3′ untranslated region are associated with atazanavir-induced nephrolithiasis in patients with HIV-1 infection: A pharmacogenetic study. J. Antimicrob. Chemother., 2014, 69(12), 3320-3328.
[http://dx.doi.org/10.1093/jac/dku304] [PMID: 25151207]

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