Effect of the African-specific promoter polymorphisms on the SLC22A2 gene expression levels
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Brendon Pearce
Abstract
Background:
Single nucleotide polymorphisms in promoter regions have been shown to alter the transcription of genes. Thus, SNPs in SLC22A2 can result in inter-individual variable response to medication.
Methods:
The objective of the study was to investigate the effect of the African-specific promoter polymorphisms on the SLC22A2 gene expression levels in vitro. These included rs572296424 and rs150063153, which have been previously identified in the Xhosa population of South Africa. The promoter region (300 bp) for the two haplotypes was cloned into the pGLOW promoterless GFP reporter vector. The GFP expression levels of each haplotype was determined in the HEK293 cells using a GlowMax Multi-Detection E7031 luminometer in the form of light emission.
Results:
The relative promoter activity suggests that no significant variation exists between the expression levels of the WT and -95 haplotypes and the -95 and -156 haplotypes (p=0.498). However, the relative promoter activity of the WT haplotype in comparison to the -156 haplotype displayed a significant difference in expression level (p=0.016).
Conclusions:
The data presented here show that the African-specific promoter polymorphisms can cause a decrease in the SLC22A2 gene expression levels in vitro, which in turn, may influence the pharmacokinetic profiles of cationic drugs.
Acknowledgments
This study was partly supported by grants from the Medical Research Council of South Africa, the National Research Foundation of South Africa and the University of the Western Cape. The authors would also like to thank the study participants.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: National Research Foundation, South African Medical Research Council, University of the Western Cape.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Gorboulev V, Ulzheimer JC, Akhoundova A, Ulzheimer-Teuber I, Karbach U, Quester S, et al. Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol 1997;16:871–81.10.1089/dna.1997.16.871Suche in Google Scholar PubMed
2. Gründemann D, Schömig E. Gene structures of the human non-neuronal monoamine transporters EMT and OCT2. Hum Genet 2000;106:627–35.10.1007/s004390000309Suche in Google Scholar PubMed
3. Koehler MR, Wissinger B, Gorboulev V, Koepsell H, Schmid M. The two human organic cation transporter genes SLC22A1 and SLC22A2 are located on chromosome 6q26. Cytogenet Cell Genet 1997;79:198–200.10.1159/000134720Suche in Google Scholar PubMed
4. Motohashi H, Sakurai Y, Saito H, Masuda S, Urakami Y, Goto M, et al. Gene expression levels and immunolocalization of organic ion transporters in the human kidney. J Am Soc Nephrol 2002;13:866–74.10.1681/ASN.V134866Suche in Google Scholar PubMed
5. Jung N, Lehmann C, Rubbert A, Knispel M, Hartmann P, van Lunzen J, et al. Relevance of the organic cation transporters 1 and 2 for antiretroviral drug therapy in human immunodeficiency virus infection. Drug Metab Dispos 2008;36:1616–23.10.1124/dmd.108.020826Suche in Google Scholar PubMed
6. Kimura N, Masuda S, Tanihara Y, Ueo H, Okuda M, Katsura T, et al. Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. Drug Metab Pharmacokinet 2005;20:379–86.10.2133/dmpk.20.379Suche in Google Scholar PubMed
7. Koepsell H, Lips K, Volk C. Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res 2007;24:1227–51.10.1007/s11095-007-9254-zSuche in Google Scholar PubMed
8. Sakurai Y, Motohashi H, Ueo H, Masuda S, Saito H, Okuda M, et al. Expression levels of renal organic anion transporters (OATs) and their correlation with anionic drug excretion in patients with renal diseases. Pharm Res 2004;21:61–7.10.1023/B:PHAM.0000012153.71993.cbSuche in Google Scholar
9. Ji L, Masuda S, Saito H, Inui K. Down-regulation of rat organic cation transporter rOCT2 by 5/6 nephrectomy. Kidney Int 2002;62:514–24.10.1046/j.1523-1755.2002.00464.xSuche in Google Scholar PubMed
10. Deguchi T, Takemoto M, Uehara N, Lindup WE, Suenaga A, Otagiri M. Renal clearance of endogenous hippurate correlates with expression levels of renal organic anion transporters in uremic rats. J Pharmacol Exp Ther 2005;314:932–8.10.1124/jpet.105.085613Suche in Google Scholar PubMed
11. Georgitsi M, Zukic B, Pavlovic S, Patrinos G. Transcriptional regulation and pharmacogenomics. Pharmacogenomics 2011;12:665–73.10.2217/pgs.10.215Suche in Google Scholar PubMed
12. Smith RP, Lam ET, Markova A, Yee SW, Ahituv N. Pharmacogene regulatory elements: from discovery to applications. Genome Med 2012;4:1–13.10.1186/gm344Suche in Google Scholar PubMed PubMed Central
13. Ramsay M. Africa: continent of genome contrasts with implications for biomedical research and health. FEBS Lett 2012;586:2813–9.10.1016/j.febslet.2012.07.061Suche in Google Scholar PubMed
14. Jacobs C, Pearce B, Du Plessis M, Hoosain N, Benjeddou M. Single nucleotide polymorphisms of the SLC22A2 gene within the Xhosa population of South Africa. Drug Metab Pharmacokinet 2015;30:457–60.10.1016/j.dmpk.2015.11.002Suche in Google Scholar PubMed
15. Conover WJ. Practical nonparametric statistics, 3rd ed. New York: John Wiley & Sons, 1999.Suche in Google Scholar
16. Aken BL, Achuthan P, Akanni W, Amode MR, Bernsdorff F, Bhai J, et al. Ensembl 2017. Nucleic Acids Res 2016;45:D635–42.10.1093/nar/gkw1104Suche in Google Scholar PubMed PubMed Central
17. Blumberg LH. Recommendations for the treatment and prevention of malaria: update for the 2015 season in South Africa. S Afr Med J 2015;105:175–8.10.7196/SAMJ.9407Suche in Google Scholar
18. Lazarus EM, Otwombe K, Fairlie L, Untiedt S, Violari A, Laher F, et al. Lamivudine monotherapy as a holding strategy in HIV-infected children in South Africa. J AIDS Clin Res 2013;4:246.10.4172/2155-6113.1000246Suche in Google Scholar
19. Leabman MK, Huang CC, Kawamoto M, Johns SJ, Stryke D, Ferrin TE, et al. Polymorphisms in a human kidney xenobiotic transporter, OCT2, exhibit altered function. Pharmacogenet Genom 2002;12:395–405.10.1097/00008571-200207000-00007Suche in Google Scholar PubMed
20. Ogasawara K, Terada T, Motohashi H, Asaka J, Aoki M, Katsura T, et al. Analysis of regulatory polymorphisms in organic ion transporter genes (SLC22A) in the kidney. J Hum Genet 2008;53:607–14.10.1007/s10038-008-0288-9Suche in Google Scholar PubMed
21. Wilson N, Choudhury A, Carstens N, Mavri-Damelin D. Organic cation transporter 2 (OCT2/SLC22A2) gene variation in the South African Bantu-speaking population and functional promoter variants. OMICS 2017;21:1–8.10.1089/omi.2016.0165Suche in Google Scholar PubMed PubMed Central
22. Asaka J, Terada T, Ogasawara K, Katsura K, Inui K. Characterization of the basal promoter element of human organic cation transporter 2 gene. J Pharmacol Exp Ther 2007;321:684–9.10.1124/jpet.106.118695Suche in Google Scholar PubMed
23. Kajiwara M, Terada T, Asaka JI, Ogasawara K, Katusra T, Ogawa O, et al. Critical roles of Sp1 in gene expression of human and rat H+/organic cation antiporter MATE1. Am J Physiol Renal Physiol 2007;293:F1564–70.10.1152/ajprenal.00322.2007Suche in Google Scholar PubMed
©2018 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Editorial
- New perspectives in personalised medicine for ethnicity in cancer: population pharmacogenomics and pharmacometrics
- Original Articles
- Which cytochrome P450 metabolizes phenazepam? Step by step in silico, in vitro, and in vivo studies
- Correlation between plasma concentrations of tramadol and its metabolites and the incidence of seizure in tramadol-intoxicated patients
- Effect of the African-specific promoter polymorphisms on the SLC22A2 gene expression levels
- Pharmacogenetic testing by polymorphic markers 681G>A and 636G>A CYP2C19 gene in patients with acute coronary syndrome and gastric ulcer in the Republic of Sakha (Yakutia)
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Artikel in diesem Heft
- Frontmatter
- Editorial
- New perspectives in personalised medicine for ethnicity in cancer: population pharmacogenomics and pharmacometrics
- Original Articles
- Which cytochrome P450 metabolizes phenazepam? Step by step in silico, in vitro, and in vivo studies
- Correlation between plasma concentrations of tramadol and its metabolites and the incidence of seizure in tramadol-intoxicated patients
- Effect of the African-specific promoter polymorphisms on the SLC22A2 gene expression levels
- Pharmacogenetic testing by polymorphic markers 681G>A and 636G>A CYP2C19 gene in patients with acute coronary syndrome and gastric ulcer in the Republic of Sakha (Yakutia)
- Homocysteine is the confounding factor of metabolic syndrome-confirmed by siMS score
- Case Report
- Remission of relapsing polychondritis after successful treatment of myelodysplastic syndrome with azacitidine: a case and review of the literature
