An exploratory pharmacogenetic screening of SLC22A6, SLC22A8, ABCC4 and ABCC10 genes in a cohort of Ghanaian HBV patients

Thomford et al. Egyptian Journal of Medical Human Genetics https://doi.org/10.1186/s43042-023-00428-8 (2023) 24:50 Egyptian Journal of Medical Human Genetics Open Access RESEARCH An exploratory pharmacogenetic screening of SLC22A6, SLC22A8, ABCC4 and ABCC10 genes in a cohort of Ghanaian HBV patients Nicholas Ekow Thomford1,2,3* , Faustina Adu1,2, Cyril Gavor‑Kwashi1, Samuel Badu Nyarko1,2, Paul Nsiah4, Richard Dadzie Ephraim5, George Adjei6 and Akwasi Anyanful1 Abstract Background Organic anion transporters and efflux transporters are involved in the metabolism of drugs such as ten‑ ofovir disoproxil fumarate (TDF). Given the important role of organic anions and efflux transporters in drug disposi‑ tion, genetic variations lead to interindividual differences in drug response. Variations in the SLC and ABC transporters have been associated with drug-induced renal dysfunction. Looking at the prevalence of HBV infection in our popula‑ tion and the use of drugs such as TDF in managing this condition, this study aimed to undertake an exploratory analy‑ sis of genetic variation in renal transporters SLC22A6, SLC22A8, ABCC10 and ABCC4 in a Ghanaian HBV infected cohort. Methods We genotyped 160 HBV infected patients for SNPs in SLC22A6 (rs12293966, rs4149170, rs6591722, rs955434), SLC22A8 (rs11568487), ABCC10 (rs700008, rs831311) and ABCC4 (rs9282570) genes. Clinicodemographic data was taken, and glomerular filtration rate (eGFR) was estimated using the CKD-EPI formula. Genotyping was under‑ taken using Iplex gold SNP genotyping protocol on the Agena MassARRAY® system. Statistical analysis was under‑ taken using packages in Stata SE (v17) and GraphPad prism. Hardy–Weinberg equilibrium, haplotype inference, and linkage disequilibrium (LD) were evaluated using web-based tools LDlink and Shesis. Results The average eGFR was 79.78 ± 33.08 mL/min/1.73 m2 with 31% classified as stage 1 with normal or high GFR (eGFR > 90 mL/min/1.73 m2) and 45% with stage 2 CKD (> 60–89.99 mL/min/1.73 m2). All variants were in HWE except rs4149170, rs9282570 and rs700008 where p < 0.05. Strong LD was observed in the variants rs6591722, rs4149170, rs12293966, rs955434 and rs11568487. There was significant association between rs12293966 and eGFR stage under crude dominant inheritance model (OR 0.27, 95% CI 0.08–0.81; p = 0.019). Under crude model (OR 0.21, 95% CI 0.07–0.66; p = 0.008), adjusted model 1 (OR 76, 95% CI 0.39–7.89; p = 0.014) and adjusted model 2 (OR 0.30, 95% CI 0.12–0.78; p = 0.013) there was significant association observed between rs12293966 and eGFR stage in a codomi‑ nant inheritance. Conclusion The associations observed in this study point to the need for further evaluation with the population of HBV patients on TDF treatment in addition to other factors that would lead to unfavorable outcomes. This explora‑ tory finding may require confirmation in a larger cohort with proper phenotyping to investigate the exact pharmaco‑ genetic mechanisms. Keywords Tenofovir, SLC22A6, HBV, Pharmacogenetics, eGFR, Renal impairment, Transporters *Correspondence: Nicholas Ekow Thomford Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Thomford et al. Egyptian Journal of Medical Human Genetics (2023) 24:50 Introduction Membrane transporters are important in drug disposition as they are key determinants in the pharmacokinetics of drugs where they affect absorption, distribution, metabolism and elimination (ADME) [1, 2]. Their role in the overall response to drugs and subsequent adverse reactions is well established. Several of these membrane transporters have been elucidated with their physiological roles highlighted. The ATP-binding cassette proteins (ABC) and solute carrier (SLC) transporters are two major superfamilies of membrane transporters [3–5]. ABC transporters use energy from ATP hydrolysis to function as efflux transporters, while SLC transporters are involved in the uptake of molecules into cells. These transporters play an important role in regulating the inflow and outflow of substances across plasma membranes such as organic or inorganic molecules, sterol, metal ions, polypeptides and proteins [6, 7]. In drug metabolism, considerable interest lies in these transporters, especially for drugs that are not metabolized by the cytochrome p450 family of enzymes. These transporters then serve in ADME of such pharmacologically diverse drugs and may serve as sites for interactions that underlie drug toxicities and adverse drug reactions. In this study, we screened for transporters that are relevant to nephrotoxic drugs that are of clinical and pharmacological importance, such as tenofovir disoproxil fumarate (TDF), which has been recommended in treatment guidelines for human immunodeficiency virus (HIV) and hepatitis B virus [8]. Drug clearance in the proximal tubule of the renal nephron is controlled mostly by membrane transport proteins [9] and its uptake in the epithelial cells of the kidney tubules is mediated through anion transporters coded for by solute carrier family 22 member (SLCs) through basolateral membranes [10, 11]. There are other transporters involved in active efflux through the apical membrane responsible for excreting drugs. The anion transporters are encoded by SLC22A6 and SLC22A8 which act in the uptake of drugs into the renal proximal tubule while ABCC10, ABCC2 and ABCC4 control efflux across the apical membrane [11– 14]. The genes that code for transporters have genetic variations which affect their accumulation, function, and efficiency. The organic anion transporter SLC22A6, located on 11q12.3, has been shown to transport several substances including xenobiotics with its important role in renal function been greatly elucidated in literature [15]. Variants in SLC22A6 have been previously associated with pharmacokinetic differences in nucleoside analogues such as adefovir, cidofovir and tenofovir [16–18]. The SLC22A8 gene which is located on 11q12.3 encoding a protein is involved in N a+ -independent transport Page 2 of 11 and excretion of organic anions. This protein appears to b (...truncated)