FREQUENCIES OF SINGLE-NUCLEOTIDE POLYMORPHISMS AND HAPLOTYPES OF THE SLCO1B1 GENE IN SELECTED POPULATIONS OF THE WESTERN BALKANS
Daka Grapci A1, Dimovski AJ2, Kapedanovska A2, Vavlukis M3, Eftimov A2, Matevska Geshkovska N2, Labachevski N4, Jakjovski K4, Gorani D5, Kedev S3, Mladenovska K2,*
*Corresponding Author: Professor Kristina Mladenovska, Faculty of Pharmacy, Center for Biomolecular Pharmaceutical Analyses, University “Ss Cyril and Methodius” in Skopje, Blv. “Mother Theresa” 47, 1000 Skopje, Republic of Macedonia. Tel: +389-2-3126-032. Fax: +389-2-3132-015. E-mail: krml@ff.ukim.edu.mk
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INTRODUCTION

Membrane influx and efflux transporters have a significant role in facilitating or preventing drug movement through biological membranes. Drug responses are largely dependent on their interplay with phases I and II metabolism and the physicochemical properties of a drug. They function in the selective absorption and elimination of drugs, mediate tissuespecific drug distribution and are also targets of many clinically used drugs. In addition, they play a critical role in the development of resistance to anticancer drugs, anticonvulsants and antiviral agents. When considering drug transport, two major super-families, ABC (ATP binding cassette) and SLC (solute carrier) transporters attract the highest scientific attention. The SLC super family includes genes that encode facilitating transporters and ion-coupled secondary active transporters that reside in various cell membranes. Genes of the solute carrier organic anion transporter (SLCO) family encode organic aniontransporting polypeptides (OATPs), membrane influx transporters identified mostly in the intestine, liver, kidney, lung, testes, placenta and blood-brain barrier among other organs. The OATP1B1 [previously OATP2, OATP-C and liver specific transporter 1 (LST-1)], expressed in the sinusoidal membrane of the hepatocytes, is known to be involved in the hepatic uptake of a broad array of endogenous compounds (e.g., steroid conjugates, bile acids, eicosanoids and thyroid hormones) and drugs such as methotrexate, fexofenadine, repaglinide and statins [1-6]. Examples of in vitro OATP1B1 drug substrates include several HMG-CoA reductase inhibitors, angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists [6-8]. Many drugs have also been identified in vitro as OATP1B1 inhibitors and there are some in vivo interactions where OATP1B1 inhibition can be regarded as an important mechanism. Examples include cyclosporine, atorvastatin, gemfibrozil and rifampicin [9,10]. The OATP1B1 protein is a 691-amino acid glycoprotein with 12 putative membrane-spanning domains and a large fifth extracellular loop. Its encoding gene, solute carrier organic anion transporter family member 1B1 (SLCO1B1), is located on chromosome 12 (gene locus 12p12) [11]. A large number of single nucleotide polymorphisms (SNPs), both non synonymous and synonymous, have been discovered in the SLCO1B1 gene, and several of these have proven to affect a substrate-dependent transport function in vitro and in vivo [12,13]. While no firm evidence for association between these SNPs and development of certain diseases (e.g., gallstone development, essential hypertension) due to dysregulation of endogenous compounds transport exists, there are numerous research data pointing to their effects on drugs responses. The SNPs 388 (A>G) (*1b, rs2306283) and 521 (C>T) (*5, rs4149056) are considered to be the most prevalent and most relevant variants, encoding a substitution of alanine for valine at amino acid 174 (p.Val174Ala), and amino acid change at position 130 (p.Asn130Asp), respectively. Increased transport activity of pravastatin as well as decreased plasma concentration of ezetimibe in carriers of the SLCO1B1*1b allele was observed [14,15], unlike reduced uptake of all statins except fluvastatin in hepatocytes and increased area under curve (AUC) of fexofenadine, repaglinide and irinotecan in carriers of SLCO1B1*5 [3,4,16,17]. The carriers of the c.521T>C variant were also highlighted by a genomewide association study as a population with an increased risk for simvastatin-induced myopathy because of the increased plasma and muscle exposure to statins [18]. These findings were further confirmed by Santos et al. [19], who suggested that the SLCO1B1 genetic risk depends on the specific drug that was used. It was also shown that subjects carrying the SLCO1B1 c.388GG genotype exhibit significantly higher low-density-lipoprotein cholesterol reduction relative to c.388AA+ c.388AG carriers, pointing out that the SLCO 1B1 c.388A>G polymorphism may be used as an important marker for predicting the efficacy of a lipid-lowering therapy [20]. Recent data point out that these two variants are in linkage disequilibrium (LD) and exist in variable SLCO 1B1 haplotypes; AT, a haplotype known as *1A (reference haplotype), GT as *1B, AC as *5 and GC as *15, for c.388 A>G and c.521T>C, respectively [13]. The *15 haplotype has been consistently associated with a decreased transport activity, while controversial results have been reported for the*1B haplotype [21]. It was also demonstrated that the SLCO1B1*17 haplotype (g.-11187G>A, c.388G>A and c.521T>C) was associated with increased plasma concentrations of pravastatin in humans [22], while the *14 haplo type (c.388G-c.463A-c.521T) was characterized with enhanced response to fluvastatin [23]. It is becoming evident that the incidence of sequence variations in the SLCO1B1 gene is largely dependent on the ethnic background. The c.521T>C variant showed an allele frequency of approximately 10.0-15.0% in Asian populations, 10.0-20.0% in Caucasians and 1.0-2.0% in African-American populations. The c.388A>G SNP showed an allele frequency of approximately 30.0-45.0% in Caucasians, 70.0-80.0% in African-American/Sub-Saharan African populations and 60.0-90.0% in Asian populations [12,22,24-26]. Therefore, characterization of the genetic variation in this transporting gene is an important step towards understanding the individual variation in drugs-substrates responses and developing a personalized and safer drug therapy. To the best of our knowledge, there is no evidence about genotyping of OATP1B1 in the populations living in Western Balkans. Also, there is no evidence when considering the populations living in the whole Balkan Peninsula, with exception of one report evaluating association between three SLCO1B1 SNPs and statin response in the Greek population [27]. In this respect, there has not been any report on the genotype of SLCO1B1 allelic variants in Macedonian and Albanian populations who are considered Caucasians. The origin of the Macedonians and Albanians is a continuing matter of discussion among historians; they also showed unequivocal signs of a common genetic history. In addition, Western Balkan countries have always been a historical crossroads between Asia, Africa and Europe. Considering all the above, the overall aim was to analyze the diversity of the SLCO1B1 gene in selected ethnically diverse populations living in the Western Balkans [Republic of Macedonia (RoM) and Republic of Kosovo (RoK)]. In this article, the results from the allele and genotypic frequencies of the several known SNPs in the SLCO1B1 gene and the haplotypes they form are presented. The results from this study could serve as a baseline clinical data for dosing of all drugs substrates of OATAP1B1 and avoiding the adverse drug reactions.



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