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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DISCUSSION

It is clearly evident that the mutations in the SLCO1B1 gene and their clinical significance for a large number of endogenous and xenobiotic substrates transported by OATP1B1 is a persistent motivation for scientific research. To the best of our knowledge, this is the first study in which polymorphisms contained in the SLCO1B1 gene were studied in the populations living in the Western Balkan Peninsula. For this reason, commonly seen mutations (c.388A>G, c.521T>C, c.571T>C, c.597C>T, c.*439 T>G) as well as coding region SNPs that were not identified in the Caucasian (European) population (c.1086C>T, c.1463G>C) were selected for genotyping. Our data confirmed that SLCO1B1 is highly polymorphic and that several variants appear at a high frequency, both in the Macedonian and Albanian populations. The SNPs c.388A>G (Asn130Asp), c.571T>C (Leu- 191Leu), c.597C>T (Phe199 Phe) and c.*439T>G, all occurred with an allelic frequency between 40.0 and 65.0%. The non synonymous c.521T>C SNP, which has been constantly associated with a reduced OATP1B1 activity, was found with an allele frequency of approximately 14.0 and 12.0% in the Macedonian and Albanian population, respectively, which is nearly equal to that reported for Caucasians (15.0%) [32], slightly lower than that reported previously for Dutch (18.0%) [33], Finish (20.0%) [13], Algerian (17.0%) [11], Israeli (20.0%) [11], Japanese (16.0-19.0%) [11,34] and Korean (25.0%) [35] ethnic groups, and much higher than that reported for African Americans (2.3%) [12] and Sub-Saharan Africans (1.9%) [11] (Table 4). So far, literature data point to equal allele frequency for this SNP in Macedonians and European Americans [12] and Han Chinese [29], although a lower number of subjects in the last two groups was included in the study. The same was observed in Albanian and Turkish subjects, with an equal number of subjects in the study [36]. Compared to studies with Native Americans, Caucasian Europeans, Sub-Saharan Africans, Japanese and Israeli subjects [11], the variant alleles found in the Macedonian and Albanian subjects were lower for c.388A>G (41.0-42.0% vs. 46.0-79.0%), higher for c.571 T>C (62.0-65.0% vs. 13.0-61.0%) and nearly equal for c.597C>T (40.0-45.0% vs. 42.0-50.0%), with the exception of Native Americans in which a much lower allele frequency was observed (28.0%). The allele frequency for SNP c.*439T>G was lower in comparison with Sub-Saharan Africans (47.0-50.0% vs. 76.0%), higher than that of Caucasian Europeans (30.0%) and almost equal to the frequency of other ethnic groups, where a variant G allele existed with a frequency between 41.0% (Native Americans) and 55.0% (Israeli) (Table 4). No variant alleles were found for c.1086C>T and c.1463G>C SNPs in the Macedonian and Albanian populations and the same was observed in German, Finish, Japanese, Israeli and Turkish subjects [11,36], while in the studied Native American and Sub-Saharan African, Ugandan and Pakistani ethnic groups, a low frequency of variant alleles was observed, between 1.0 and 7.0% for variant T in c.1086C>T and 0.5 and 3.0% for variant C in c.1463G>C [11]. For all SNPs, the distributions of the genotypes did not differ significantly (p >0.05) between healthy subjects and patients and between male and female subjects. These data are partly in accordance with the results obtained in the study of Hubacek et al. [37], in which no difference for genotype distributions of rs4149056 variant between male and female subjects was observed. However, the results of the same study pointed to possible gender-dependent effects of this SNP within the SLCO1B1 gene on statin treatment efficacy. It is increasingly evident that the most relevant variants, the SNPs 388A>G and 521C>T, have a major effect on OATP1B1 activity. However, their association and other SNPs in LD with these functionalities may modify the respective phenotype and explain the discrepant effects of some SNPs on OATP1B1 activity in vivo. Most of the literature data point to a strong association between this SNP pair and its effect on drug response [20,29]. In the actual study, the association between c.388A>G and c.521 T>C was relatively weaker compared to other SNP pairs, especially those in the Albanian population. These data and generally, the differences between the two populations in LD data, are probably explained by the significantly smaller number of Albanian subjects included in the study and random sampling variation. The c.521T>C SNP showed the strongest correlation with the c.597C>T in both populations and the similar results have been obtained in the study of Pasanen et al. [13], in which a large sample (468) of Caucasian subjects was included. Compared with the analysis performed with single SNPs, haplotypes often better predict the associated phenotype. In the present study, the most common SLCO1B1 haplotype, *IJ/*IK/*IL, contained the synonymous c.571 T>C SNP as compared with the reference sequence. It occurred at a frequency (35.6%) similar to that reported in the study of Pasanen et al. [13]. The c.521T>C SNP existed in two (*5 and *15/*16/*17) major haplotypes in the Macedonian and Albanian populations and one new, identified in the Albanian population only. Both common haplotypes, with a frequency of 2.0 and 3.7% (for *5) and 2.4 and 8.6% (for *15/*16/*17) in the Macedonian and Albanian subjects, respectively, contained the c.597C>T and c.439T>G SNPs. In the new haplotype identified in the Albanian population, instead of variant G allele in the c.439T>G SNP, variant C allele of c.571T>C existed, with referent alleles in other SNPs. Considering the significantly smaller number of subjects in the Albanian population, as potential limitation of this study, this result should be confirmed in a study in which a larger number of Albanian subjects would be included. The frequencies of the major haplotype *15/*16/*17 containing the variant alleles of the functionally most significant SNP pair c.388A>G/ c.521T>C (8.6 and 2.4% for Macedonians and Albanians, respectively) were lower than the frequency of haplotype *15 reported for Chinese (14.0%) and Japanese (15.8%), higher for Macedonians and comparable for Albanians with that of Caucasians (2.4%) and significantly higher than the one of African Americans (0.0%) [13,29]. In conclusion, this study presents an extensive analysis of SLCO1B1 variant genotype and haplotype distribution in selected populations living in the Western Balkan Peninsula, Macedonians and Albanians for the first time. No significant differences (p >0.05) in allelic frequencies and genotype distributions of the analyzed SNPs were observed between the two ethnic groups and the data are similar to those for Caucasians. About 8.6 and 2.4% of the Macedonians and Albanians, respectively, carrying the SLCO1B1*15 or SLCO1B1*16 or SLCO1B1*17 variant may exhibit altered/impaired transport activity of OATP1B1. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.



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