Analysis of regulatory polymorphisms in organic ion transporter genes (SLC22A) in the kidney

Abstract

Organic cation transporters (OCTs) and organic anion transporters (OATs) (SLC22A family) play crucial roles in the renal secretion of various drugs. Messengar ribonucleic acid (mRNA) expression of transporters can be a key factor regulating interindividual differences in drug pharmacokinetics. However, the source of variations in mRNA levels of transporters is unclear. In this study, we focused on single nucleotide polymorphisms (SNP) in the promoter region [regulatory SNPs (rSNPs)] as candidates for the factor regulating mRNA levels of SLC22A. We sequenced the promoter regions of OCT2 and OAT1-4 in 63 patients and investigated the effects of the identified rSNPs on transcriptional activities and mRNA expression. In the OCT2 promoter region, one deletion polymorphism (-578_-576delAAG) was identified; -578_-576delA-AG significantly reduced OCT2 promoter activity (p \ 0.05), and carriers of -578_-576delAAG tend to have lower OCT2 mRNA levels, but the difference is not significant. There was no rSNP in the OAT1 and OAT2 genes. The five rSNPs of OAT3 and one rSNP of OAT4 were unlikely to influence mRNA expression and promoter activity. This is the first study to investigate the influences of rSNPs on mRNA expression of SLC22A in the kidney and to identify a regulatory polymorphism affecting OCT2 promoter activity.

Current Updates in the Genetic Polymorphisms of Human Organic Anion Transporters (OATs)

“…Four SNPs (-18C>T, rs3782099, rs1783811 and rs2078267) resulted in moderate decrease of torsemide renal clearance, while the SNP (rs4930423) led to an increased clearance of such drug. Ogasawara et al [57] also discovered one same mutation (-18C>T) from the Japanese cohort, which study concluded that it did not affect the promoter activity or the mRNA expression of this gene. Meanwhile, Lee et al [60] explored the functional consequence of E278K, which mutant possessed a reduced uptake activity of ES, Dehydroepiandrosteon sulfate (DHEA-s) and ochratoxin A (OTA).…”

“…In the study of 50 Korean human subjects, an additional synonymous SNP (1539G>A) and three more intronic SNPs (i4+269G>A, i7+154T>C and i9+206A>G), were recently reported [52]. However, Ogasawara et al [57] observed no polymorphism in the promoter region of OAT2, with 63 kidney samples from Japanese.…”

“…These mutants were further investigated in terms of their functional consequence, since they are relatively common. Later than that, five additional polymorphisms in the 5' UTR were described by Ogasawara et al [57]. None of the haplotypes showed an altered promoter activity of this gene, however, the individual mutational outcome was not studied.…”

Фармакогенетичні Аспекти Дії Метформіну У Хворих На цукровий Діабет 2-Го Типу

“…У кількох дослідженнях вказується на те, що ген SLC22A2 є ви-сокополіморфним за своєю природою [40][41][42][43]. Zolk et al [44] виявили, що такий варіант гена SLC22A2, як 808G > T (270Ala > Ser), сприяє зниженню біо-трансформації ліків.…”

Pharmacogenetics of Organic Cation Transporters

“…Ogasawara изучал регуляторные полиморфизмы в транспортерах и обнару-жил в ОСТ2 делецию в промоторной зоне (578-576delAAG). Было показано, что при наличии этого полиморфизма уменьшался уровень экспрессии мРНК ОСТ2 [23].…”