Functional Consequences of Single Nucleotide Polymorphisms in the Human Organic Anion Transporter hOAT1 (SLC22A6)

Abstract As a membrane influx transporter, organic anion- transporting polypeptide 1B1 (OATP1B1) regulates the cellular uptake of a number of endogenous compounds and drugs. The aim of this study was to characterize the diversity of the solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene encoding this transporter in two ethnic groups populating the Western Balkans. The distribution of SCLO1B1 alleles was determined at seven variant sites (c.388A>G, c.521T>C, c.571T>C, c.597C>T, c.1086C>T, c.1463G>C and c.*439T>G) in 266 Macedonians and 94 Albanians using the TaqMan allelic discrimination assay. No significant difference in the frequencies of the single nucleotide polymorphisms (SNPs) was observed between these populations. The frequency of the c.521T>C SNP was the lowest (<13.7 and 12.2%, respectively), while the frequencies of all other SNP alleles were above 40.0%. Variant alleles of c.1463G>C and c.1086 C>T SNPs were not identified in either ethnic group. The haplotype analysis revealed 20 and 21 different haplotypes in the Macedonian and Albanian population, respectively. The most common haplotype in both ethnic groups, *1J/*1K/*1L, had a frequency of 39.0% and 26.6%, respectively. In both populations, the variant alleles of the functionally significant c.521T>C and c.388A>G SNPs existed in one major haplotype (*15/*16/*17), with a frequency of 8.6 and 2.4% in the Macedonian and Albanian subjects, respectively. In conclusion, sequence variations of the SLCO1B1 gene in the studied populations occur at high frequencies, which are similar to that of the Caucasian population. Further studies are needed to evaluate the clinical significance of these SNPs and/ or the major SLCO1B1 haplotypes they form for a large number of substrates and for susceptibility to certain diseases.

Download Full-text

The organic anion transporter family: from physiology to ontogeny and the clinic

AJP Renal Physiology ◽

10.1152/ajprenal.2001.281.2.f197 ◽

2001 ◽

Vol 281 (2) ◽

pp. F197-F205 ◽

Cited By ~ 100

Author(s):

Douglas H. Sweet ◽

Kevin T. Bush ◽

Sanjay K. Nigam

Keyword(s):

Kidney Development ◽

Organic Anion ◽

Organic Anion Transporter ◽

New Drugs ◽

Spatiotemporal Pattern ◽

Nucleotide Polymorphisms ◽

Anion Transporter ◽

Transporter Family ◽

Computer Based ◽

Anionic Drugs

The organic anion transporter (OAT) family handles a wide variety of clinically important compounds (antibiotics, nonsteriodal anti-inflammatory drugs, etc.) and toxins. However, little is known about their appearance during development despite documented differences in the handling of anionic drugs among neonates, children, and adults. A similar spatiotemporal pattern of mRNA expression of the OATs (OAT1–4) during kidney development suggests that OAT genes may be useful in understanding the mechanisms of proximal tubule maturation. Moreover, OAT expression in unexpected extrarenal sites (e.g., spinal cord, bone, skin) has also been detected during development, possibly indicating a role for these transporters in the formation or preservation of extrarenal tissues. The cloning of these transporters also paves the way for computer-based modeling of drug-transporter interactions at the molecular level, potentially aiding in the design and assessment of new drugs. Additionally, increased understanding of single nucleotide polymorphisms in OATs and other transporters may eventually allow the use of a patient's expression profile and polymorphisms to individualize drug therapy.

Download Full-text

Germline variant in SLCO2B1 and response to abiraterone acetate plus prednisone (AA) in men with metastatic castration-resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.311 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. 311-311

Author(s):

Andrew W Hahn ◽

Darshan Patel ◽

David Michael Gill ◽

Camryn Froerer ◽

Roberto Nussensveig ◽

...

Keyword(s):

Prostate Cancer ◽

Cox Regression ◽

Salt Lake ◽

Organic Anion ◽

Predictive Biomarkers ◽

Organic Anion Transporter ◽

Nucleotide Polymorphisms ◽

Castration Resistant Prostate Cancer ◽

First Line ◽

Anion Transporter

311 Background: Currently, there are no predictive biomarkers of response to AA in mCRPC routinely used in the clinic. SLCO2B1 encodes a sodium-independent organic anion transporter that mediates transport of endogenous sex hormones and drugs, including AA, into tissue. Single nucleotide polymorphisms (SNPs) in SLCO2B1 are a validated predictive biomarker of response to androgen deprivation therapy in hormone sensitive prostate cancer. In a recent pre-clinical study, the AA/AG genotype for rs12422149 and the AA genotype for rs1789693 of SLCO2B1 had significantly higher mean tissue abiraterone levels. We hypothesize that the variant allele for rs12422149 and rs1789693 are predictive of improved response to AA in mCRPC. Methods: Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah (Salt Lake City, UT). Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was progression-free survival (PFS) on first-line AA in men with mCRPC. We performed pre-specified multivariate Cox regression analyses to assess the independent predictive value of SLCO2B1 rs12422149 and rs1789693 on PFS on AA (table). Results: 76 men with mCRPC treated with first-line AA were included. In a multivariate analysis for rs12422149, a trend towards improved median PFS was seen with the AG genotype (11.2 months) vs. the GG genotype (6.4 months) (HR 0.50, 95% CI 0.24-1.02, p=0.056). No such correlation was seen with rs1789693 genotypes. Conclusions: Consistent with pre-clinical studies, the AG genotype in rs12422149 of SLCO2B1 may be predictive of response to AA in men with mCRPC. This hypothesis-generating data needs further interrogation in larger and independent cohorts. [Table: see text]

Download Full-text