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SLC22A6 (OAT1) and SLC22A8 (OAT3)

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SLC22A6 (OAT1) and SLC22A8 (OAT3) J Hum Genet (2006) 51:575–580 DOI 10.1007/s10038-006-0398-1 SHORT COMMUNICATION Vibha Bhatnagar Æ Gang Xu Æ Bruce A. Hamilton David M. Truong Æ Satish A. Eraly Æ Wei Wu Sanjay K. Nigam Analyses of 5¢ regulatory region polymorphisms in human SLC22A6 (OAT1) and SLC22A8 (OAT3) Received: 6 January 2006 / Accepted: 23 February 2006 / Published online: 29 April 2006 Ó The Japan Society of Human Genetics and Springer-Verlag 2006 Abstract Kidney excretion of numerous organic anionic Keywords SLC22A6, OAT1, NKT Æ SLC22A8, OAT3, drugs and endogenous metabolites is carried out by a ROCT Æ Organic anion transporters Æ Promoters Æ family of multispecific organic anion transporters Single nucleotide polymorphisms (OATs). Two closely related transporters, SLC22A6, initially identified by us as NKT and also known as OAT1, and SLC22A8, also known as OAT3 and ROCT, are thought to mediate the initial steps in the transport of Introduction organic anionic drugs between the blood and proximal tubule cells of the kidney. Coding region polymorphisms The organic anion transporters (OATs) constitute a in these genes are infrequent and pairing of these genes in subfamily within the SLC22 family of solute carriers the genome suggests they may be coordinately regulated. (Eraly et al. 2003). Two members of this subfamily, Hence, 5¢ regulatory regions of these genes may be SLC22A6 (also known as OAT1), originally identified as important factors in human variation in organic anionic novel kidney transporter (NKT; Lopez-Nieto et al. 1996, drug handling. We have analyzed novel single nucleotide 1997)andSLC22A8 (also known as OAT3), originally polymorphisms in the evolutionarily conserved 5¢ regu- identified as reduced in osterosclerosis (ROCT) (Brady latory regions of the SLC22A6 and SLC22A8 genes et al. 1999), function as the major basolateral trans- (phylogenetic footprints) in an ethnically diverse sample porters of a wide variety of drugs and toxins excreted via of 96 individuals (192 haploid genomes). Only one the proximal tubule of the kidney. These drugs include polymorphism was found in the SLC22A6 5¢ regulatory nonsteroidal anti-inflammatory drugs, antibiotics, an- region. In contrast, seven polymorphisms were found in tivirals (such as adefovir and cidofovir), antihyperten- the SLC22A8 5¢ regulatory region, two of which were sives, diuretics, methotrexate and many other commonly common to all ethnic groups studied. Computational prescribed drugs (Eraly et al. 2004a, b). They are also analysis permitted phase and haplotype reconstruction. responsible for the excretion of toxins such as Ochra- Proximity of these non-coding polymorphisms to toxin A and mercurials, and are believed to be essential transcriptional regulatory elements (including potential for the mediation of the renal toxicity of these agents sex steroid response elements) suggests a potential (Sweet 2005). In addition, recent mouse knockout influence on the level of transcription of the SLC22A6 studies suggest that these two genes are sufficient to and/or SLC22A8 genes and will help define their role in explain most of the excretion of certain prototypical variation in human drug, metabolite and toxin excretion. organic anions like para-aminohippurate (PAH), es- The clustering of OAT genes in the genome raises the trone sulfate and taurocholate (Sweet et al. 2002; Eraly possibility that nucleotide polymorphisms in SLC22A6 et al. 2005), consistent with the notion that these two could also effect SLC22A8 expression, and vice versa. genes mediate the rate-limiting step for uptake of or- ganic anion drugs from the blood. For these reasons, there has been much interest in the V. Bhatnagar (&) Æ G. Xu Æ B.A. Hamilton Æ D.M. Truong S.A. Eraly Æ W. Wu Æ S.K. Nigam possibility that polymorphisms in SLC22A6 and Departments of Pediatrics, Medicine, Cellular and Molecular SLC22A8 may be partly responsible for variation in the Medicine, Family, Preventative Medicine, and the San Diego handling and efficacy of the many commonly used drugs Veterans Administration Medical Center, that are transported by these transporters. Likewise, University of California-San Diego, such polymorphisms could conceivably explain suscep- 9500 Gilman Dr., 0693, La Jolla, CA 92093-0693, USA tibility to the toxicity of drugs and environmental toxins. E-mail: [email protected] Recent studies have thus analyzed coding region 576 polymorphisms in these genes (Xu et al. 2005; Bleasby that could affect SLC22A6 expression. This approach et al. 2005; Fujita et al. 2005). However, unlike other can be more broadly applied to identify potential regu- members of this subfamily such as SLC22A11 (also latory region SNPs for SLC22A6 and SLC22A8, as well known as OAT4)andSLC22A12 (also known as as other SLC22 family members. It will be important to URAT1 and originally identified as RST in mouse), consider these polymorphisms, along with those found there appear to be relatively infrequent nonsynonymous in coding regions, in clinical studies aimed at under- coding region human polymorphisms in SLC22A6 and standing variation in drug handling and toxin suscepti- SLC22A8 (Xu et al. 2005). Thus, while some variation in bility mediated via OATs. drug/toxin handling might be explained by coding re- gion polymorphisms in these genes, the apparent paucity of such polymorphisms suggests the need to also analyze Materials and methods noncoding region variation in these genes, which might, for example, affect the transcription of SLC22A6 and Phylogenetic footprinting SLC22A8 and thereby the total levels of functional protein. We have previously defined phylogenetic footprints SLC22A6 and SLC22A8 exist as a tandem pair on (PFs) of SLC22A6 and SLC22A8 5¢ regulatory regions human chromosome 11 (Fig. 1). Given the complex (Eraly et al. 2003). Briefly, reference SLC22A6 and genomic structure and the as yet undetermined promoter SLC22A8 regulatory sequences for human, chimpanzee regions of SLC22A6 and SLC22A8, we have utilized the and mouse were acquired from the University of Cali- computational technique of phylogenetic footprinting to fornia Santa Cruz (UCSC) Genome Browser (http:// identify evolutionarily conserved noncoding regions of www.genome.ucsc.edu/). An 8 kb region of sequence the SLC22A6 and SLC22A8 genes (Fig. 1); these regions upstream from the first translational start site for the are likely to contain sequences important for regulating SLC22A6 and SLC22A8 genes was obtained for each gene expression (Kim et al. 2004; Prohaska et al. 2004). species (Fig. 1). PFs were then identified through We identified three such regions in the SLC22A6 gene sequence alignment using pairwise BLAST (http:// and five regions in the SLC22A8 gene. We then se- www.ncbi.nlm.nih.gov/BLAST) and then realigned quenced these regions in an ethnically diverse panel of using ClustalX (http://bips.u-strasbg.fr/fr/Documenta- human DNA samples in order to identify single nucle- tion/ClustalX/). Homology between human, chimpan- otide polymorphisms (SNPs) likely to affect the expres- zee, and mouse was confined to three regions on the sion of the SLC22A6 and SLC22A8 transcripts. The promoter/enhancer of SLC22A6 (designated PFi1, PFi2, data suggest a number of polymorphisms that could and PFi3) and five regions on the promoter/enhancer of affect SLC22A8 expression and a more limited number SLC22A8 (designated PFu1 to PFu5). PFi1, PFi2, and A SLC22A6/8 Phylogenetic Footprints on Human Chromosome 11 Centromere- 62510K 62520K 62530K 62540K 62545K < < 2 1 3 SLC22A6/OAT1 SLC22A8/OAT3 PFi2 PFu B SLC22A8 Promoter/Enhancer Putative Binding Sites SP1 OCT1 ISL1 TCF MEF2 PAX1 OCT1 HNF1 MYOD SRE CEBP CEBP MEF2 MEF2 CREB PFus > PFu3 PFu1 PFu2 SNP -2521C>T-2520A>G -1901C>G -1882G>C-1851G>A 30A>G 41C>A Fig. 1a,b Locations of single nucleotide polymorphisms (SNPs) regions of PFs are indicated relative to the transcriptional start on phylogenetic footprints (PFs) of human SLC22A6 and sites. The locations of the PFs are relative to each other, and the SLC22A8 on chromosome 11. a Locations of SLC22A6 and distances between them are not proportional. b Conserved regions SLC22A8 on human chromosome 11. The genomic distance is on the promoter/enhancer SLC22A8 (PFus) are depicted relative relative to the centromere, derived from the University of to the transcription start site (arrow). Selected putative transcrip- California Santa Cruz (UCSC) genome database. SLC22A6 and tion factor sites are listed according to general localization on the SLC22A8 are separated by a small interval of 8 kb, and the PFus. Positions of the SNPs, by distance to the transcription start direction of their transcription is indicated by arrows. The site, are marked to indicate the proximity to the transcription proximal locations of the evolutionarily conserved regulatory factor binding sites functional kidney. Thisrecognition polymorphism site, was a gene found critical in for the a development of a stream from theSLC22A6 consensus Wilm’s tumor gene ( population size. lated haplotypesarlequin/). inferred This network by alsosoftware PHASE incorporates package the ARLEQUIN from extrapo- (http://anthro.unige.ch/ each a haplotype, larger of the a algorithm. Topopulation network discern of the 10,000 was phylogenetic in lineagedetermined order of created to for satisfy the thetypes using requirement for population each individual; the and haplotypesegments frequencies extrapolated and are then then toemploys creates a statistically an probable algorithmstat.washington.edu/stephens/software.html). haplo- that partitionstypes PHASE each were
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