Genotyping of coding single nucleotide variants of the hOAT2[SLC22A7] gene in Japanese patients with non-viral liver tumor (2023)

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Humanorganic anion transporters2 (hOAT2[SLC22A7]) there and after+-independent multispecific organic solute (SLC) transporter. To date, there are several findings regarding the function and substrates of hOAT2 [SLC22A7] has been reported; there is still limited data ongenetic variantsofhOAT2[SLC22A7]gene in Japanese, especially in patients with non-viral hepatocellular carcinoma (LC). In this study, we isolated genomic DNA from a normal part of the liver cancer and comprehensively screened 88 codingsingle nucleotide polymorphologies(cSNPs) selected from a database of SNPs (dbSNPs). We found genotype and allele frequencies for 1 synonymous SNP [rs2270860 (1324C>T, Ser425Is)] are statistically significant compared to the SNP database ( Our present results suggest that, at least in part, within the entire coding region sequence ofhOAT2[SLC22A7]gen, rs2270860 (1324C>T, Ser425Is) may be useful as a biomarker of susceptibility to non-viral LC in Japanese.


Over the past two decades, many researchers have succeeded in isolating several multi-specific organic ion transporters, such as multi-drug resistance associated proteins (Mrps), organic anion transporting polypeptides (OATPs), organic cation transporters (OCTs ) and organic anion transporters (Oats). Among them,SLC22A612ISLC22A20genes encoding OATs (Nigam et al., 2015). hOAT2[SLC22A7] is abundantly expressed in the liver and weakly expressed in the kidney (Sun et al., 2001). Therefore, hOAT2[SLC22A7], next to hOAT5[SLC22A10] (Shin et al., 2007) i hOAT7 (SLC22A9) (Klein et al., 2010), is considered an important transport protein in the processing of organic anions in the liver.

Liver malignancies as well as advanced gastric, colon and lung carcinomas are known to be the most common causes of cancer-related death worldwide (Parkin et al., 2005). Several causes of hepatocellular carcinoma (LC) have been reported to date (Hamed and Ali, 2013); chronic infection with hepatitis C virus (HCV) is considered a major cause of LC (De Bac et al., 1994) and is associated with more than 70% of liver tumors in Japan (Colombo, 1992; Tanaka et al., 1991 ) . , Okuda, 1992, Tanaka et al., 2014a). Although chronic HCV infection is strongly correlated with the development of LC (Bartosch et al., 2009), non-viral factors also play a central role in the progression of LC. In this regard, several non-viral factors contribute to the occurrence of hepatocellular carcinoma (HCC): hereditary hemochromatosis (Powell et al., 2000), diabetes mellitus (Tanaka et al., 1991, Tanaka, 2014b), obesity (Blonski et al. al. al. al., 2010), Wilson's disease (Reyes, 2008), congestive liver disease (Muguti et al., 1992), a family history of liver tumors (Turati et al., 2012) and non-alcoholic fatty liver disease (NAFLD) ( Caldwell et al. Crespo, 2004). In addition, hepatocarcinoma risks may be influenced by exposure to small molecules such as pesticides (Anwar et al., 2008) and aflatoxins (Qian et al., 1994).

Because hOAT2[SLC22A7] primarily expressed in the human liver (Sun et al., 2001), we hypothesized that a single nucleotide variation ofhOAT2[SLC22A7]the gene may be related to the development and/or progression of non-viral LC, as observed in our publication (Toda et al., 2014). At present, however, there are still limited data on whether genetic variation ofhOAT2[SLC22A7]the gene influences the risk of non-viral LC.

Therefore, in this study we analyzed 88 cSNPs ihOAT2[SLC22A7]gene and studied about genetic variants inhOAT2[SLC22A7]the gene is associated with non-viral LC in Japanese.

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Noncancerous human liver tissue (normal parts) was obtained from 17 Japanese partial hepatectomy patients with nonviral LC at Showa University Hospital. The liver samples were numbered anonymously. All patients gave their written informed consent before surgery. This study was conducted in accordance with the Declaration of Helsinki and its amendments and was approved by the Human Genome Ethics Committee, Showa University (57-2).

Genomic DNA purification

Genotyping was determined by direct sequencing


Table 2 shows the list of cSNP IDs and the results of genotype and allele frequencies ofhOAT2[SLC22A7]gen. As reported in Table 2, we found that 3 synonymous cSNPs [rs144441599 (Pro52Pro), rs2270860 (Ser425Is), rs70953694 (Thr515Thr)], and 1 non-synonymous cSNPs [rs202191934 (Arg339Is)] shows a genetic variation inhOAT2[SLC22A7]gen. On the other hand, no genetic polymorphisms were observed in the remaining 84 cSNPs. Based on this, we then analyzed the genotype and the allele


The current study is the first report of polymorphisms of the gene encoding human organic anion transporter 2 (hOAT2[SLC22A7]) in Japanese patients with non-viral hepatocellular carcinoma. Although genotype and allele frequencies of hOAT2[SLC22A7] has been reported in healthy Japanese subjects (Xu et al., 2005) and in Koreans (Shin et al., 2010), we found a significant difference in rs2270860 (1324C>T, Ser425)Is) when we compared dbSNPs (HapMap-JPT, ld

Conflict of interest

There is no conflict of interest.


This work was supported in part by Grants-in-Aid for Private University High Technology Research Center Project Matching Fund Grant fromMEKST(Ministry of Education, Culture, Sports, Science and Technology) (2011-2015).


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    What is the function of the organic anion transporter? ›

    Organic anion transporters (OATs) are the secondary/tertiary active transporter proteins that regulate anion balance in the body. They are primarily expressed in the kidney and liver and control the excretion of common drugs, toxins, and endogenous metabolites into the urine.

    What are the substrates of Oat2? ›

    Substrates for Oat2 include salicylate, acetylsalicylate, prostaglandin E2, dicarboxylates, glutamate, and PAH, as well as some antivirals (Table 1) (34).

    What are the substrates of OAT1 and oat3? ›

    OAT1 and 3 have strongly overlapping substrate specificities; important drug substrates of both include penicillins, NSAIDs, methotrexate, HIV protease inhibitors, and antivirals. Inhibition of OATs results in reduced or delayed renal elimination.

    What is an example of an organic anion? ›

    Examples of such anions are hippurate, long chain fatty acids, bile salts, urate, prostaglandins, antibiotics, and diuretics, and examples of cations are choline, catecholamines, histamine, quinine, and cimetidine.

    What are the 2 most important organic cation transporters in the liver and kidney? ›

    In the kidney, human organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) are the major transporters for the secretion of cationic drugs into the urine.

    Which drugs are secreted via organic anion transporters in the kidney? ›

    Organic Anion Transporters

    Several clinically important anionic drugs are OAT substrates, such as β-lactam antibiotics, diuretics, and nonsteroidal anti-inflammatories (NSAIDs).

    What is organic anion transporter 1 in kidney? ›

    OAT1 is a transmembrane protein that is expressed in the brain, the placenta, the eyes, smooth muscles, and the basolateral membrane of proximal tubular cells of the kidneys. It plays a central role in renal organic anion transport.

    How do organic cation transporters work? ›

    9.6 Organic Cation Transporters (OCTs) OCT refers to one of the most abundant transporters of the liver. OCTs are considered as poly-specific membrane transporters that act by mediating the hepatic uptake of hydrophilic compounds that are small and positively charged including dopamine, serotonin, and histamine.

    Where is organic anion transporter located in kidney? ›

    Renal transporters for organic anions are located in the proximal tubule segment of the nephron. The primary transporters of organic anions on the basolateral membrane (BLM) of proximal tubule cells are members of the organic anion transporter (OAT) family (mainly OAT1 and OAT3).

    What is the function of co transport protein? ›

    Cotransporters are a major class of membrane transport proteins that are responsible for the accumulation of nutrients, neurotransmitters, osmolytes and ions in cells from bacteria to man. The energy for solute accumulation comes from the proton and/or sodium electrochemical gradients that exist across cell membranes.


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