Dataset Information

Genetic polymorphism of the human organic solute carrier protein 1 (hOSCP1) gene in Japanese patients with non-viral liver carcinoma.

ABSTRACT: Human organic solute carrier protein 1 (hOSCP1) is a Na(+)-independent multispecific organic solute transporter. To date, several studies have revealed that gene mutations of the transporters are likely to be associated with some diseases; however, there are no data concerning the genetic polymorphism of the hOSCP1 gene in Japanese patients with non-viral liver carcinoma (LC). In the present study, we isolated genomic DNA from a normal portion of LC, and analyzed 41 single nucleotide polymorphisms (SNPs) chosen from a database of SNPs (dbSNPs). We found genotype frequencies for 2 non-synonymous SNPs [rs34409118 (Thr(131) ? Ala) and rs1416840 (Ile(219) ? Thr)] and 1 synonymous SNP [rs16822954 (Ser(193) ? Ser)] to be statistically significant when compared with dbSNPs. No statistical significance was observed in rs2275477 (Gly(307) ? Arg) in the hOSCP1 gene. With respect to the allele frequency, we also observed rs34409118 to be statistically significant. Interestingly, we found that non-viral LC patients do not carry heterozygous mutations in rs1416840 (A/G) and rs16822954 (A/G), suggesting that a non-carrier of heterozygous mutations in these two SNPs might be a biomarker for susceptibility for non-viral LC in Japanese. Further analyses of patients with hOSCP1 variants may elucidate the relationship between the hOSCP1 gene and susceptibility of non-viral LC in Japanese patients.

SUBMITTER: Toda M

PROVIDER: S-EPMC4287821 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Genetic polymorphism of the human organic solute carrier protein 1 (hOSCP1) gene in Japanese patients with non-viral liver carcinoma.

Toda Mayumi M Kobayashi Yasuna Y Koizumi Tomotake T Saito Koji K Ohbayashi Masayuki M Kohyama Noriko N Aoki Takeshi T Murakami Masahiko M Yasuhara Hajime H Yamamoto Toshinori T

Meta gene 20141001

Human organic solute carrier protein 1 (hOSCP1) is a Na(+)-independent multispecific organic solute transporter. To date, several studies have revealed that gene mutations of the transporters are likely to be associated with some diseases; however, there are no data concerning the genetic polymorphism of the hOSCP1 gene in Japanese patients with non-viral liver carcinoma (LC). In the present study, we isolated genomic DNA from a normal portion of LC, and analyzed 41 single nucleotide polymorphis ...[more]

PMID: 25606452

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Project description:The human solute carrier (SLC) superfamily of transporters is comprised of over 400 membrane-bound proteins, and plays essential roles in a multitude of physiological and pharmacological processes. In addition, perturbation of SLC transporter function underlies numerous human diseases, which renders SLC transporters attractive drug targets. Common genetic polymorphisms in SLC genes have been associated with inter-individual differences in drug efficacy and toxicity. However, despite their tremendous clinical relevance, epidemiological data of these variants are mostly derived from heterogeneous cohorts of small sample size and the genetic SLC landscape beyond these common variants has not been comprehensively assessed. In this study, we analyzed Next-Generation Sequencing data from 141,456 individuals from seven major human populations to evaluate genetic variability, its functional consequences, and ethnogeographic patterns across the entire SLC superfamily of transporters. Importantly, of the 204,287 exonic single-nucleotide variants (SNVs) which we identified, 99.8% were present in less than 1% of analyzed alleles. Comprehensive computational analyses using 13 partially orthogonal algorithms that predict the functional impact of genetic variations based on sequence information, evolutionary conservation, structural considerations, and functional genomics data revealed that each individual genome harbors 29.7 variants with putative functional effects, of which rare variants account for 18%. Inter-ethnic variability was found to be extensive, and 83% of deleterious SLC variants were only identified in a single population. Interestingly, population-specific carrier frequencies of loss-of-function variants in SLC genes associated with recessive Mendelian disease recapitulated the ethnogeographic variation of the corresponding disorders, including cystinuria in Jewish individuals, type II citrullinemia in East Asians, and lysinuric protein intolerance in Finns, thus providing a powerful resource for clinical geneticists to inform about population-specific prevalence and allelic composition of Mendelian SLC diseases. In summary, we present the most comprehensive data set of SLC variability published to date, which can provide insights into inter-individual differences in SLC transporter function and guide the optimization of population-specific genotyping strategies in the bourgeoning fields of personalized medicine and precision public health.

Project description:BACKGROUND & AIMS:Bile acid transporters maintain bile acid homeostasis. Little is known about the functions of some transporters in cholestasis or their regulatory mechanism. We investigated the hepatic expression of solute carrier organic anion transporter family member 3A1 (SLCO3A1, also called OATP3A1) and assessed its functions during development of cholestasis. METHODS:We measured levels of OATP3A1 protein and messenger RNA and localized the protein in liver tissues from 22 patients with cholestasis and 21 patients without cholestasis, using real-time quantitative polymerase chain reaction, immunoblot, and immunofluorescence analyses. We performed experiments with Slco3a1-knockout and C57BL/6J (control) mice. Mice and Sprague-Dawley rats underwent bile duct ligation (BDL) or a sham operation. Some mice were placed on a 1% cholic acid (CA) diet to induce cholestasis or on a control diet. Serum and liver tissues were collected and analyzed; hepatic levels of bile acids and 7-?-C4 were measured using liquid chromatography/mass spectrometry. Human primary hepatocytes and hepatoma (PLC/PRF/5) cell lines were used to study mechanisms that regulate OATP3A1 expression and transport. RESULTS:Hepatic levels of OATP3A1 messenger RNA and protein were significantly increased in liver tissues from patients with cholestasis and from rodents with BDL or 1% CA diet-induced cholestasis. Levels of fibroblast growth factor 19 (FGF19, FGF15 in rodents) were also increased in liver tissues from patients and rodents with cholestasis. FGF19 signaling activated the Sp1 transcription factor and nuclear factor ?B to increase expression of OATP3A1 in hepatocytes; we found binding sites for these factors in the SLCO3A1 promoter. Slco3a1-knockout mice had shorter survival times and increased hepatic levels of bile acid, and they developed more liver injury after the 1% CA diet or BDL than control mice. In hepatoma cell lines, we found OATP3A1 to take prostaglandin E2 and thyroxine into cells and efflux bile acids. CONCLUSIONS:We found levels of OATP3A1 to be increased in cholestatic liver tissues from patients and rodents compared with healthy liver tissues. We show that OATP3A1 functions as a bile acid efflux transporter that is up-regulated as an adaptive response to cholestasis.

Project description:Background & aimsBile acid transporters maintain bile acid homeostasis. Little is known about the functions of some transporters in cholestasis or their regulatory mechanism. We investigated the hepatic expression of solute carrier organic anion transporter family member 3A1 (SLCO3A1, also called OATP3A1) and assessed its functions during development of cholestasis.MethodsWe measured levels of OATP3A1 protein and messenger RNA and localized the protein in liver tissues from 22 patients with cholestasis and 21 patients without cholestasis, using real-time quantitative polymerase chain reaction, immunoblot, and immunofluorescence analyses. We performed experiments with Slco3a1-knockout and C57BL/6J (control) mice. Mice and Sprague-Dawley rats underwent bile duct ligation (BDL) or a sham operation. Some mice were placed on a 1% cholic acid (CA) diet to induce cholestasis or on a control diet. Serum and liver tissues were collected and analyzed; hepatic levels of bile acids and 7-α-C4 were measured using liquid chromatography/mass spectrometry. Human primary hepatocytes and hepatoma (PLC/PRF/5) cell lines were used to study mechanisms that regulate OATP3A1 expression and transport.ResultsHepatic levels of OATP3A1 messenger RNA and protein were significantly increased in liver tissues from patients with cholestasis and from rodents with BDL or 1% CA diet-induced cholestasis. Levels of fibroblast growth factor 19 (FGF19, FGF15 in rodents) were also increased in liver tissues from patients and rodents with cholestasis. FGF19 signaling activated the Sp1 transcription factor and nuclear factor κB to increase expression of OATP3A1 in hepatocytes; we found binding sites for these factors in the SLCO3A1 promoter. Slco3a1-knockout mice had shorter survival times and increased hepatic levels of bile acid, and they developed more liver injury after the 1% CA diet or BDL than control mice. In hepatoma cell lines, we found OATP3A1 to take prostaglandin E2 and thyroxine into cells and efflux bile acids.ConclusionsWe found levels of OATP3A1 to be increased in cholestatic liver tissues from patients and rodents compared with healthy liver tissues. We show that OATP3A1 functions as a bile acid efflux transporter that is up-regulated as an adaptive response to cholestasis.

Project description:BackgroundHydrallantois is the excessive accumulation of fluid within the allantoic cavity in pregnant animals and is associated with fetal mortality. Although the incidence of hydrallantois is very low in artificial insemination breeding programs in cattle, recently 38 cows with the phenotypic appearance of hydrallantois were reported in a local subpopulation of Japanese Black cattle. Of these, 33 were traced back to the same sire; however, both their parents were reported healthy, suggesting that hydrallantois is a recessive inherited disorder. To identify autozygous chromosome segments shared by individuals with hydrallantois and the causative mutation in Japanese Black cattle, we performed autozygosity mapping using single-nucleotide polymorphism (SNP) array and exome sequencing.ResultsShared haplotypes of the affected fetuses spanned 3.52 Mb on bovine chromosome 10. Exome sequencing identified a SNP (g.62382825G > A, p.Pro372Leu) in exon 10 of solute carrier family 12, member 1 (SLC12A1), the genotype of which was compatible with recessive inheritance. SLC12A1 serves as a reabsorption molecule of Na(+)-K(+)-2Cl(-) in the apical membrane of the thick ascending limb of the loop of Henle in the kidney. We observed that the concentration of Na(+)-Cl(-) increased in allantoic fluid of homozygous SLC12A1 (g.62382825G > A) in a hydrallantois individual. In addition, SLC12A1-positive signals were localized at the apical membrane in the kidneys of unaffected fetuses, whereas they were absent from the apical membrane in the kidneys of affected fetuses. These results suggested that p.Pro372Leu affects the membrane localization of SLC12A1, and in turn, may impair its transporter activity. Surveillance of the risk-allele frequency revealed that the carriers were restricted to the local subpopulation of Japanese Black cattle. Moreover, we identified a founder individual that carried the mutation (g.62382825G > A).ConclusionsIn this study, we mapped the shared haplotypes of affected fetuses using autozygosity mapping and identified a de novo mutation in the SLC12A1 gene that was associated with hydrallantois in Japanese Black cattle. In kidneys of hydrallantois-affected fetuses, the mutation in SLC12A1 impaired the apical membrane localization of SLC12A1 and reabsorption of Na(+)-K(+)-2Cl(-) in the thick ascending limb of the loop of Henle, leading to a defect in the concentration of urine via the countercurrent mechanism. Consequently, the affected fetuses exhibited polyuria that accumulated in the allantoic cavity. Surveillance of the risk-allele frequency indicated that carriers were not widespread throughout the Japanese Black cattle population. Moreover, we identified the founder individual, and thus could effectively manage the disorder in the population.

Dataset Information

Genetic polymorphism of the human organic solute carrier protein 1 (hOSCP1) gene in Japanese patients with non-viral liver carcinoma.

Publications

Genetic polymorphism of the human organic solute carrier protein 1 (hOSCP1) gene in Japanese patients with non-viral liver carcinoma.

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