Objectives: Common dysfunctional variants of ATP binding cassette subfamily G member 2 (Junior blood group) (ABCG2), a high-capacity urate transporter gene, that result in decreased urate excretion are major causes of hyperuricemia and gout. In the present study, our objective was to determine the frequency and effect on gout of common and rare non-synonymous and other functional allelic variants in the ABCG2 gene. Methods: The main cohort recruited from the Czech Republic consisted of 145 gout patients; 115 normouricaemic controls were used for comparison. We amplified, directly sequenced and analysed 15 ABCG2 exons. The associations between genetic variants and clinical phenotype were analysed using the t-test, Fisher's exact test and a logistic and linear regression approach. Data from a New Zealand Polynesian sample set and the UK Biobank were included for the p.V12M analysis. Results: In the ABCG2 gene, 18 intronic (one dysfunctional splicing) and 11 exonic variants were detected: 9 were non-synonymous (2 common, 7 rare including 1 novel), namely p.V12M, p.Q141K, p.R147W, p.T153M, p.F373C, p.T434M, p.S476P, p.D620N and p.K360del. The p.Q141K (rs2231142) variant had a significantly higher minor allele frequency (0.23) in the gout patients compared with the European-origin population (0.09) and was significantly more common among gout patients than among normouricaemic controls (odds ratio = 3.26, P < 0.0001). Patients with non-synonymous allelic variants had an earlier onset of gout (42 vs 48 years, P = 0.0143) and a greater likelihood of a familial history of gout (41% vs 27%, odds ratio = 1.96, P = 0.053). In a meta-analysis p.V12M exerted a protective effect from gout (P < 0.0001). Conclusion: Genetic variants of ABCG2, common and rare, increased the risk of gout. Non-synonymous allelic variants of ABCG2 had a significant effect on earlier onset of gout and the presence of a familial gout history. ABCG2 should thus be considered a common and significant risk factor for gout.

• MeSH
• ABC transportér z rodiny G, člen 2 genetika   MeSH
• alely MeSH
• běloši genetika   MeSH
• dna (nemoc) genetika   MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• genetická variace MeSH
• hyperurikemie genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lineární modely MeSH
• logistické modely MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové proteiny genetika   MeSH
• původní obyvatelé Havajských a ostatních tichomořských ostrovů genetika   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Nový Zéland MeSH
• Spojené království MeSH

• MeSH
• ABC transportér z rodiny G, člen 2 genetika   MeSH
• antigeny krevních skupin * MeSH
• buněčná membrána metabolismus   MeSH
• lidé MeSH
• nádorové proteiny genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• dopisy MeSH

INTRODUCTION: All HIV positive pregnant women should receive combination antiretroviral therapy (cART) to prevent mother-to-child transmission (MTCT) of the virus. It has recently been shown that fetal exposure of nucleoside reverse transcriptase inhibitors (NRTIs) tenofovir disoproxil fumarate (TDF) and abacavir is decreased by placental ABC transporters p-glycoprotein (ABCB1) and BCRP (ABCG2). The aim of this study was to evaluate transporter-mediated drug-drug interactions (DDI) between etravirine (TMC125), a novel non-nucleoside reverse transcriptase inhibitor used in cART, and the NRTIs and to assess the relevance of such DDI for transplacental pharmacokinetics of TDF and abacavir. METHODS: In vitro accumulation assays and transport experiments on ABCB1 and ABCG2 overexpressing MDCKII monolayers were employed. Furthermore, the effect of etravirine on the transplacental passage of TDF and abacavir was assessed using in situ dually perfused rat placenta. RESULTS: We confirmed significant inhibition of ABCG2 but not ABCB1 by etravirine in hoechst accumulation assays. In transport studies on MDCKII-ABCG2 monolayers etravirine completely abolished the ABCG2-mediated transfer of [3H]-TDF. Similar effect was observed in [3H]-abacavir albeit at markedly lower etravirine concentration. Using dually perfused rat placenta, etravirine co-administration resulted in reduced fetal-to-maternal passage of TDF but not abacavir. DISCUSSION: Etravirine is able to affect transplacental passage of TDF but not that of abacavir through interactions on ABCG2. These results should be considered when introducing etravirine into TDF-containing cART in pregnancy.

• MeSH
• ABC transportér z rodiny G, člen 2 metabolismus   MeSH
• buněčné linie MeSH
• inhibitory reverzní transkriptasy farmakologie   MeSH
• krysa rodu rattus MeSH
• látky proti HIV farmakologie   MeSH
• lidé MeSH
• P-glykoprotein metabolismus   MeSH
• placenta účinky léků   metabolismus   MeSH
• potkani Wistar MeSH
• pyridaziny farmakologie   MeSH
• těhotenství MeSH
• tenofovir farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

ATP-binding cassette (ABC) transporters actively export a wide variety of molecules from cells, contributing to reduce the local cellular burden of toxic compounds. ABCG2/BCRP is abundantly expressed in epithelial cells of the intestine and colon. The expression and activity of this transporter in the gut differ between individuals, due at least in part to genetic polymorphisms, which may thus affect the risk of colorectal cancer (CRC). We selected 15 tagging SNPs, covering all the known genetic variation of the gene, and typed them in 680 CRC cases and 593 controls. We found that heterozygous carriers of the minor alleles of SNPs rs2622621 and rs1481012 had a decreased risk of CRC, respectively, with odds ratios of 0.73 (95% confidence interval 0.56-0.94; P(value)=0.017), and 0.72 (95% CI 0.53-0.97; P(value)=0.03). Thus, we found no strong and clearcut association between ABCG2 polymorphisms and CRC risk. To our knowledge this is the first report on ABCG2 and CRC risk.

• MeSH
• ABC transportér z rodiny G, člen 2 MeSH
• ABC transportéry genetika   MeSH
• alely MeSH
• dospělí MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci MeSH
• heterozygot MeSH
• jednonukleotidový polymorfismus * MeSH
• kolorektální nádory genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové proteiny genetika   MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

BACKGROUND: ABCG2 is a high-capacity urate transporter that plays a crucial role in renal urate overload and extra-renal urate underexcretion. Previous studies have suggested an association between hyperuricemia and gout susceptibility relative to dysfunctional ABCG2 variants, with rs2231142 (Q141K) being the most common. In this study, we analyzed the ABCG2 gene in a hyperuricemia and gout cohort focusing on patients with pediatric-onset, i.e., before 18 years of age. METHOD: The cohort was recruited from the Czech Republic (n = 234) and consisted of 58 primary hyperuricemia and 176 gout patients, with a focus on pediatric-onset patients (n = 31, 17 hyperuricemia/14 gouts); 115 normouricemic controls were used for comparison. We amplified, sequenced, and analyzed 15 ABCG2 exons. The chi-square goodness-of-fit test was used to compare minor allele frequencies (MAF), and the log-rank test was used to compare empirical distribution functions. RESULTS: In the pediatric-onset cohort, two common (p.V12M, p.Q141K) and three very rare (p.K360del, p.T421A, p.T434M) allelic ABCG2 variants were detected. The MAF of p.Q141K was 38.7% compared to adult-onset MAF 21.2% (OR = 2.4, P = 0.005), to the normouricemic controls cohort MAF 8.5% (OR = 6.8, P <  0.0001), and to the European population MAF 9.4% (OR = 5.7, P <  0.0001). The MAF was greatly elevated not only among pediatric-onset gout patients (42.9%) but also among patients with hyperuricemia (35.3%). Most (74%) of the pediatric-onset patients had affected family members (61% were first-degree relatives). CONCLUSION: Our results show that genetic factors affecting ABCG2 function should be routinely considered in a hyperuricemia/gout diagnosis, especially in pediatric-onset patients. Genotyping of ABCG2 is essential for risk estimation of gout/hyperuricemia in patients with very early-onset and/or a family history.

• MeSH
• ABC transportér z rodiny G, člen 2 genetika   MeSH
• alopurinol terapeutické užití   MeSH
• antiuratika terapeutické užití   MeSH
• dítě MeSH
• dna (nemoc) diagnóza   farmakoterapie   genetika   MeSH
• dospělí MeSH
• febuxostat terapeutické užití   MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci genetika   MeSH
• genotyp MeSH
• hyperurikemie diagnóza   farmakoterapie   genetika   MeSH
• jednonukleotidový polymorfismus * MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• předškolní dítě MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

ATP-binding cassette subfamily G member 2 (ABCG2) is a physiologically important urate transporter. Accumulating evidence demonstrates that congenital dysfunction of ABCG2 is an important genetic risk factor in gout and hyperuricemia; recent studies suggest the clinical significance of both common and rare variants of ABCG2. However, the effects of rare variants of ABCG2 on the risk of such diseases are not fully understood. Here, using a cohort of 250 Czech individuals of European descent (68 primary hyperuricemia patients and 182 primary gout patients), we examined exonic non-synonymous variants of ABCG2. Based on the results of direct sequencing and database information, we experimentally characterized nine rare variants of ABCG2: R147W (rs372192400), T153M (rs753759474), F373C (rs752626614), T421A (rs199854112), T434M (rs769734146), S476P (not annotated), S572R (rs200894058), D620N (rs34783571), and a three-base deletion K360del (rs750972998). Functional analyses of these rare variants revealed a deficiency in the plasma membrane localization of R147W and S572R, lower levels of cellular proteins of T153M and F373C, and null urate uptake function of T434M and S476P. Accordingly, we newly identified six rare variants of ABCG2 that showed lower or null function. Our findings contribute to deepening the understanding of ABCG2-related gout/hyperuricemia risk and the biochemical characteristics of the ABCG2 protein.

• MeSH
• ABC transportér z rodiny G, člen 2 genetika   metabolismus   MeSH
• běloši genetika   MeSH
• biologický transport MeSH
• dítě MeSH
• dna (nemoc) genetika   krev   metabolismus   MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• HEK293 buňky MeSH
• hyperurikemie genetika   krev   MeSH
• jednonukleotidový polymorfismus MeSH
• kohortové studie MeSH
• kyselina močová krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• nádorové proteiny MeSH
• předškolní dítě MeSH
• přenašeče organických aniontů MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Geografické názvy
• Česká republika MeSH

• MeSH
• ABC transportér z rodiny G, člen 2 genetika   MeSH
• dna (nemoc) diagnóza   genetika   MeSH
• genetická variace genetika   MeSH
• hyperurikemie diagnóza   genetika   MeSH
• lidé MeSH
• nádorové proteiny genetika   MeSH
• rodokmen MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• práce podpořená grantem MeSH

BACKGROUND: Nestin, CD133 and ABCG2 are recently discussed as putative markers, co-expression of which might determine a cancer stem cell (CSC) phenotype in sarcomas. OBJECTIVE: Our study is focused on immunohistochemical analysis of nestin, CD133 and ABCG2 expression in rhabdomyosarcoma, Ewing sarcoma and osteosarcoma. Furthermore, we also analyzed the possible correlation of nestin, CD133 and ABCG2 expression levels with the patient outcome to identify potential prognostic values of these three putative CSC markers in the same cohorts. METHODS: Using immunohistochemistry, expression of nestin, CD133 and ABCG2 was analyzed in 24 rhabdomyosarcoma, 22 Ewing sarcoma and 10 osteosarcoma tissue samples and expression levels of these markers were correlated with clinical outcome. RESULTS: High nestin levels indicate poor prognosis in patients with Ewing sarcoma (P = 0.001), and high CD133 expression is associated with shorter survival in rhabdomyosarcoma patients (P = 0.002). In contrast, no significant relationship was found between ABCG2 expression and the clinical outcome. CONCLUSIONS: Our analysis represents the first complex study of these three putative CSCs markers together in three different types of pediatric sarcomas and showed their possible prognostic values in these tumors.

• MeSH
• ABC transportér z rodiny G, člen 2 genetika   metabolismus   MeSH
• antigen AC133 genetika   metabolismus   MeSH
• dítě MeSH
• dospělí MeSH
• exprese genu MeSH
• imunohistochemie MeSH
• Kaplanův-Meierův odhad MeSH
• kojenec MeSH
• lidé MeSH
• metastázy nádorů MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové biomarkery * MeSH
• nádorové kmenové buňky metabolismus   MeSH
• nestin genetika   metabolismus   MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• prognóza MeSH
• sarkom diagnóza   genetika   metabolismus   mortalita   MeSH
• staging nádorů MeSH
• stupeň nádoru MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The ABCG2 gene is a well-established hyperuricemia/gout risk locus encoding a urate transporter that plays a crucial role in renal and intestinal urate excretion. Hitherto, p.Q141K-a common variant of ABCG2 exhibiting approximately one half the cellular function compared to the wild-type-has been reportedly associated with early-onset gout in some populations. However, compared with adult-onset gout, little clinical information is available regarding the association of other uricemia-associated genetic variations with early-onset gout; the latent involvement of ABCG2 in the development of this disease requires further evidence. We describe a representative case of familial pediatric-onset hyperuricemia and early-onset gout associated with a dysfunctional ABCG2, i.e., a clinical history of three generations of one Czech family with biochemical and molecular genetic findings. Hyperuricemia was defined as serum uric acid (SUA) concentrations 420 μmol/L for men or 360 μmol/L for women and children under 15 years on two measurements, performed at least four weeks apart. The proband was a 12-year-old girl of Roma ethnicity, whose SUA concentrations were 397-405 µmol/L. Sequencing analyses focusing on the coding region of ABCG2 identified two rare mutations-c.393G>T (p.M131I) and c.706C>T (p.R236X). Segregation analysis revealed a plausible link between these mutations and hyperuricemia and the gout phenotype in family relatives. Functional studies revealed that p.M131I and p.R236X were functionally deficient and null, respectively. Our findings illustrate why genetic factors affecting ABCG2 function should be routinely considered in clinical practice as part of a hyperuricemia/gout diagnosis, especially in pediatric-onset patients with a strong family history.

• MeSH
• ABC transportér z rodiny G, člen 2 genetika   metabolismus   MeSH
• dítě MeSH
• dna (nemoc) komplikace   genetika   MeSH
• dospělí MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• HEK293 buňky MeSH
• hyperurikemie krev   komplikace   genetika   MeSH
• jednonukleotidový polymorfismus * MeSH
• kyselina močová krev   MeSH
• lidé MeSH
• mutace MeSH
• nádorové proteiny genetika   metabolismus   MeSH
• přenašeče organických aniontů genetika   metabolismus   MeSH
• rodokmen MeSH
• transfekce MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH

Atazanavir and ritonavir are preferred protease inhibitors frequently used in combination antiretroviral therapy for prevention of HIV mother-to-child transmission. Although their use is associated with higher risk of congenital anomalies, factors affecting atazanavir and ritonavir placental transfer are not known. This study is the first attempt to evaluate whether the placental drug efflux ATP-binding cassette (ABC) transporters, p-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2), and/or multidrug resistance-associated proteins 2 (ABCC2), affect placental pharmacokinetics of atazanavir or ritonavir. Transport experiments across MDCKII cells expressing respective human ABC carrier showed that atazanavir is a substrate of ABCB1 and dual perfusion studies in a rat placenta confirmed this finding. In conclusion, we suggest that placental ABCB1 might reduce ATV maternal-to-fetal transfer and therefore represent a site for pharmacokinetic drug-drug interactions of ATV. Further studies in human placenta models are necessary to provide additional data closer to clinical environment.

• MeSH
• ABC transportér z rodiny G, člen 2 MeSH
• ABC transportéry metabolismus   MeSH
• atazanavir sulfát * farmakokinetika   farmakologie   MeSH
• buňky MDCK MeSH
• inhibitory HIV-proteasy * farmakokinetika   farmakologie   MeSH
• lékové interakce MeSH
• maternofetální výměna látek MeSH
• nádorové proteiny metabolismus   MeSH
• placenta * metabolismus   MeSH
• potkani Wistar MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům metabolismus   metabolismus   MeSH
• psi MeSH
• ritonavir * farmakokinetika   farmakologie   MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• psi MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH