RESUMO
BACKGROUND: Replication studies showed conflicting effects of ABCG2 and SLC2A9 polymorphisms on gout and serum urate. This meta-analysis therefore aimed to pool their effects across studies. METHODS: Studies were located from MEDLINE and Scopus from inception to 17th June 2018. Observational studies in adults with any polymorphism in ABCG2 or SLC2A9, and outcome including gout, hyperuricemia, and serum urate were included for pooling. Data extractions were performed by two independent reviewers. Genotype effects were pooled stratified by ethnicity using a mixed-effect logistic model and a multivariate meta-analysis for dichotomous and continuous outcomes. RESULTS: Fifty-two studies were included in the analysis. For ABCG2 polymorphisms, mainly studied in Asians, carrying 1-2 minor-allele-genotypes of rs2231142 and rs72552713 were respectively about 2.1-4.5 and 2.5-3.9 times higher odds of gout than non-minor-allele-genotypes. The two rs2231142-risk-genotypes also had higher serum urate about 11-18 µmol/l. Conversely, carrying 1-2 minor alleles of rs2231137 was about 36-57% significantly lower odds of gout. For SLC2A9 polymorphisms, mainly studied in Caucasians, carrying 1-2 minor alleles of rs1014290, rs6449213, rs6855911, and rs7442295 were about 25-43%, 31-62%, 33-64%, and 35-65% significantly lower odds of gout than non-minor-allele-genotypes. In addition, 1-2 minor-allele-genotypes of the latter three polymorphisms had significantly lower serum urate about 20-49, 21-51, and 18-54 µmol/l than non-minor-allele-genotypes. CONCLUSIONS: Our findings should be useful in identifying patients at risk for gout and high serum urate and these polymorphisms may be useful in personalized risk scores. TRIAL REGISTRATION: PROSPERO registration number: CRD42018105275 .
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Proteínas Facilitadoras de Transporte de Glucose/genética , Gota/genética , Hiperuricemia/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Ácido Úrico/sangue , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Alelos , Povo Asiático , Feminino , Expressão Gênica , Frequência do Gene , Genótipo , Proteínas Facilitadoras de Transporte de Glucose/sangue , Gota/sangue , Gota/diagnóstico , Gota/etnologia , Humanos , Hiperuricemia/sangue , Hiperuricemia/diagnóstico , Hiperuricemia/etnologia , Masculino , Proteínas de Neoplasias/sangue , Razão de Chances , População BrancaRESUMO
OBJECTIVES: To measure the blood expression levels of related drug-resistant ATP-binding cassette (ABC) transporters in colorectal cancer (CRC) patients and to assess these examined transporters for whether they present signi cant expression in connection with the tumor appearance of CRC. METHODS: In this case-control study, the messenger ribonucleic acids were isolated from the blood of 62 CRC patients who were recruited from King Abdulaziz University Hospital Oncology Clinic and 46 controls from King Fahad General Hospital Blood Bank (Jeddah, Saudi Arabia) from September 2016 to March 2017. The Biomedical Ethics Unit at King Abdulaziz University, Jeddah, Saudi Arabia approved this study. The expressions of ABC transporters were measured using quantitative polymerase chain reaction. GraphPad Prism 5 and REST 2009 Software were used to correlate the expressions with clinicopathological independent stages and body mass index. A p-value of less than 0.05 was considered significant. RESULTS: The results showed that the 3 ABC transporters, particularly ABCC1 (p less than 0.0001), were highly expressed in the blood of CRC patients compared with controls. However, none of the 3 transporters was related to the progression of CRC, age, gender, or body mass index. CONCLUSION: The expressions of ABC transporters were found to be significantly higher in CRC patients, and they may act as diagnostic markers and should potentially be tested for their contribution to drug sensitivity in CRC patients.
Assuntos
Transportadores de Cassetes de Ligação de ATP/sangue , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/diagnóstico , Expressão Gênica , Subfamília B de Transportador de Cassetes de Ligação de ATP/sangue , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Estudos de Casos e Controles , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/sangue , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/genética , Reação em Cadeia da Polimerase , Arábia SauditaRESUMO
Hyperuricemia is an important risk factor of chronic kidney disease, metabolic syndrome and cardiovascular disease. We aimed to assess the time-feature relationship of hyperuricemia mouse model on uric acid excretion and renal function. A hyperuricemia mouse model was established by potassium oxonate (PO) and adenine for 21 days. Ultra Performance Liquid Chromatography was used to determine plasma uric acid level. Hematoxylin-eosin staining was applied to observe kidney pathological changes, and Western blot was used to detect renal urate transporters' expression. In hyperuricemia mice, plasma uric acid level increased significantly from the 3rd day, and tended to be stable from the 7th day, and the clearance rate of uric acid decreased greatly from the 3rd day. Further study found that the renal organ of hyperuricemia mice showed slight damage from the 3rd day, and significantly deteriorated renal function from the 10th day. In addition, the expression levels of GLUT9 and URAT1 were upregulated from the 3rd day, while ABCG2 and OAT1 were downregulated from the 3rd day, and NPT1 were downregulated from the 7th day in hyperuricemia mice kidney. This paper presents a method suitable for experimental hyperuricemia mouse model, and shows the time-feature of each index in a hyperuricemia mice model.
Assuntos
Modelos Animais de Doenças , Hiperuricemia/sangue , Hiperuricemia/fisiopatologia , Rim/patologia , Ácido Úrico/sangue , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Adenina/toxicidade , Animais , Cromatografia Líquida de Alta Pressão , Creatinina/sangue , Proteínas Facilitadoras de Transporte de Glucose/sangue , Hiperuricemia/induzido quimicamente , Hiperuricemia/metabolismo , Rim/metabolismo , Camundongos , Proteína 1 Transportadora de Ânions Orgânicos/sangue , Transportadores de Ânions Orgânicos/sangue , Transportadores de Ânions Orgânicos/metabolismo , Ácido Oxônico/toxicidade , Proteínas Cotransportadoras de Sódio-Fosfato Tipo I/sangue , Fatores de TempoRESUMO
This study was aimed at evaluating the prospect of edible chrysanthemum extract as a potential substance for the prevention and treatment of hyperuricemia. Chrysanthemum morifolium Ramat. 'Boju' extract (CBE), which had the strongest xanthine oxidase inhibitory activity, showed a significant hypouricemic effect on potassium oxonate-induced hyperuricemic rats through inhibiting serum xanthine oxidase activity, regulating renal uric acid transport-related protein (ABCG2, URAT1 and GLUT9) expression and blood lipid levels, and protecting renal function. Serum metabolomics based on UPLC-ESI-QTOF/MS was used to illustrate mechanisms underlying the amelioration effect of CBE on hyperuricemia. A total of 35 potential biomarkers were identified. CBE prevented the pathological process of hyperuricemia by regulating 16/17 biomarkers associated with tryptophan, sphingolipid, glycerophospholipid and arachidonic acid metabolisms. CBE could alleviate hyperuricemia-related diseases including chronic kidney disease, hyperlipidemia and inflammation via reducing indoxyl sulfate, lysophosphatidylcholines and arachidonic acid levels, exhibiting its applicability and superiority in the treatment of hyperuricemia.
Assuntos
Chrysanthemum/química , Medicamentos de Ervas Chinesas/administração & dosagem , Hiperuricemia/tratamento farmacológico , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Cromatografia Líquida de Alta Pressão , Proteínas Facilitadoras de Transporte de Glucose/sangue , Proteínas Facilitadoras de Transporte de Glucose/genética , Humanos , Hiperuricemia/sangue , Hiperuricemia/genética , Masculino , Espectrometria de Massas , Metabolômica , Transportadores de Ânions Orgânicos/sangue , Transportadores de Ânions Orgânicos/genética , Ratos , Soro/química , Soro/metabolismo , Xantina Oxidase/sangue , Xantina Oxidase/genéticaRESUMO
PURPOSE: Ceftriaxone elimination occurs through breast cancer resistance transporter (BCRP) and multidrug resistance-associated protein 2 (MRP-2) which are expressed on the canalicular membrane of hepatocytes. Eltrombopag, a thrombopoetin receptor agonist used in the treatment of immune thrombocytopenic purpura, is reported in in vitro studies as an inhibitor of intestinal BCRP but not an inhibitor of hepatic BCRP. Thus, the present study evaluates the effect of therapeutic doses of eltrombopag on the clinical pharmacokinetics of intravenous ceftriaxone. METHODS: Healthy adult (n=12) were treated with oral doses of eltrombopag (0, 25 or 50 mg) 28 and 4 h prior to intravenous ceftriaxone administration (1g). Serial blood samples were collected up to 48 h after ceftriaxone administration and plasma samples were analysed by LC-MS/MS using 50 µL aliquots (total concentration) and 100 µL (unbound concentration). RESULTS: A method to analyze total and unbound ceftriaxone in plasma using LC-MS/MS was developed and validated with linearity from 1 to 200 µg/mL. Both methods are sensitive, precise and accurate with coefficients of variation less than 15% in the study of inter- and intra-assay precision and accuracy. Ceftriaxone pharmacokinetics in healthy adults were described using a bicompartmental model, with a mean clearance of 0.96 L/h (CI95% 0.71-1.20) and AUC0-∞of 1106 mg.h/mL (CI95% 811-1400) for volunteers that received only ceftriaxone; clearance of 0.95 L/h (CI95% 0.77-1.13) and AUC0-∞ of 1083 mg.h/mL (CI95% 876-1290) for volunteers that received ceftriaxone plus 25 mg of eltrombopag and clearance of 0.96 L/h (CI95% 0.74-1.19) and AUC0-∞ of 1072 mg.h/mL (CI95% 872-1273) for volunteers that received ceftriaxone plus 50 mg of eltrombopag. CONCLUSIONS: The results do not support the existence of a clinical pharmacokinetic drug interaction involving hepatic BCRP in human subjects receiving intravenous ceftriaxone and oral eltrombopag. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Benzoatos/farmacocinética , Ceftriaxona/farmacocinética , Hidrazinas/farmacocinética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Pirazóis/farmacocinética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Administração Intravenosa , Administração Oral , Adulto , Benzoatos/administração & dosagem , Benzoatos/sangue , Ceftriaxona/administração & dosagem , Ceftriaxona/sangue , Feminino , Voluntários Saudáveis , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hidrazinas/administração & dosagem , Hidrazinas/sangue , Intestinos/efeitos dos fármacos , Masculino , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/metabolismo , Pirazóis/administração & dosagem , Pirazóis/sangue , Adulto JovemRESUMO
Transporters at the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) play a pivotal role as gatekeepers for efflux or uptake of endogenous and exogenous molecules. The protein expression of a number of them has already been determined in the brains of rodents, nonhuman primates, and humans using quantitative targeted absolute proteomics (QTAP). The dog is an important animal model for drug discovery and development, especially for safety evaluations. The purpose of the present study was to clarify the relevance of the transporter protein expression for drug distribution in the dog brain and CSF. We used QTAP to examine the protein expression of 17 selected transporters and receptors at the dog BBB and BCSFB. For the first time, we directly linked the expression of two efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), to regional brain and CSF distribution using specific substrates. Two cocktails, each containing one P-gp substrate (quinidine or apafant) and one BCRP substrate (dantrolene or daidzein) were infused intravenously prior to collection of the brain. Transporter expression varied only slightly between the capillaries of different brain regions and did not result in region-specific distribution of the investigated substrates. There were, however, distinct differences between brain capillaries and choroid plexus. Largest differences were observed for BCRP and P-gp: both were highly expressed in brain capillaries, but no BCRP and only low amounts of P-gp were detected in the choroid plexus. Kp,uu,brain and Kp,uu,CSF of both P-gp substrates were indicative of drug efflux. Also, Kp,uu,brain for the BCRP substrates was low. In contrast, Kp,uu,CSF for both BCRP substrates was close to unity, resulting in Kp,uu,CSF/Kp,uu,brain ratios of 7 and 8, respectively. We conclude that the drug transporter expression profiles differ between the BBB and BCSFB in dogs, that there are species differences in the expression profiles, and that CSF is not a suitable surrogate for unbound brain concentrations of BCRP substrates in dogs.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Encéfalo/irrigação sanguínea , Capilares/metabolismo , Plexo Corióideo/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/sangue , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/líquido cefalorraquidiano , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/líquido cefalorraquidiano , Animais , Azepinas/farmacocinética , Transporte Biológico , Barreira Hematoencefálica , Encéfalo/metabolismo , Dantroleno/farmacocinética , Cães , Feminino , Perfilação da Expressão Gênica , Isoflavonas/farmacocinética , Masculino , Proteômica/métodos , Quinidina/farmacocinética , Distribuição Tecidual , Triazóis/farmacocinéticaRESUMO
The ATP-binding cassette transporters B1 (ABCB1) and G2 (ABCG2) are both expressed in the intestine and known as efflux transporters of drugs. Dolutegravir was identified recently as a substrate of both ABCB1 and ABCG2. This study aimed to determine the relations between single-nucleotide polymorphisms of ABCB1 and ABCG2 genes and plasma dolutegravir concentrations. Plasma samples were obtained from 42 HIV-1-infected patients treated with dolutegravir-containing regimens 0.5-4 h after dolutegravir dosing. Plasma dolutegravir concentrations were measured by liquid chromatography-mass spectrometry. Genomic DNA was isolated from peripheral blood mononuclear cells. Genotyping of allelic variants of ABCB1 1236 C>T (rs1128503), 2677 G>T/A (rs2032582), 3435 C>T (rs1045642), 4036 A>G (rs3842), and ABCG2 421 C>A (rs2231142) was performed using the TaqMan drug metabolism assays. None of the genotypes in ABCB1 1236 C>T, 2677 G>T/A, 3435 C>T, and 4036 A>G correlated with plasma dolutegravir concentration. In contrast, the mean peak plasma concentration of dolutegravir was significantly higher in the genotypes of ABCG2 421 AA (5002 ng/ml, n=3) compared with the genotypes of ABCG2 421 CC (2569 ng/ml, n=22) and ABCG2 421 CA (2479 ng/ml, n=17) (P=0.0005). The speculated peak level of plasma dolutegravir concentration was significantly higher in ABCG2 genetic variant holders, probably, at least in part, because of low expression levels of efflux transporters in the intestines associated with these genetic variants.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/sangue , Proteínas de Neoplasias/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/sangue , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Adulto , Feminino , Genótipo , Infecções por HIV/sangue , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/patogenicidade , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue , Oxazinas , Piperazinas , Polimorfismo de Nucleotídeo Único , PiridonasRESUMO
Despite the favorable clinical evolution of patients with chronic myeloid leukemia (CML), resistance or intolerance to imatinib is present in approximately 35% of patients. Sokal score is a widely used risk factor, however efflux and influx transporters are provisional risk factors implicated in imatinib resistance. This study analyzed Sokal score, ABCB1, ABCG2 and OCT1 mRNA transporter expression levels as well as P-glycoprotein expression and efflux transporters activity to seek a possible correlation between these factors and the molecular response at 12 months from imatinib start as well as 8-year overall survival (OS). Low plus intermediate Sokal score correlated to optimal imatinib responses, as well as OS at 8-years, thus confirming the established role of Sokal score as a prognostic factor in CML patients. Low ABCB1 and high OCT1 mRNA levels were associated with an optimal molecular response, while the inverse levels were associated with non-responders (warning and failure) patients. Our results suggest that ABCB1 and OCT1 mRNA expressions may present biological relevance to identify responder and non-responder patients to imatinib treatment.
Assuntos
Antineoplásicos/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Transportador 1 de Cátions Orgânicos/genética , RNA Mensageiro/sangue , Subfamília B de Transportador de Cassetes de Ligação de ATP/sangue , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Adolescente , Adulto , Idoso , Resistencia a Medicamentos Antineoplásicos , Feminino , Hospitais Comunitários , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
The blood-brain barrier (BBB) protects the brain from toxic substances within the peripheral circulation. It maintains brain homeostasis and is a hurdle for drug delivery to the CNS to treat neurodegenerative diseases, including Alzheimer's disease and brain tumors. The drug efflux transporter P-glycoprotein (P-gp) is highly expressed on brain endothelial cells and blocks the entry of most drugs delivered to the brain. Here, we show that activation of the A2A adenosine receptor (AR) with an FDA-approved A2A AR agonist (Lexiscan) rapidly and potently decreased P-gp expression and function in a time-dependent and reversible manner. We demonstrate that downmodulation of P-gp expression and function coincided with chemotherapeutic drug accumulation in brains of WT mice and in primary mouse and human brain endothelial cells, which serve as in vitro BBB models. Lexiscan also potently downregulated the expression of BCRP1, an efflux transporter that is highly expressed in the CNS vasculature and other tissues. Finally, we determined that multiple pathways, including MMP9 cleavage and ubiquitinylation, mediated P-gp downmodulation. Based on these data, we propose that A2A AR activation on BBB endothelial cells offers a therapeutic window that can be fine-tuned for drug delivery to the brain and has potential as a CNS drug-delivery technology.
Assuntos
Barreira Hematoencefálica/metabolismo , Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Receptor A2A de Adenosina/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/biossíntese , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Agonistas do Receptor A2 de Adenosina/farmacologia , Animais , Linhagem Celular , Humanos , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/genética , Proteólise/efeitos dos fármacos , Purinas/farmacologia , Pirazóis/farmacologia , Receptor A2A de Adenosina/genética , Ubiquitinação/efeitos dos fármacos , Ubiquitinação/genéticaRESUMO
OBJECTIVE: Hyperuricaemia and gout are well-recognized complications of diuretic use. The aim of this study was to examine the clinical and genetic features of diuretic-associated gout. METHODS: Participants (n = 1365) fulfilling the 1977 ARA gout classification criteria, recruited from primary and secondary care, attended a study visit that included a detailed clinical assessment. Use of diuretic therapy was recorded during the study visit, and was confirmed by electronic dispensing data [n = 426 (31.2%) on diuretics]. Gout-associated single nucleotide polymorphisms were genotyped. Clinical and genetic features of diuretic-associated gout were analysed using a case-control study design (diuretics vs no diuretics). RESULTS: In the diuretic group there were more women, higher rates of comorbid conditions, higher BMI and lower estimated glomerular filtration rate compared with those not taking diuretics. Gout disease duration, frequency of gout flares and presence of tophi were similar in the two groups. Patients on diuretics had higher age of gout presentation and higher recorded serum urate. The ABCG2 rs2231142 risk allele was present less frequently in the diuretic group (36.1%) compared with those not on diuretics (47.6%, P = 1.2 × 10(-4)). The differences in ABCG2 were observed in both men and women with gout. CONCLUSION: Diuretic-associated gout represents a medically complex condition. Although age of gout onset is later and serum urate concentrations are higher in those on diuretics, other clinical features of gout are similar. The observed differences in the ABCG2 risk allele frequency suggest that some genetic factors play a less dominant role in diuretic-associated gout compared with primary gout.
Assuntos
Diuréticos/efeitos adversos , Gota/induzido quimicamente , Gota/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Idade de Início , Idoso , Alelos , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Genótipo , Gota/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Ácido Úrico/sangueRESUMO
OBJECTIVE: To investigate the contributions towards hyperuricaemia of known risk factors, focusing on fractional (renal) clearance of urate (FCU) and variation in the ATP-binding cassette transporter, sub-family G 2 (ABCG2) gene. METHODS: The contributions of age, sex, ancestry, Q141K genotype for ABCG2, FCU, sugar-sweetened beverage and alcohol consumption, metabolic syndrome disorders and measures of renal function to the risk of hyperuricaemia were evaluated by comparing hyperuricaemic (serum urate≥0.42â mmol/L, n=448) with normouricaemic (serum urate<0.42â mmol/L, n=344) participants using stepwise logistic regression. Model performance was evaluated using the area under the receiver operator characteristic curve (AUROC). RESULTS: ABCG2 genotype, FCU, male sex, body mass index, serum triglyceride concentrations, estimated glomerular filtration rate and consumption of alcohol were the best predictors of hyperuricaemia (AUROC 0.90, 81% accuracy). Homozygosity in the 141K variant for ABCG2 conferred an adjusted OR of 10.5 for hyperuricaemia (95% CI 2.4 to 46.2). For each 1% decrease of FCU, the adjusted OR increased by 51% (OR 1.51, 95% CI 1.37 to 1.66). There was no association between ABCG2 genotype and FCU (r=0.02, p=0.83). CONCLUSIONS: The ABCG2 141K variant and the FCU contribute strongly but independently to hyperuricaemia. These findings provide further evidence for a significant contribution of ABCG2 to extra-renal (gut) clearance of urate.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/sangue , Hiperuricemia/genética , Hiperuricemia/metabolismo , Proteínas de Neoplasias/sangue , Eliminação Renal , Ácido Úrico/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Variação Genética , Humanos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Abnormal level of Serum Uric Acid (SUA) is an important marker and risk factor for complex diseases including Type 2 Diabetes. Since genetic determinant of uric acid in Indians is totally unexplored, we tried to identify common variants associated with SUA in Indians using Genome Wide Association Study (GWAS). Association of five known variants in SLC2A9 and SLC22A11 genes with SUA level in 4,834 normoglycemics (1,109 in discovery and 3,725 in validation phase) was revealed with different effect size in Indians compared to other major ethnic population of the world. Combined analysis of 1,077 T2DM subjects (772 in discovery and 305 in validation phase) and normoglycemics revealed additional GWAS signal in ABCG2 gene. Differences in effect sizes of ABCG2 and SLC2A9 gene variants were observed between normoglycemics and T2DM patients. We identified two novel variants near long non-coding RNA genes AL356739.1 and AC064865.1 with nearly genome wide significance level. Meta-analysis and in silico replication in 11,745 individuals from AUSTWIN consortium improved association for rs12206002 in AL356739.1 gene to sub-genome wide association level. Our results extends association of SLC2A9, SLC22A11 and ABCG2 genes with SUA level in Indians and enrich the assemblages of evidence for SUA level and T2DM interrelationship.