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OBJECTIVES: To identify genetic variants and polygenic risk score (PRS) relating to female gout and asymptomatic hyperuricaemia (AH) in a genome-wide association study (GWAS). METHODS: Gout, AH and normouricemia controls were included from Taiwan biobank and China Medical University Hospital. All participants were divided into discovery and replication cohorts for GWAS. PRS was estimated according to whether the variant exhibited a protective effect on the phenotypes or not. Each cohort was separated into two groups by the age of 50 years old. RESULTS: A total of 59 472 females were enrolled, and gout and AH occupied 1.60% and 19.59%, respectively. Six variants located in genes SLC2A9, C5orf22, CNTNAP2 and GLRX5 were significantly predictors of female gout in those aged ≥50. For those aged <50 years old, only the variant rs147750368 (SPANXN1) on chromosome X was found. Most variants located in genes SLC2A9, ZNF518B, PKD2 and ABCG2 were found to be significantly related to AH in both age groups. The PRS could explain â¼0.59% to 0.89% of variance of gout in variants with protective effects, which showed 6.2 times of mean PRS in the risk variants, but only 1.2 times in the AH phenotype. Moreover, the PRS also revealed a dose-response trend between AH rates and quartile scores. CONCLUSION: The variants in gene SLC2A9 are the major genetic factors for females associated with gout in those aged ≥50. PRS can provide a more robust prediction of the gout/AH under a homogeneous selection of variants that show effects on the traits.
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Gota , Hiperuricemia , Feminino , Humanos , Hiperuricemia/genética , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença , Gota/genética , Ácido Úrico , Fatores de Risco , Polimorfismo de Nucleotídeo Único , Proteínas Facilitadoras de Transporte de Glucose/genéticaRESUMO
Rheumatoid arthritis (RA) is a systemic disease characterized by non-infectious inflammation of the joints and surrounding tissues, which can cause severe health problems, affect the patient's daily life, and even cause death. RA can be clinically diagnosed by the occurrence of blood serological markers, rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP). However, about 20% of RA patients exhibit negative results for both markers, which makes RA diagnosis difficult and, therefore, may delay the effective treatment. Previous studies found some evidence that human leukocyte antigen (HLA)-related genes might be the susceptibility genes for RA and their polymorphisms might contribute to varieties of susceptibility and disease severity. This study aimed for the genetic polymorphisms of the RA patient genome and their effects on the RA patient's serological makers, RF and anti-CCP. A total of 4580 patients' electronic medical records from 1992 to 2020 were retrieved from the China Medical University Hospital database. The most representative single-nucleotide polymorphisms (SNPs) were identified through a genome-wide association study (GWAS) followed by enzyme-linked immunosorbent assay (ELISA) validation using the blood from 30 additional RA patients. The results showed significant changes at the position of chromosome 6 with rs9270481 being the most significant locus, which indicated the location of the HLA-DRB1 gene. Further, patients with the CC genotype at this locus were more likely to exhibit negative results for RF and anti-CCP than those with the TT genotype. The C allele was also more likely to be associated with negative results for RF and anti-CCP. The results demonstrated that a genetic polymorphism at rs9270481 affected the expression of RF and anti-CCP in RA patients, which might indicate the necessity to develop a personalized treatment plan for each individual patient based on the genetic profile.
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While genetic analyses have revealed ~100 risk loci associated with osteoarthritis (OA), only eight have been linked to hand OA. Besides, these studies were performed in predominantly European and Caucasian ancestries. Here, we conducted a genome-wide association study in the Han Chinese population to identify genetic variations associated with the disease. We recruited a total of 1136 individuals (n = 420 hand OA-affected; n = 716 unaffected control subjects) of Han Chinese ancestry. We carried out genotyping using Axiom Asia Precisi on Medicine Research Array, and we employed the RegulomeDB database and RoadMap DNase I Hypersensitivity Sites annotations to further narrow down our potential candidate variants. Genetic variants identified were tested in the Geisinger's hand OA cohort selected from the Geisinger MyCode community health initiative (MyCode®). We also performed a luciferase reporter assay to confirm the potential impact of top candidate single-nucleotide polymorphisms (SNPs) on hand OA. We identified six associated SNPs (p-value = 6.76 × 10-7-7.31 × 10-6) clustered at 2p13.2 downstream of the CYP26B1 gene. The strongest association signal identified was rs883313 (p-value = 6.76 × 10-7, odds ratio (OR) = 1.76), followed by rs12713768 (p-value = 1.36 × 10-6, OR = 1.74), near or within the enhancer region closest to the CYP26B1 gene. Our findings showed that the major risk-conferring CC haplotype of SNPs rs12713768 and rs10208040 [strong linkage disequilibrium (LD); D' = 1, r2 = 0.651] drives 18.9% of enhancer expression activity. Our findings highlight that the SNP rs12713768 is associated with susceptibility to and severity of hand OA in the Han Chinese population and that the suggested retinoic acid signaling pathway may play an important role in its pathogenesis.
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Osteoartrite , Vitamina A , Humanos , Ácido Retinoico 4 Hidroxilase/genética , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença , Alelos , Osteoartrite/genética , Polimorfismo de Nucleotídeo Único , Genes Reguladores , Estudos de Casos e Controles , Genótipo , ChinaRESUMO
LncRNA transcripts have been emerged as gene regulators through transcriptional and posttranscriptional regulation. Monosodium urate monohydrate (MSU) elicits inflammatory response and a critical regulator of bone erosion in gout. The aim of this study is to clarify the pro-osteogenic role of LncRNA in MSU-induced osteoclast differentiation. We performed microarray analysis to identify stage specific expressions of LncRNA and mRNA during osteoclast differentiation in RAW264.7 cells. Among the 314 pairs of LncRNA-mRNA coexpressed patterns in the osteoclast lineage, 22 pairs revealed to have inflammatory function. Importantly, LncRNA-Jak3 and Jak3 co-expression patterns were significantly upregulated in the osteoclasts. In specific, Jak3 contributes to MSU-induced osteoclasts differentiation by positively regulating expression of the osteoclast factor, nuclear factor of activated T-cells 1 (Nfatc1). Mechanistically, LncRNA-Jak3-mediated Nfatc1 activation upregulated cathepsin K (Ctsk) expressions. LncRNA-Jak3 knockdown abolished formation of MSU-induced mature osteoclasts. In addition, we found that gout patients showed increased levels of LncRNA-Jak3 in the mononuclear cells. Our data demonstrate that the critical functional role of LncRNA-Jak3 in osteoclast differentiation via Jak3/Nfatc1/Ctsk axis. Finally, characterization of these regulatory networks is likely to reveal novel drug targets and opportunities for therapeutic intervention in bone erosion.
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Catepsina K/genética , Diferenciação Celular/efeitos dos fármacos , Janus Quinase 3/genética , Fatores de Transcrição NFATC/genética , Osteoclastos/efeitos dos fármacos , RNA Longo não Codificante/genética , Ácido Úrico/toxicidade , Animais , Diferenciação Celular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Gota/metabolismo , Células HEK293 , Humanos , Camundongos , Osteoclastos/citologia , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Células RAW 264.7 , Ácido Úrico/metabolismoRESUMO
We investigated the interactions of ALPK1 variants and the loci of ABCG2, SLC2A9, and SLC22A12 on gout risk. We conducted two case-control studies. Participants were recruited from hospitals (n = 410; 104 gout cases and 306 controls) and communities (n = 678; 373 gout cases and 305 controls) in Taiwan. The genotypes of ALPK1 (rs11726117 M861T, rs231247 R1084R, and rs231253 3' UTR), ABCG2 (rs2231142 Q141K and rs2231137 V12M), SLC2A9 (rs3733591 R265H and rs1014290), and SLC22A12 (rs3825016 H86H, rs11231825 H142H, and rs475688) were genotyped. Under a recessive model, the joint effects of ALPK1 variants and the SNPs rs2231142 of ABCG2, rs1014290 of SLC2A9, or rs475688 and rs3825016 of SLC22A12 were associated with gout. The rs11726117 [CC] of ALPK1 and rs2231142 [TT] of ABCG2 with the sequential addition of the rs1014290 [AA] of SLC2A9 and rs3825016 [CC] of SLC22A12 were associated with gout risk (odds ratio (OR): 13.01, 15.11, and 55.00 and positive predictive value (PPV): 56%, 69%, and 99% in the Han group, respectively; OR: 3.76, 5.78, and 12.30 and PPV: 74%, 80%, and 81% in the aboriginal group, respectively). Combined exposure to the four high-risk genotypes of ALPK1 and the uric-acid-related loci of ABCG2, SLC2A9, and SLC22A12 was associated with an increased gout risk and a high PPV for gout.
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Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Loci Gênicos , Proteínas Facilitadoras de Transporte de Glucose/genética , Gota/genética , Proteínas de Neoplasias/genética , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Polimorfismo Genético , Proteínas Quinases/genética , Adulto , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos TestesRESUMO
Alpha-kinase 1 (ALPK1) is associated with chronic kidney disease (CKD), type 2 diabetes mellitus and gout. Elevated ALPK1 levels have been observed in the kidneys of patients with diabetes and the white blood cells of patients with gout. As renal injury is a common outcome of CKD, diabetes and gout, the aim of this study was to investigate the effect of ALPK1 in the development of renal injury in a hyperglycemic condition. Hyperglycemia was induced in wild-type and ALPK1 transgenic mice by an intraperitoneal injection of streptozotocin (STZ). Functional and histological examinations were performed after 3weeks. STZ-treated ALPK1 transgenic mice exclusively showed arteriolar sclerosis and fibrous thickening of the Bowman's capsule in the kidney. This was accompanied by body weight loss, severe hyperglycemia, and low serum insulin levels. Renal renin and serum renin protein levels were higher in STZ-treated ALPK1 transgenic mice, whereas cGKII protein level was decreased by ALPK1 in human embryonic kidney 293 (HEK293) cells. ALPK1 up-regulated TGF-beta1 levels and transcription of fibrosis-related genes, including MMP-9, FIBRONECTIN, and TIMP1. MSU crystals increased ALPK1 transcription in cultured kidney cells. Finally, ALPK1 enhanced production of MSU crystals-induced IL-1beta in mice. Stimulation of soluble sodium urate induced IL-1beta and Alpk1 mRNA production in mice kidney. Taken together, these data show that an increase in ALPK1 results in accelerated fibrotic nephropathies, primarily through the enhancement of renin, TGF-beta1, and IL-1beta. Renal or blood ALPK1 levels are involved in the induction of fibrotic renal injury in an experimental model of hyperglycemia.
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Objective: The aim of this study was to identify a protein for urate transporter 1 (URAT1) regulation. Methods: The clinical dataset consisted of 492 case-control samples of Han Chinese (104 gout and 388 controls). Three alpha kinase 1 ( ALPK1 ) and SLC22A12 loci associated with high gout risk and uric acid levels were genotyped. The overexpression of ALPK1 on URAT1 protein expression was evaluated in vivo in h ALPK1 transgenic mice. The in vitro protein levels of ALPK1 and URAT1 in ALPK1 small interfering RNA-transfected human kidney-2 cells with MSU crystal stimulation were examined. Results: ALPK1 , which is a single nucleotide polymorphism (SNP) of rs11726117 (M861T; T), reduced the risk of gout via the SLC22A12 gene SNPs rs3825016 and rs475688, as compared with the subject of ALPK1 rs11726117 (C) allele {rs11726117 [CT + TT] vs rs3825016, odds ratio [OR] 0.39 [95% confidence interval (CI) 0.23, 0.67]; rs11726117 [CT + TT] vs rs475688, OR 0.39 [95% CI 0.23, 0.67]}. ALPK1-overexpressed mice demonstrated lower levels of URAT1 protein ( P = 0.0045). Mouse endogenous ALPK1 proteins were detected in renal proximal tubule cells. MSU crystals inhibited URAT1 expressions through an upregulation of ALPK1 in human kidney-2 cells. Conclusion: Elevated ALPK1 expression decreased URAT1 expression. ALPK1 might prevent the impact of urate reuptake via SLC22A12 and appeared to be negatively associated with gout. ALPK1 is a potential repressor of URAT1 protein expression.
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Gota/metabolismo , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Proteínas Quinases/farmacologia , Ácido Úrico/metabolismo , Animais , Estudos de Casos e Controles , Células Cultivadas , Cristalização , Gota/genética , Homeostase/genética , Homeostase/fisiologia , Humanos , Hiperuricemia/genética , Hiperuricemia/metabolismo , Túbulos Renais Proximais/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Proteínas Quinases/genética , Regulação para Cima/fisiologiaRESUMO
BACKGROUND: We have previously described the association between rheumatoid arthritis (RA) prevalence and the two mutY Homolog (E. coli) (MUTYH) SNPs (rs3219463 and rs3219476) among the Taiwanese population. This present study will aim to elucidate whether the SNPs can alter the expression of EGFR in the progression of RA. METHODS: The cohort study included 368 Taiwan's Han Chinese RA patients and 364 healthy controls. Blood samples collected from the participants were analyzed to determine their serum MUTYH levels and to identify rs3219463 SNP of MUTYH from their genomic DNA. RESULTS: Our data resulted in a statistically significant difference in genotype frequency distributions at rs3219463 for RA patients and controls (p < 0.0002). Also, the patients with G carrier at rs3219463 were less likely to suffer from painful joints (p < 0.006) and DAS28 scores (p < 0.003). Furthermore, the increase in serum level of MUTYH was also observed in RA patients (p < 0.005). CONCLUSIONS: Our study showed that RA is associated with rs3219463 SNP in EGFR gene and an increased serum level of the MUTYH protein. These findings suggest MUTYH is worthy of further investigation as a therapeutic target for RA.
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Artrite Reumatoide/diagnóstico , Artrite Reumatoide/genética , DNA Glicosilases/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Artrite Reumatoide/sangue , Estudos de Coortes , DNA Glicosilases/sangue , Feminino , Expressão Gênica , Predisposição Genética para Doença/epidemiologia , Humanos , Masculino , Projetos Piloto , Fatores de RiscoRESUMO
The aim of the present study was to evaluate the contribution of urate transporter genes and alcohol use to the risk of gout/tophi. Eight variants of ABCG2, SLC2A9, SLC22A12, SLC22A11 and SLC17A3 were genotyped in male individuals in a case-control study with 157 gout (33% tophi), 106 asymptomatic hyperuricaemia and 295 control subjects from Taiwan. The multilocus profiles of the genetic risk scores for urate gene variants were used to evaluate the risk of asymptomatic hyperuricaemia, gout and tophi. ABCG2 Q141K (T), SLC2A9 rs1014290 (A) and SLC22A12 rs475688 (C) under an additive model and alcohol use independently predicted the risk of gout (respective odds ratio for each factor=2.48, 2.03, 1.95 and 2.48). The additive composite Q141K, rs1014290 and rs475688 scores of high-risk alleles were associated with gout risk (P<0.0001). We observed the supramultiplicative interaction effect of genetic urate scores and alcohol use on gout and tophi risk (P for interaction=0.0452, 0.0033). The synergistic effect of genetic urate score 5-6 and alcohol use indicates that these combined factors correlate with gout and tophi occurrence.
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Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Consumo de Bebidas Alcoólicas/efeitos adversos , Alelos , Proteínas Facilitadoras de Transporte de Glucose/genética , Gota/epidemiologia , Gota/etiologia , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Adulto , Idade de Início , Idoso , Estudos de Casos e Controles , Comorbidade , Genótipo , Humanos , Hiperuricemia/epidemiologia , Hiperuricemia/genética , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Risco , Taiwan/epidemiologiaRESUMO
Previous case-control studies of Caucasian ethnicity have reported the association of adhesive capsulitis (AC) with diabetes mellitus (DM). To further investigate the risk of AC in subjects with DM in an Asian population, we performed the present cohort study featured the analyses of a randomly selected sub-dataset of one million individuals insured by the Taiwan National Health Insurance for the period spanning 1996-2008. The study and comparison cohorts consisted of 5,109 newly diagnosed diabetic patients and 20,473 randomly selected non-diabetic subjects aged ≥ 20 years in the year 2000. Both cohorts were followed up until December 2008 to measure AC incidence. We found that the incidence density of AC in the DM cohort was 3.08 times that of the comparison cohort (146.9 vs. 47.7 per 10,000 person-years), and rate ratios varied from 1.23 to 4.98 by categorized sociodemographic factors and comorbidity. The hazard ratio (HR) of AC for DM subjects remained significantly higher than that for non-DM subjects (p < 0.001) in all models. The HR increased in older age-groups (p < 0.001) and females (p < 0.001). Hyperlipidemia consistently increases the risk of AC in both univariate (HR = 2.67, 95% confidence interval (CI) 2.36-4.06) and multivariate analyses (HR = 1.29, 95% CI 1.11-1.49). In this eight-year study period, we found that DM and accompanying hyperlipidemia were independent risk factors for AC. The risks are higher for older-aged women. Findings in the present study help to identify high-risk patient groups to exercise early prevention of AC and enhance comprehensive care quality of DM subjects.
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Bursite/epidemiologia , Diabetes Mellitus/epidemiologia , Hiperlipidemias/epidemiologia , Adulto , Fatores Etários , Idoso , Bursite/diagnóstico , Diabetes Mellitus/diagnóstico , Feminino , Humanos , Hiperlipidemias/diagnóstico , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Taiwan/epidemiologia , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: X-ray repair cross-complementing group 3 (XRCC3) plays a crucial role in mammalian DNA repair processes. The polymorphism of XRCC3, rs861539 (Thr > Met at codon 241), is common in populations worldwide. This study analyzed the relationship between this functional single nucleotide polymorphism and systemic lupus erythematosus (SLE) in the Han Chinese population in Taiwan (HC-TW). METHODS: Genotyping was performed using polymerase chain reaction restriction fragment length polymorphism on 163 SLE patients and 191 healthy participants in the control group. RESULTS: The data showed that the genotype frequency at codon 241 did not differ significantly between the SLE patients and the healthy participants in the control group; however, the allele frequency analysis indicated a significant difference between these groups. In addition, we used the genotype and allele frequencies of 191 healthy HC-TW participants for comparison with HapMap populations. The results indicated a significant difference of XRCC3 Thr241Met allele and genotype frequencies between the HC-TW population and HapMap populations, except for the other Han Chinese populations. A prior study showed that Thr241 > Met substitution in XRCC3 protein was positive as damaging and functional consequences as well. CONCLUSION: This is the first study to demonstrate the difference of XRCC3 Thr241 > Met variant between the HC-TW population and HapMap population.
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Povo Asiático/genética , Proteínas de Ligação a DNA/genética , Etnicidade/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Alelos , Substituição de Aminoácidos/genética , Estudos de Casos e Controles , Frequência do Gene/genética , Haplótipos/genética , Humanos , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , TaiwanRESUMO
OBJECTIVE: To identify new genetic variants associated with SLE in Taiwan and establish polygenic risk score (PRS) models to improve the early diagnostic accuracy of SLE. METHODS: The study enrolled 2429 patients with SLE and 48 580 controls from China Medical University Hospital in Taiwan. A genome-wide association study (GWAS) and PRS analyses of SLE and other three SLE markers, namely ANA, anti-double-stranded DNA antibody (dsDNA) and anti-Smith antibody (Sm), were conducted. RESULTS: Genetic variants associated with SLE were identified through GWAS. Some novel genes, which have been previously reported, such as RCC1L and EGLN3, were revealed to be associated with SLE in Taiwan. Multiple PRS models were established, and optimal cut-off points for each PRS were determined using the Youden Index. Combining the PRSs for SLE, ANA, dsDNA and Sm yielded an area under the curve of 0.64 for the optimal cut-off points. An analysis of human leucocyte antigen (HLA) haplotypes in SLE indicated that individuals with HLA-DQA1*01:01 and HLA-DQB1*05:01 were at a higher risk of being classified into the SLE group. CONCLUSIONS: The use of PRSs to predict SLE enables the identification of high-risk patients before abnormal laboratory data were obtained or symptoms were manifested. Our findings underscore the potential of using PRSs and GWAS in identifying SLE markers, offering promise for early diagnosis and prediction of SLE.
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Estratificação de Risco Genético , Estudo de Associação Genômica Ampla , Lúpus Eritematoso Sistêmico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Antinucleares/sangue , Estudos de Casos e Controles , Haplótipos , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/epidemiologia , Polimorfismo de Nucleotídeo Único , Taiwan/epidemiologiaRESUMO
Cancer patients regularly suffer from the behavioral symptoms of chemotherapy-induced nausea and vomiting. Particularly, it is involved in Pavlovian conditioning. Lithium chloride (LiCl) was used as the unconditioned stimulus (US) and contingent with the tastant, for example, a saccharin solution (i.e., the conditioned stimulus; CS), resulted in conditioned taste aversion (CTA) to the CS intake. The present study employed an animal model of LiCl-induced CTA to imitate chemotherapy-induced nausea and vomiting symptoms. Recently, the basolateral amygdala (BLA) was shown to mediate LiCl-induced CTA learning; however, which brain mechanisms of the BLA regulate CTA by LiCl remain unknown. The present study was designed to test this issue, and 4% lidocaine or D2 blocker haloperidol were microinjected into BLA between the 0.1% saccharin solution intake and 0.15M LiCl. The results showed lidocaine microinjections into the BLA could attenuate the LiCl-induced CTA. Microinjections of haloperidol blunted the CTA learning by LiCl. Altogether, BLA via the sodium chloride ion channel and D2 receptors control LiCl-induced conditioned saccharin solution intake suppression. The findings can provide some implications and contributions to cancer chemotherapy-induced nausea and vomiting side effects, and will help to develop novel strategies to prevent the side effects of cancer chemotherapy.
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OBJECTIVES: This study investigates the efficacy and adverse events of beta-3 agonists and antimuscarinic agents for managing overactive bladder syndrome in Sjogren syndrome. METHODS: Sjogren's syndrome patients with an Overactive Bladder Symptom Score (OABSS) >5 were enrolled and were randomly assigned to mirabegron 50 mg/day or solifenacin 5 mg/day. Patients were evaluated on the recruitment day and reassessed at Week 1, 2, 4, and 12. The study's primary endpoint was to have a significant change in OABSS at Week 12. The secondary endpoint was the adverse event and crossover rate. RESULTS: A total of 41 patients were included in the final analysis, with 24 in the mirabegron group and 17 in the solifenacin group. The study's primary outcome was a change of the OABSS at Week 12. We found that both mirabegron and solifenacin significantly reduce patients' OABSS after 12 weeks of treatment. The evolution of the OABSS was -3.08 for mirabegron and -3.71 for solifenacin (p = .56). Six out of 17 patients from the solifenacin group crossed over to the mirabegron arm due to severe dry mouth or constipation, while none from the mirabegron arm crossed over to the solifenacin group. Sjogren's syndrome-related pain was also improved in the mirabegron group (4.96-1.67, p = .008) compared to the solifenacin group (4.39-3.4, p = .49). CONCLUSIONS: Our study showed that mirabegron is equally effective as solifenacin in treating Sjogren's syndrome patients with overactive bladder. Mirabegron is superior to solifenacin in terms of treatment-related adverse events.
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Síndrome de Sjogren , Bexiga Urinária Hiperativa , Agentes Urológicos , Humanos , Succinato de Solifenacina/efeitos adversos , Bexiga Urinária Hiperativa/etiologia , Bexiga Urinária Hiperativa/complicações , Síndrome de Sjogren/complicações , Síndrome de Sjogren/tratamento farmacológico , Resultado do Tratamento , Quimioterapia Combinada , Acetanilidas/efeitos adversos , Antagonistas Muscarínicos/efeitos adversos , Agentes Urológicos/efeitos adversosRESUMO
The involvement of the epidermal growth factor receptor (EGFR) in the pathogenesis of cancer is well documented. In contrast, its role in rheumatoid arthritis (RA) development is not that well defined although previous studies suggested the possible link between autoimmune diseases and malignancy. Therefore, we aimed to examine whether there is a link between the EGFR genetic polymorphisms and the RA. Our study gauged the effects of EGFR (rs11543848 and rs17337023) single-nucleotide polymorphisms (SNPs) on RA among Taiwan's Han Chinese population. Polymorphism of EGFR gene was analyzed in 188 RA patients and 128 control subjects. Genotyping for EGFR SNPs was performed by restriction fragment length polymorphism (RFLP) assay. Our data confirmed statistically significant increased risk of RA development in subjects with A carrier at rs17337023 SNP (P < 0.0001), and subjects with A allele at rs17337023 SNP (odds ratio [OR] = 1.52; 95% confidence interval [CI] = 1.10-2.09). Furthermore, comparison of haplotype frequencies between patients and controls suggested GA and AT haplotypes were more "at-risk" for RA development (P < 0.0001 and P < 0.01, respectively). However, comparisons of the clinical features of RA patients according to different genotypes and haplotypes revealed no significant difference. In conclusion, our data yield the new information on EGFR polymorphisms (rs11543848 and rs17337023) with the susceptibility of RA development and polymorphism revealed by this study merit further investigation.
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Artrite Reumatoide/genética , Povo Asiático/genética , Receptores ErbB/genética , Polimorfismo de Nucleotídeo Único , Artrite Reumatoide/etnologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , China/etnologia , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Razão de Chances , Fenótipo , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Medição de Risco , Fatores de Risco , Taiwan/epidemiologiaRESUMO
The purpose of this study was to determine whether toll-like receptor 9 (TLR9) gene polymorphisms were markers of susceptibility to or severity of systemic lupus erythematosus (SLE) in Taiwanese patients. The study included 211 healthy individuals and 167 Chinese patients with SLE. Polymorphisms of TLR9 [rs2066807 and rs187084 (-1486 T/C)] were typed from genomic DNA. The genotypes, allelic frequencies, and carriage rates were compared between patients with SLE and control subjects. The relationship between allelic frequencies and clinical manifestations of 167 patients with SLE was evaluated. There was no statistically significant difference in TLR9 (rs2066807) gene polymorphism, allelic frequency, and carriage rate between the SLE and control groups. However, for the genotype of TLR9 -1486 T/C (rs187084) polymorphism, there was a statistically significant difference between the SLE and the control groups (P < 0.001, χ(2) = 15.9). Moreover, there was a significant association between the two groups in allelic frequency and carriage rate of the T allele (P < 0.001, χ(2) = 18.5 and P < 0.01, χ(2) = 8.06, respectively). We did not detect any association between the TLR9 genotype and the clinical or laboratory profiles in patients with SLE. The results suggest that the TLR9 -1486 T/C (rs187084), but not TLR9 (rs2066807), polymorphism is related to SLE in Taiwanese patients.
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Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Receptor Toll-Like 9/genética , Adulto , Povo Asiático/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Masculino , Polimorfismo Genético , TaiwanRESUMO
This study examines whether or not MBD4 polymorphism is a marker for rheumatoid arthritis (RA) susceptibility or severity for Chinese patients in Taiwan. This study included 193 patients with RA, while 190 unrelated healthy individuals living in Central Taiwan served as controls. The relationship between MBD4 polymorphism and clinical manifestations of RA was evaluated. For the genotype and allelic frequency of MBD4-1057 polymorphism, there were no statistically significant differences between patients with RA and controls. There were significant differences in the distribution of MBD4-8666 polymorphism frequencies between patients with RA and controls [P = 0.013; P (corrected) (Pc) = 0.039]. There were also significant relationships in the distribution of MBD4-9229 polymorphism genotype between patients with RA and controls (P = 0.007; Pc = 0.021). However, we did not detect any associations for MBD4-1057, MBD4-8666 or MBD4-9229 with rheumatoid factor presence, extra-articular involvement or bone erosion in patients with RA. Results suggest that MBD4-8666 and MBD4-9229, but not MBD4-1057, gene polymorphisms are related to RA in Chinese patients in Taiwan.
Assuntos
Artrite Reumatoide/etnologia , Artrite Reumatoide/genética , Endodesoxirribonucleases/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Artrite Reumatoide/epidemiologia , Povo Asiático/etnologia , Povo Asiático/genética , Estudos de Casos e Controles , China/etnologia , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Taiwan/epidemiologiaRESUMO
The involvement of uracil-DNA glycosylase (UNG) in the pathogenesis of cancer is well documented. In contrast, the role of this protein in rheumatoid arthritis (RA) development is not well defined, although previous studies suggest a possible link between autoimmune diseases and malignancy. Therefore, we aimed to examine whether there is a link between UNG genetic polymorphisms and RA. Our present study investigated the effects of UNG (rs3219218 and rs246079) single nucleotide polymorphisms (SNPs) on RA among Taiwan's Han Chinese population. Polymorphism of the UNG gene was analyzed in 192 controls and 183 RA patients. Genotyping for UNG SNPs was performed by restriction fragment length polymorphism assay. Our data confirmed statistically significant variations in genotype frequency distributions at rs246079 SNP between RA patients and controls (P = 3.05 × 10(-4)). The G allele at rs246079 SNP is a high-risk factor in developing RA (odds ratio [OR] = 1.77; 95% confidence interval [CI] = 1.290-2.42). A comparison of haplotype frequencies between the case and the control revealed that RA patients with the Ht2 haplotype are at additional risk for RA development (P = 0.042). Our data yielded new information on UNG polymorphisms associated with RA development and as RA molecular markers. The polymorphisms revealed by the present study merit further investigation.
Assuntos
Artrite Reumatoide/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Uracila-DNA Glicosidase/genética , Adulto , Alelos , Povo Asiático/genética , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Masculino , TaiwanRESUMO
Rheumatoid arthritis (RA) is a chronic autoimmune disease and can lead to deformities and severe disabilities, due to irreversible damage of tendons, joints, and bones. Previous study indicated that DNA repair system was involved in the pathology of RA. In this study, we investigated the association of two 8-oxoguanine glycosylase 1 (OGG1) gene polymorphisms (rs159153 and rs3219008) with the susceptibility to RA in 384 Taiwanese individuals (192 patients with RA and 192 controls). Our data showed that statistically significant difference in genotype frequency distributions was found at rs3219008 SNP between patients with RA and control groups (P = 5.6E-0.5). Our data also indicated that individuals with the AG genotype at rs3219008 SNP may have a higher risk of developing RA. We did not observe any statistically significant association of OGG1 haplotype frequencies (rs159153 and rs3219008) with RA progression. The study suggested that OGG1 polymorphisms (rs159153 and rs3219008) are associated with RA progression and that these may be used as molecular markers of RA.
Assuntos
Artrite Reumatoide/genética , DNA Glicosilases/genética , Reparo do DNA , Polimorfismo de Nucleotídeo Único , Artrite Reumatoide/enzimologia , Artrite Reumatoide/mortalidade , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Progressão da Doença , Frequência do Gene , Marcadores Genéticos , Predisposição Genética para Doença , Haplótipos , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Razão de Chances , Fenótipo , Medição de Risco , Fatores de Risco , TaiwanRESUMO
ABSTRACT: Studies on the thyroid disease risk in patients with rheumatoid arthritis (RA) associated with comorbidities are limited. This population-based retrospective cohort study investigated the hypothyroidism risk in patients with RA and the role of comorbidities.We used Taiwan National Health Insurance Research Database to identify 16,714 RA patients newly diagnosed in 2000 to 2008 and 66,856 control persons without RA, frequency matched by sex, age, and index year. Incidence and the RA group to controls hazard ratio of hypothyroidism were estimated.The hypothyroidism incidence was 1.74-fold higher in the RA group than in controls (16.6 vs 9.52 per 10,000 person-years), with the Cox method estimated adjusted hazard ratio of 1.67 (95% confidence intervalâ=â1.39-2.00) after controlling for covariates. Near 75% of the study population were women, with the incidence 3.6-time higher than men in both groups. The hypothyroidism incidence increased with age, from 12.1 per 1000 person-years in 20 to 39âyears to 20.0 per 1000 person-years in 60+ years in RA patients, higher than that in controls (7.17 vs 10.0 per 1000 person-years, respectively by age). Each comorbidity was related to an increased incidence and higher in the RA group than in controls. Among all comorbidities, stroke exerted the greatest impact in the RA group with an adjusted hazard ratio of 3.85 (95% confidence intervalâ=â1.24-12.0).RA patients have an increased risk of developing hypothyroidism; this risk was pronounced in women and the elderly. RA patients should be closely monitored to prevent the development of hypothyroidism.