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The minor allele of rs373863828, a missense variant in CREB3 Regulatory Factor, is associated with several cardiometabolic phenotypes in Polynesian peoples. To better understand the variant, we tested the association of rs373863828 with a panel of correlated phenotypes (body mass index [BMI], weight, height, HDL cholesterol, triglycerides, and total cholesterol) using multivariate Bayesian association and network analyses in a Samoa cohort (n = 1632), Aotearoa New Zealand cohort (n = 1419), and combined cohort (n = 2976). An expanded set of phenotypes (adding estimated fat and fat-free mass, abdominal circumference, hip circumference, and abdominal-hip ratio) was tested in the Samoa cohort (n = 1496). In the Samoa cohort, we observed significant associations (log10 Bayes Factor [BF] ≥ 5.0) between rs373863828 and the overall phenotype panel (8.81), weight (8.30), and BMI (6.42). In the Aotearoa New Zealand cohort, we observed suggestive associations (1.5 < log10 BF < 5) between rs373863828 and the overall phenotype panel (4.60), weight (3.27), and BMI (1.80). In the combined cohort, we observed concordant signals with larger log10 BFs. In the Samoa-specific expanded phenotype analyses, we also observed significant associations between rs373863828 and fat mass (5.65), abdominal circumference (5.34), and hip circumference (5.09). Bayesian networks provided evidence for a direct association of rs373863828 with weight and indirect associations with height and BMI.
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Adiposidade , População das Ilhas do Pacífico , Proteínas Supressoras de Tumor , Humanos , Teorema de Bayes , Índice de Massa Corporal , Análise Multivariada , Obesidade/genética , Proteínas Supressoras de Tumor/genética , Mutação de Sentido IncorretoRESUMO
Gout is of particularly high prevalence in the Maori and Pacific (Polynesian) populations of Aotearoa New Zealand (NZ). Here, we investigated the contribution of common population-specific copy number variation (CNV) to gout in the Aotearoa NZ Polynesian population. Microarray-generated genome-wide genotype data from Aotearoa NZ Polynesian individuals with (n = 1196) and without (n = 1249) gout were analyzed. Comparator population groups were 552 individuals of European ancestry and 1962 of Han Chinese ancestry. Levels of circulating major histocompatibility complex (MHC) class I polypeptide-related sequence A (MICA) were measured by enzyme-linked immunosorbent assay. Fifty-four CNV regions (CNVRs) appearing in at least 10 individuals were detected, of which seven common (>2%) CNVRs were specific to or amplified in Polynesian people. A burden test of these seven revealed associations of insertion/deletion with gout (odds ratio (OR) 95% confidence interval [CI] = 1.80 [1.01; 3.22], P = 0.046). Individually testing of the seven CNVRs for association with gout revealed nominal association of CNVR1 with gout in Western Polynesian (Chr6: 31.36-31.45 Mb, OR = 1.72 [1.03; 2.92], P = 0.04), CNVR6 in the meta-analyzed Polynesian sample sets (Chr1: 196.75-196.92 Mb, OR = 1.86 [1.16; 3.00], P = 0.01) and CNVR9 in Western Polynesian (Chr1: 189.35-189.54 Mb, OR = 2.75 [1.15; 7.13], P = 0.03). Analysis of European gout genetic association data demonstrated a signal of association at the CNVR1 locus that was an expression quantitative trait locus for MICA. The most common CNVR (CNVR1) includes deletion of the MICA gene, encoding an immunomodulatory protein. Expression of MICA was reduced in the serum of individuals with the deletion. In summary, we provide evidence for the association of CNVR1 containing MICA with gout in Polynesian people, implicating class I MHC-mediated antigen presentation in gout.
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Variações do Número de Cópias de DNA , Gota , Antígenos de Histocompatibilidade Classe I , Havaiano Nativo ou Outro Ilhéu do Pacífico , Humanos , Genótipo , Gota/etnologia , Gota/genética , Antígenos de Histocompatibilidade Classe I/genética , Antígenos HLA , Havaiano Nativo ou Outro Ilhéu do Pacífico/genéticaRESUMO
Colchicine has an important role in managing various conditions, including gout, familial Mediterranean fever, amyloidosis, Behçet's syndrome, recurrent pericarditis and calcium pyrophosphate deposition disease. The adverse effect profile of colchicine is well understood. However, due to its narrow therapeutic index, colchicine has been associated with overdose and fatalities. When ingested in toxic amounts, the mainstay of management is supportive care. Strategies to minimize the risk of colchicine poisoning can focus on three broad causes: unauthorized access, intentional overdose and inappropriate dosing. Culturally safe and appropriate education about storage and appropriate use of colchicine is essential to minimize the risk of overdose.
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Amiloidose , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Febre Familiar do Mediterrâneo , Gota , Humanos , Colchicina/efeitos adversos , Febre Familiar do Mediterrâneo/tratamento farmacológico , Supressores da Gota/efeitos adversos , Gota/tratamento farmacológico , Gota/induzido quimicamente , Amiloidose/tratamento farmacológicoRESUMO
OBJECTIVES: The minor allele of the common rs2231142 ABCG2 variant predicts inadequate response to allopurinol urate lowering therapy. We hypothesize that additional variants in genes encoding urate transporters and allopurinol-to-oxypurinol metabolic enzymes also predict allopurinol response. METHODS: This study included a subset of participants with gout from the Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients, whose whole genome was sequenced (n = 563). Good responders had a 4:1 or 5:1 ratio of good (serum urate (SU) <0.36 mmol/l on allopurinol ≤300 mg/day) to poor (SU ≥ 0.36 mmol/l despite allopurinol >300 mg/day) responses over 5-6 timepoints, while inadequate responders had a 1:4 or 1:5 ratio of good to poor responses. Adherence to allopurinol was determined by pill counts, and for a subgroup (n = 303), by plasma oxypurinol >20µmol/l. Using the sequence kernel association test (SKAT) we estimated the combined effect of rare and common variants in urate secretory (ABCC4, ABCC5, ABCG2, SLC17A1, SLC17A3, SLC22A6, SLC22A8) and reuptake genes (SLC2A9, SLC22A11) and in allopurinol-to-oxypurinol metabolic genes (AOX1, MOCOS, XDH) on allopurinol response. RESULTS: There was an association of rare and common variants in the allopurinol-to-oxypurinol gene group (PSKAT-C = 0.019), and in MOCOS, encoding molybdenum cofactor sulphurase, with allopurinol response (PSKAT-C = 0.011). Evidence for genetic association with allopurinol response in the allopurinol-to-oxypurinol gene group (PSKAT-C = 0.002) and MOCOS (PSKAT-C < 0.001) was stronger when adherence to allopurinol therapy was confirmed by plasma oxypurinol. CONCLUSION: We provide evidence for common and rare genetic variation in MOCOS associating with allopurinol response.
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Allopurinol is the most widely used urate-lowering medication worldwide. However, allopurinol failure is frequently observed in clinical practice. In this review, we provide a framework for assessing allopurinol failure, which includes failure of allopurinol to control serum urate concentrations, failure of allopurinol to control clinical symptoms, and failure of allopurinol due to an adverse drug reaction. Understanding the causes of allopurinol failure underpins the approach required to turn failure into success in gout management.
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Alopurinol , Supressores da Gota , Gota , Falha de Tratamento , Alopurinol/uso terapêutico , Alopurinol/efeitos adversos , Humanos , Gota/tratamento farmacológico , Gota/sangue , Supressores da Gota/uso terapêutico , Supressores da Gota/efeitos adversos , Ácido Úrico/sangueRESUMO
OBJECTIVES: To determine the influence of patient characteristics and disease activity on adalimumab (ADA) concentrations; to assess the relationships between ADA concentrations, the presence of antidrug antibodies (ADAb), and disease activity in rheumatoid arthritis (RA); and to determine the association between cytokine concentrations and ADA concentrations. METHODS: A cross-sectional study of people with RA receiving ADA for at least 4 weeks was undertaken. Disease activity was assessed by the Disease Activity Score in 28 joints (DAS28), with responders defined as DAS28 ≤ 3.2. Serum and plasma were obtained for ADA concentrations and ADAb, and a panel of cytokines were obtained for a subgroup. ADA concentrations were compared between demographic and clinical subgroups using ANOVA. The independent associations between clinical and demographic features were analyzed using a general linear model. Variables significantly associated with ADA concentrations from the univariate analyses were entered into multivariate analyses. RESULTS: Of the 156 participants, 69.2% were female and the mean age was 57.4 (SD 12.7) years. Multivariate analysis revealed that higher C-reactive protein (P < 0.001) and higher weight (P < 0.004) were independently associated with lower ADA concentrations. ADA concentrations were higher in those with DAS28 ≤ 3.2 compared to those with DAS28 > 3.2 (median 10.8 [IQR 6.4-20.8] mg/L vs 7.1 [IQR 1.5-12.6] mg/L, P < 0.001). There was a significant negative correlation between interleukin 6 (IL-6) and ADA concentrations (r = -0.04, P < 0.01). CONCLUSION: ADA concentration correlates negatively with markers of inflammatory disease activity in RA, including IL-6. ADA concentration in the range 5 to 7 mg/L over the dose interval are associated with better disease control.
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Artrite Reumatoide , Interleucina-6 , Feminino , Humanos , Pessoa de Meia-Idade , Masculino , Adalimumab/uso terapêutico , Estudos Transversais , Artrite Reumatoide/tratamento farmacológico , Anticorpos , CitocinasRESUMO
OBJECTIVE: To investigate the effect of colchicine prophylaxis on gout remission when commencing urate lowering therapy (ULT), and illness perceptions of people in remission, using two definitions of gout remission. METHODS: Data from a 12-month double-blind placebo-controlled trial of 200 people with gout commencing allopurinol were analyzed. Participants were randomly assigned to prophylaxis with 0.5mg daily colchicine or placebo for six months, followed by six months of additional follow-up. Gout remission was assessed using the 2016 preliminary definition or simplified definition without patient reported outcomes. Illness perceptions were assessed using a gout-specific brief illness perception questionnaire (BIPQ). RESULTS: In the first six months, few participants were in remission according to either the 2016 preliminary definition (3% for colchicine and 4% for placebo) or the simplified definition (7% for colchicine and 12% for placebo). In the second six months, after study drug (colchicine or placebo) discontinuation, fewer participants in the colchicine group than in the placebo group were in remission according to the 2016 preliminary definition (4% vs. 14%, p=0.03), and the simplified definition (14% vs 28%, p=0.02). Participants fulfilling remission using either definition had more favorable perceptions about their gout symptoms and illness concerns, as well as consequences, when using the simplified definition. CONCLUSION: Using either definition, six months of colchicine prophylaxis when initiating ULT does not provide an advantage in the fulfilment of gout remission. People fulfilling either definition report fewer symptoms, lower concern about their gout, and when using the simplified definition, are less affected by gout.
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AIMS: Dose escalation at the initiation of allopurinol therapy can be protracted and resource intensive. Tools to predict the allopurinol doses required to achieve target serum urate concentrations would facilitate the implementation of more efficient dose-escalation strategies. The aim of this research was to develop and externally evaluate allopurinol dosing tools, one for use when the pre-urate-lowering therapy serum urate is known (Easy-Allo1) and one for when it is not known (Easy-Allo2). METHODS: A revised population pharmacokinetic-pharmacodynamic model was developed using data from 653 people with gout. Maintenance doses to achieve the serum urate target of <0.36 mmol L-1 in >80% of individuals were simulated and evaluated against external data. The predicted and observed allopurinol doses were compared using the mean prediction error (MPE) and root mean square error (RMSE). The proportion of Easy-Allo predicted doses within 100 mg of the observed was quantified. RESULTS: Allopurinol doses were predicted by total body weight, baseline urate, ethnicity and creatinine clearance. Easy-Allo1 produced unbiased and suitably precise dose predictions (MPE 2 mg day-1 95% confidence interval [CI] -13-17, RMSE 91%, 90% within 100 mg of the observed dose). Easy-Allo2 was positively biased by about 70 mg day-1 and slightly less precise (MPE 70 mg day-1 95% CI 52-88, RMSE 131%, 71% within 100 mg of the observed dose). CONCLUSIONS: The Easy-Allo tools provide a guide to the allopurinol maintenance dose requirement to achieve the serum urate target of <0.36 mmol L-1 and will aid in the development of novel dose-escalation strategies for allopurinol therapy.
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Alopurinol , Relação Dose-Resposta a Droga , Supressores da Gota , Gota , Modelos Biológicos , Ácido Úrico , Alopurinol/administração & dosagem , Alopurinol/farmacocinética , Humanos , Gota/tratamento farmacológico , Gota/sangue , Supressores da Gota/administração & dosagem , Supressores da Gota/farmacocinética , Ácido Úrico/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Cálculos da Dosagem de Medicamento , Simulação por ComputadorRESUMO
Gout is a common and treatable chronic disease of monosodium urate crystal deposition. It is experienced as extremely painful episodes of joint inflammation that impact all aspects of the person's life. This Clinical Perspectives article provides an update on gout diagnosis, medications and strategies to improve the quality of gout care.
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Supressores da Gota , Gota , Ácido Úrico , Humanos , Gerenciamento Clínico , Gota/tratamento farmacológico , Gota/terapia , Gota/diagnóstico , Supressores da Gota/uso terapêutico , Ácido Úrico/sangueRESUMO
OBJECTIVES: To determine whether placebo is non-inferior to low-dose colchicine for reducing gout flares during the first 6 months of allopurinol using the 'start-low go-slow' dose approach. METHODS: A 12-month double-blind, placebo-controlled non-inferiority trial was undertaken. Adults with at least one gout flare in the preceding 6 months, fulfilling the American College of Rheumatology (ACR) recommendations for starting urate-lowering therapy and serum urate ≥0.36 mmol/L were recruited. Participants were randomised 1:1 to colchicine 0.5 mg daily or placebo for the first 6 months. All participants commenced allopurinol, increasing monthly to achieve target urate <0.36 mmol/L. The primary efficacy outcome was the mean number of gout flares/month between 0 and 6 months, with a prespecified non-inferiority margin of 0.12 gout flares/month. The primary safety outcome was adverse events over the first 6 months. RESULTS: Two hundred participants were randomised. The mean (95% CI) number of gout flares/month between baseline and month 6 was 0.61 (0.47 to 0.74) in the placebo group compared with 0.35 (0.22 to 0.49) in the colchicine group, mean difference 0.25 (0.07 to 0.44), non-inferiority p=0.92. There was no difference in the mean number of gout flares/month between randomised groups over the 12-month period (p=0.68). There were 11 serious adverse events in 7 participants receiving colchicine and 3 in 2 receiving placebo. CONCLUSIONS: Placebo is not non-inferior to colchicine in prevention of gout flares in the first 6 months of starting allopurinol using the 'start-low go-slow' strategy. After stopping colchicine, gout flares rise with no difference in the mean number of gout flares/month between groups over a 12-month period. TRIAL REGISTRATION NUMBER: ACTRN 12618001179224.
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Gota , Adulto , Humanos , Gota/tratamento farmacológico , Alopurinol/uso terapêutico , Colchicina/uso terapêutico , Supressores da Gota/uso terapêutico , Ácido Úrico , Exacerbação dos Sintomas , Resultado do TratamentoRESUMO
OBJECTIVE: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. METHODS: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. RESULTS: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score>56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). CONCLUSION: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.
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Calcinose , Condrocalcinose , Reumatologia , Humanos , Estados Unidos , Condrocalcinose/diagnóstico por imagem , Pirofosfato de Cálcio , SíndromeRESUMO
The fat mass and obesity associated (FTO) locus consistently associates with higher body mass index (BMI) across diverse ancestral groups. However, previous small studies of people of Polynesian ancestries have failed to replicate the association. In this study, we used Bayesian meta-analysis to test rs9939609, the most replicated FTO variant, for association with BMI with a large sample (n = 6095) of Aotearoa New Zealanders of Polynesian (Maori and Pacific) ancestry and of Samoan people living in the Independent State of Samoa and in American Samoa. We did not observe statistically significant association within each separate Polynesian subgroup. Bayesian meta-analysis of the Aotearoa New Zealand Polynesian and Samoan samples resulted in a posterior mean effect size estimate of +0.21 kg/m2, with a 95% credible interval [+0.03 kg/m2, +0.39 kg/m2]. While the Bayes Factor (BF) of 0.77 weakly favors the null, the BF = 1.4 Bayesian support interval is [+0.04, +0.20]. These results suggest that rs9939609 in FTO may have a similar effect on mean BMI in people of Polynesian ancestries as previously observed in other ancestral groups.
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Índice de Massa Corporal , Povo Maori , População das Ilhas do Pacífico , Humanos , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Teorema de Bayes , Predisposição Genética para Doença , Povo Maori/genética , Nova Zelândia , População das Ilhas do Pacífico/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
OBJECTIVES: In 2015, the 20-item Tophus Impact Questionnaire (TIQ-20) was developed as a tophus-specific patient reported outcome measure. The aim of this study was to determine whether TIQ-20 scores change during urate-lowering therapy. METHODS: We analysed data from a two-year clinical trial of allopurinol dose escalation using a treat-to-target serum urate approach. For participants with tophaceous gout, the longest diameter of up to three index tophi was measured using Vernier calipers and the TIQ-20 was recorded at study visits. Participants at the one site were invited into a dual energy CT (DECT) sub-study. Participants were included in this analysis if they had tophaceous gout and TIQ-20 scores available at baseline, Year 1, and Year 2 (n = 58, 39 with DECT data). Data were analysed using mixed model approach to repeated measures. RESULTS: Improvements were observed in all tophus measures over the two-year period. The mean (SD) TIQ-20 scores reduced over two years from 3.59 (1.77)-2.46 (1.73), P< 0.0001, and the mean (95%CI) TIQ-20 change over the two years was -1.13 (-1.54, -0.71). Effect size (Cohen's d) for the change in the sum of the index tophi diameter over two years was 0.68, for DECT urate volume was 0.50, and for the TIQ-20 was 0.71. CONCLUSION: For people with tophaceous gout treated with allopurinol using a treat to target serum urate approach, improvements in TIQ-20 occur, as well as improvements in physical and imaging tophus measures. These findings demonstrate that the TIQ-20 is a responsive patient-reported instrument of tophus impact.
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AIMS: This study aimed to develop and evaluate an allopurinol adherence tool based on steady-state oxypurinol plasma concentrations, allopurinol's active metabolite. METHODS: Plasma oxypurinol concentrations were simulated stochastically from an oxypurinol pharmacokinetic model for allopurinol doses of 100-800 mg daily, accounting for differences in renal function, diuretic use and ethnicity. For each scenario, the 20th percentile for peak and trough concentrations defined the adherence threshold, below which imperfect adherence was assumed. Predictive performance was evaluated using both simulated low adherence and against data from 146 individuals with paired oxypurinol plasma concentrations and adherence measures. Sensitivity and specificity (S&S), negative and positive predictive values (NPV, PPV) and receiver operating characteristic (ROC) area under the curve (AUC) were determined. The predictive performance of the tool was evaluated using adherence data from an external study (CKD-FIX). RESULTS: The allopurinol adherence tool produced S&S values for trough thresholds of 89-98% and 76-84%, respectively, and 90%-98% and 76-83% for peak thresholds. PPV and NPV were 79-84% and 88-94%, respectively, for trough and 80-85% and 89-98%, respectively, for peak concentrations. The ROC AUC values ranged from 0.84 to 0.88 and from 0.86 to 0.89 for trough and peak concentrations, respectively. S&S values for the external evaluation were found to be 75.8% and 86.5%, respectively, producing an ROC AUC of 0.8113. CONCLUSION: A tool to identify people with gout who require additional support to maintain adherence using plasma oxypurinol concentrations was developed and evaluated. The predictive performance of the tool is suitable for adherence screening in clinical trials and may have utility in some clinical practice settings.
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Gota , Comportamento de Utilização de Ferramentas , Humanos , Alopurinol/farmacocinética , Oxipurinol , Supressores da Gota/farmacocinética , Gota/tratamento farmacológicoRESUMO
BACKGROUND: Two recent randomized clinical trials of escalating doses of allopurinol for the progression of chronic kidney disease (CKD) reported no benefits but potentially increased risk for death. Whether the risk could occur in patients with gout and concurrent CKD remains unknown. OBJECTIVE: To examine the relation of allopurinol initiation, allopurinol dose escalation, and achieving target serum urate (SU) level after allopurinol initiation to all-cause mortality in patients with both gout and CKD. DESIGN: Cohort study. SETTING: The Health Improvement Network U.K. primary care database (2000 to 2019). PARTICIPANTS: Patients aged 40 years or older who had gout and concurrent moderate-to-severe CKD. MEASUREMENTS: The association between allopurinol initiation and all-cause mortality over 5-year follow-up in propensity score (PS)-matched cohorts was examined. Analysis of hypothetical trials were emulated: achieving target SU level (<0.36 mmol/L) versus not achieving target SU level and dose escalation versus no dose escalation for mortality over 5-year follow-up in allopurinol initiators. RESULTS: Mortality was 4.9 and 5.8 per 100 person-years in 5277 allopurinol initiators and 5277 PS-matched noninitiators, respectively (hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.93]). In the target trial emulation analysis, the HR of mortality for the achieving target SU level group compared with the not achieving target SU level group was 0.87 (CI, 0.75 to 1.01); the HR of mortality for allopurinol in the dose escalation group versus the no dose escalation group was 0.88 (CI, 0.73 to 1.07). LIMITATION: Residual confounding cannot be ruled out. CONCLUSION: In this population-based data, neither allopurinol initiation, nor achieving target SU level with allopurinol, nor allopurinol dose escalation was associated with increased mortality in patients with gout and concurrent CKD. PRIMARY FUNDING SOURCE: Project Program of National Clinical Research Center for Geriatric Disorders.
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Alopurinol , Gota , Insuficiência Renal Crônica , Adulto , Idoso , Alopurinol/efeitos adversos , Estudos de Coortes , Feminino , Gota/complicações , Gota/tratamento farmacológico , Gota/mortalidade , Supressores da Gota/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/mortalidade , Resultado do TratamentoRESUMO
BACKGROUND: Historically, geneticists have relied on genotyping arrays and imputation to study human genetic variation. However, an underrepresentation of diverse populations has resulted in arrays that poorly capture global genetic variation, and a lack of reference panels. This has contributed to deepening global health disparities. Whole genome sequencing (WGS) better captures genetic variation but remains prohibitively expensive. Thus, we explored WGS at "mid-pass" 1-7x coverage. RESULTS: Here, we developed and benchmarked methods for mid-pass sequencing. When applied to a population without an existing genomic reference panel, 4x mid-pass performed consistently well across ethnicities, with high recall (98%) and precision (97.5%). CONCLUSION: Compared to array data imputed into 1000 Genomes, mid-pass performed better across all metrics and identified novel population-specific variants with potential disease relevance. We hope our work will reduce financial barriers for geneticists from underrepresented populations to characterize their genomes prior to biomedical genetic applications.
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Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Genoma , Genoma Humano , Genômica , Genótipo , Humanos , Sequenciamento Completo do GenomaRESUMO
RATIONALE & OBJECTIVE: The association between hyperuricemia and urolithiasis has been previously reported. However, this association is based on observational data, which are prone to residual confounding. The aim of this work was to use Mendelian randomization (MR) to evaluate if this relationship represents a causal effect of hyperuricemia. STUDY DESIGN: MR analysis using 2 approaches: 2-stage MR and 2-sample MR. SETTING & PARTICIPANTS: Participants aged 40-69 years from the UK Biobank Resource. EXPOSURE: Serum urate. OUTCOME: Urolithiasis. ANALYTICAL APPROACH: An observational analysis testing for an association between serum urate level and urolithiasis was performed using logistic regression. For MR analyses, serum urate-associated single-nucleotide polymorphisms, identified from genome-wide association data, were used as instrumental variables for serum urate. In the 2-stage MR analysis, a weighted genetic urate score was calculated from the instrumental variables, and a control function estimation model was fit. In the 2-sample MR analysis, multiple-instrument MR via the inverse-variance weighted method was performed. RESULTS: Individual-level data were available for 359,827 participants, of whom 6,398 (1.8%) reported urolithiasis. In the observational analysis, serum urate was positively associated with urolithiasis in an unadjusted analysis (odds ratio [OR], 1.47 [95% CI, 1.42-1.51]); however, after adjustment for relevant confounders, no association was observed (OR, 1.03 [95% CI, 0.99-1.08]). In the 2-stage MR analysis, no significant causal effect of serum urate level on urolithiasis was observed in the unadjusted (OR, 0.93 [95% CI, 0.81-1.08]) or adjusted (OR, 0.94 [95% CI, 0.80-1.09]) models. In the 2-sample MR analysis, multiple-instrument MR did not indicate a causal effect of serum urate on urolithiasis. LIMITATIONS: Stone composition and urinalysis data, including urine pH, were not available for this study. CONCLUSIONS: Our analyses do not support a causal effect of serum urate level on urolithiasis. The association between serum urate level and urolithiasis reported in observational studies is likely due to residual confounding.
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Hiperuricemia/genética , Ácido Úrico/sangue , Urolitíase/genética , Adulto , Idoso , Causalidade , Feminino , Humanos , Hiperuricemia/epidemiologia , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Razão de Chances , Reino Unido , Urolitíase/epidemiologiaRESUMO
Gout is a complex inflammatory arthritis affecting ~20% of people with an elevated serum urate level (hyperuricemia). Gout and hyperuricemia are essentially specific to humans and other higher primates, with varied prevalence across ancestral groups. SLC2A9 and ABCG2 are major loci associated with both urate and gout in multiple ancestral groups. However, fine mapping has been challenging due to extensive linkage disequilibrium underlying the associated regions. We used trans-ancestral fine mapping integrated with primate-specific genomic information to address this challenge. Trans-ancestral meta-analyses of GWAS cohorts of either European (EUR) or East Asian (EAS) ancestry resulted in single-variant resolution mappings for SLC2A9 (rs3775948 for urate and rs4697701 for gout) and ABCG2 (rs2622621 for gout). Tests of colocalization of variants in both urate and gout suggested existence of a shared candidate causal variant for SLC2A9 only in EUR and for ABCG2 only in EAS. The fine-mapped gout variant rs4697701 was within an ancient enhancer, whereas rs2622621 was within a primate-specific transposable element, both supported by functional evidence from the Roadmap Epigenomics project in human primary tissues relevant to urate and gout. Additional primate-specific elements were found near both loci and those adjacent to SLC2A9 overlapped with known statistical epistatic interactions associated with urate as well as multiple super-enhancers identified in urate-relevant tissues. We conclude that by leveraging ancestral differences trans-ancestral fine mapping has identified ancestral and functional variants for SLC2A9 or ABCG2 with primate-specific regulatory effects on urate and gout.
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 , Locos de Características Quantitativas , Característica Quantitativa Herdável , Sequências Reguladoras de Ácido Nucleico , Animais , Evolução Molecular , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Gota/patologia , Humanos , Hiperuricemia/patologia , Masculino , Polimorfismo de Nucleotídeo Único , Primatas , Especificidade da Espécie , Ácido Úrico/sangueRESUMO
OBJECTIVE: To investigate the factors associated with discordance between patient and physician on the presence of a gout flare. METHODS: Patients' self-reports of current gout flares were assessed with the question, 'Are you having a gout flare today?' which was then compared with a concurrent, blinded, physician's assessment. Based on agreement or disagreement with physicians on the presence of a gout flare, flares were divided into concordant and discordant groups, respectively. Within the discordant group, two subgroups-patient-reported flare but the physician disagreed and physician-reported flare but the patient disagreed-were identified. The factors associated with discordance were analysed with multivariable logistic regression analysis. RESULTS: Of 268 gout flares, 81 (30.2%) flares were discordant, with either patient or physician disagreeing on the presence of a flare. Of the discordant flares, in 57 (70.4%) the patient reported a flare but the physician disagreed. In multivariable logistic regression analysis adjusted for demographics, disagreement among patients and physicians on the presence of a gout flare was associated with lower pain scores at rest [odds ratio (OR) for each point increase on 0-10 point pain scale 0.81 (95% Wald CI 0.73, 0.90), P < 0.0001] and less presence of joint swelling [OR 0.24 (95% CI 0.10, 0.61), P = 0.003] or joint warmth [OR 0.39 (95% CI 0.20, 0.75), P = 0.005]. CONCLUSION: Although patients and physicians generally agree about the presence of gout flare, discordance may occur in the setting of low pain scores and in the absence of swollen or warm joints.
Assuntos
Gota/diagnóstico , Medição da Dor/métodos , Médicos/psicologia , Autorrelato , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Exacerbação dos SintomasRESUMO
We aimed to assess expression of genes encoding the heterodimeric IL-27 cytokine and constituent subunits of the Il-27 receptor in rheumatoid arthritis (RA), including in extra-articular, subcutaneous rheumatoid nodules. Comparing between nodules and joint synovia, significantly elevated expression of IL27A within nodules, and comparable IL27B expression, identified nodules as a significant source of IL-27 in RA. T-lymphocytes were the main source of IL27RA transcript, and IL27RA expression correlated with a number of plasma cytokines, as well as tissue TNF expression in both nodules and RA synovia. In synovia, correlations between IL27A, IL27RA IL17A and CD21L expression, and significantly elevated expression of the genes encoding IL-27, associated the presence of IL-27 with B cell-dominated synovial inflammation. Impact from nodule derived IL-27 on systemic or synovial inflammation in RA remains unknown and further study of these implications is required. Our study raises questions regarding the appropriate circumstances for the blockade or administration of IL-27 as a potential therapeutic adjunct in RA.