Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 185
Filtrar
1.
Chemosphere ; 280: 130648, 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33932909

RESUMO

Cadmium (Cd) and lead (Pb) are toxic heavy metals with endocrine-disrupting properties. We investigated the associations of low-level environmental exposure to Cd/Pb and gout status (intercritical gout, gout flare and combined gout) in a cohort study. We measured by ICP-MS the levels of Cd and Pb in blood (Cd-B and Pb-B) and urine (Cd-U and Pb-U) from 408 participants with blood and 346 participants with urine samples recruited from a hospital gout clinic. The median levels of Cd-B and Pb-B (in µg/L) in the gout flare group were 0.87 (range 0.41-2.49) and 31.54 (25.38-41.46), respectively, and the median levels of Cd-U and Pb-U in the gout flare group were 1.05 (0.69-1.91) and 3.86 (3.49-4.44), respectively. These medians were significantly higher than those in the control or intercritical groups (P < 0.05). For Cd-B in tertile 2 (T2) and Cd-U in tertile 3, Cd levels were significantly associated with gout flare status compared to the reference tertile 1 (OR = 4.3, P = 0.041 and OR = 25.1, P = 0.002, respectively) after adjustment under Model 3. For Pb-U, the risk of gout flare status was significantly higher in T2 (OR = 51.0, P = 0.002) compared to the T1 under Model 3. Our results show that median levels of Cd-B, Pb-B, Cd-U and Pb-U in the gout flare group were significantly higher than participants without gout or with gout but in the intercritical period. We provide evidence that the risk of gout flare status is associated with increased Cd levels, and that blood and urine levels of Cd are a risk factor for gout flare status.

2.
ACR Open Rheumatol ; 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33856739

RESUMO

OBJECTIVES: The objectives for this study were to assess whether gout and/or rheumatoid arthritis (RA) are risk factors for coronavirus disease 2019 (COVID-19) diagnosis and to assess whether gout and/or RA are risk factors for death from COVID-19. METHODS: We used data from the UK Biobank. Multivariable-adjusted logistic regression was employed in the following analyses: analysis A, to test for association between gout and/or RA and COVID-19 diagnosis (n = 473,139); analysis B, to test for association between gout and/or RA and death from COVID-19 in a case-control cohort of people who died of or survived COVID-19 (n = 2059); analysis C, to test for association between gout and/or RA and death from COVID-19 in the entire UK Biobank cohort (n = 473,139). RESULTS: RA, but not gout, was associated with COVID-19 diagnosis in analysis A. Neither RA nor gout was associated with risk of death in the group diagnosed with COVID-19 in analysis B. However, RA was associated with risk of death related to COVID-19 by using the UK Biobank cohort in analysis C, independent of comorbidities and other measured risk factors (odds ratio [OR] 1.9; 95% confidence interval CI 1.2-3.0). Gout was not associated with death related to COVID-19 in the same UK Biobank analysis (OR 1.2; 95% CI 0.8-1.7). CONCLUSION: RA is a risk factor for death from COVID-19 by using the UK Biobank cohort. These findings require replication in larger data sets that also allow for inclusion of a wider range of factors.

3.
Sci Rep ; 11(1): 7192, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33785833

RESUMO

Genome wide association studies (GWAS) have identified more than 180 variants associated with breast cancer risk, however the underlying functional mechanisms and biological pathways which confer disease susceptibility remain largely unknown. As gene expression traits are under genetic regulation we hypothesise that differences in gene expression variability may identify causal breast cancer susceptibility genes. We performed variable expression quantitative trait loci (veQTL) analysis using tissue-specific expression data from the Genotype-Tissue Expression (GTEx) Common Fund Project. veQTL analysis identified 70 associations (p < 5 × 10-8) consisting of 60 genes and 27 breast cancer risk variants, including 55 veQTL that were observed in breast tissue only. Pathway analysis of genes associated with breast-specific veQTL revealed an enrichment of four genes (CYP11B1, CYP17A1 HSD3B2 and STAR) involved in the C21-steroidal biosynthesis pathway that converts cholesterol to breast-related hormones (e.g. oestrogen). Each of these four genes were significantly more variable in individuals homozygous for rs11075995 (A/A) breast cancer risk allele located in the FTO gene, which encodes an RNA demethylase. The A/A allele was also found associated with reduced expression of FTO, suggesting an epi-transcriptomic mechanism may underlie the dysregulation of genes involved in hormonal biosynthesis leading to an increased risk of breast cancer. These findings provide evidence that genetic variants govern high levels of expression variance in breast tissue, thus building a more comprehensive insight into the underlying biology of breast cancer risk loci.

4.
Arthritis Rheumatol ; 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33760368

RESUMO

OBJECTIVE: To systemically profile metabolic alterations and dysregulated metabolic pathways in hyperuricemia (HU) and gout, and discover potential metabolite biomarkers to discriminate gout from asymptomatic HU. METHODS: Serum samples of 330 participants, 109 gout, 102 asymptomatic HU, and 119 normouricemic (NU), were analyzed by high-resolution mass spectrometry-based metabolomics. Multivariate PCA and OPLS-DA analysis were performed to explore differential metabolites and pathways. MUVR (Multivariate methods with Unbiased Variable selection in R) algorithm was performed to identify potential biomarkers and build multivariate diagnostic models using three machine learning algorithms including Random Forest, Support Vector Machine and Logistic Regressions. RESULTS: Univariate analysis demonstrated more distinct metabolic profiles between gout and NU than HU and NU, while gout and HU showed clear metabolomic differences. Pathway enrichment analysis found diverse significantly dysregulated pathways in HU and gout compared to NU, among which arginine metabolism appears to play a critical role. The multivariate diagnostic model using MUVR found thirteen metabolites as potential biomarkers to differentiate HU and gout from NU. By randomly selecting 2/3rd of the samples as training set and the remainder as validation set, receiver operating characteristic (ROC) analysis on seven metabolites yielded area under the curve of 0.83 to 0.87 in the training set and 0.78 to 0.84 in the validation set by three machine learning algorithms for distinguishing gout from asymptomatic HU. CONCLUSION: Gout and HU have distinct serum metabolomic signatures. This diagnostic model has the potential to improve current gout care through early detection or prediction of gout progression from HU.

5.
Arthritis Res Ther ; 23(1): 75, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33663556

RESUMO

BACKGROUND: Prevention of hyperuricaemia (HU) is critical to the prevention of gout. Understanding causal relationships and relative contributions of various risk factors to hyperuricemia is therefore important in the prevention of gout. Here, we use attributable fraction to compare the relative contribution of genetic, dietary, urate-lowering therapy (ULT) and other exposures to HU. We use Mendelian randomisation to test for the causality of diet in urate levels. METHODS: Four European-ancestry sample sets, three from the general population (n = 419,060) and one of people with gout (n = 6781) were derived from the Database of Genotypes and Phenotypes (ARIC, FHS, CARDIA, CHS) and UK Biobank. Dichotomised exposures to diet, genetic risk variants, BMI, alcohol, diuretic treatment, sex and age were used to calculate adjusted population and average attributable fractions (PAF/AAF) for HU (≥0.42 mmol/L [≥7 mg/dL]). Exposure to ULT was also assessed in the gout cohort. Two sample Mendelian randomisation was done in the UK Biobank using dietary pattern-associated genetic variants as exposure and serum urate levels as outcome. RESULTS: Adherence to dietary recommendations, BMI (< 25 kg/m2), and absence of the SLC2A9 rs12498742 urate-raising allele produced PAFs for HU of 20 to 24%, 59 to 69%, and 57 to 64%, respectively, in the three non-gout cohorts. In the gout cohort, diet, BMI, SLC2A9 rs12498742 and ULT PAFs for HU were 12%, 49%, 48%, and 63%, respectively. Mendelian randomisation demonstrated weak causal effects of four dietary habits on serum urate levels (e.g. preferentially drinking skim milk increased urate, ß = 0.047 mmol/L, P = 3.78 × 10-8). These effects were mediated by BMI, and they were not significant (P ≥ 0.06) in multivariable models assessing the BMI-independent effect of diet on urate. CONCLUSIONS: Diet has a relatively minor role in determining serum urate levels and HU. In gout, the use of ULT was the largest attributable fraction tested for HU.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33704429

RESUMO

OBJECTIVE: To investigate the incidence and potential risk factors for development of fenofibrate-associated nephrotoxicity in gout patients. METHODS: 983 gout patients with fenofibrate treatment were retrospectively enrolled from the electronic record system who visited the dedicated Gout Clinic at the Affiliated Hospital of Qingdao University between September 2016 and June 2020. Fenofibrate-associated nephrotoxicity was defined as an increase in serum creatinine (SCr) ≥0.3 mg/dL within 6 months of fenofibrate initiation. The change trend of SCr and uric acid levels during treatment period were assessed by generalised additive mixed model (GAMM). Multivariate analysis was performed for risk factors affecting elevated SCr. RESULTS: 100 (10.2%) patients experienced an increase in SCr ≥0.3 mg/dL within 6 months after fenofibrate initiation. The median (quartile) change of SCr in the whole cohort was 0.11 (0.03-0.20) mg/dL, whereas it was 0.36 (0.33-0.45) mg/dL in the fenofibrate-associated nephrotoxicity group. In a multivariable regression model, chronic kidney disease (CKD) (OR, 2.39, 95% CI,1.48-3.86) and tophus (OR, 2.29, 95% CI, 1.39-3.78) were identified to be risk predictors, independent of measured covariates, of fenofibrate-associated nephrotoxicity. During the treatment period, although SCr temporarily elevated, serum urate and triglyceride concentrations decreased resulted from the interaction analysis of GAMM. Of those with fenofibrate withdrawal records, 65% of patients' SCr was reversible after an average of 49 days off the drug. CONCLUSIONS: This observational study implied that fenofibrate-associated nephrotoxicity occurs frequently in gout patients, especially in patients with tophi or CKD. The potential renal risks of fenofibrate usage in gout need additional focus.

7.
Arthritis Rheumatol ; 2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33586367

RESUMO

OBJECTIVE: Observational studies have consistently reported that serum urate positively correlates with bone mineral density (BMD). The aim of this study was to determine whether moderate hyperuricaemia induced by inosine supplements influences bone turnover markers in post-menopausal women over a six-month period. METHODS: One hundred and twenty post-menopausal women were recruited into a six-month randomised, double-blind, placebo-controlled trial. Key exclusion criteria were osteoporosis, previous fragility fracture, bisphosphonate therapy, gout, kidney stones, and urine pH ≤5.0. Participants were randomised 1:1 to placebo or inosine. The co-primary endpoints were change in procollagen type-I N-terminal propeptide (PINP) and change in ß-C-terminal telopeptide of type I collagen (ß-CTX). Change in BMD measured by dual-energy x-ray absorptiometry was an exploratory endpoint. RESULTS: Administration of inosine led to a significant increase in serum urate over the study period (P<0.0001 for all follow-up time-points). At week 26, the mean change in serum urate was +0.13 mmol/L (+2.2mg/dL) in the inosine group and 0.00mmol/L (0mg/dL) in the placebo group. There was no difference in PINP or ß-CTX between groups over the six months. There were no significant changes in bone density between groups over the six months. Adverse events and serious adverse events were similar between the two groups. CONCLUSION: This clinical trial shows that although inosine supplementation leads to sustained increases in serum urate over a six month period, it does not alter markers of bone turnover in post-menopausal women. These findings do not support the concept that urate has direct biological effects on bone turnover.

8.
Eur J Hum Genet ; 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637890

RESUMO

Hypertension, obesity, chronic kidney disease and type 2 diabetes are comorbidities that have very high prevalence among persons with hyperuricemia (serum urate > 6.8 mg/dL) and gout. Here we use multivariate genetic models to test the hypothesis that the co-association of traits representing hyperuricemia and its comorbidities is genetically based. Using Bayesian whole-genome regression models, we estimated the genetic marker-based variance and the covariance between serum urate, serum creatinine, systolic blood pressure (SBP), blood glucose and body mass index (BMI) from two independent family-based studies: The Framingham Heart Study-FHS and the Hypertension Genetic Epidemiology Network study-HyperGEN. The main genetic findings that replicated in both FHS and HyperGEN, were (1) creatinine was genetically correlated only with urate and (2) BMI was genetically correlated with urate, SBP, and glucose. The environmental covariance among the traits was generally highest for trait pairs involving BMI. The genetic overlap of traits representing the comorbidities of hyperuricemia and gout appears to cluster in two separate axes of genetic covariance. Because creatinine is genetically correlated with urate but not with metabolic traits, this suggests there is one genetic module of shared loci associated with hyperuricemia and chronic kidney disease. Another module of shared loci may account for the association of hyperuricemia and metabolic syndrome. This study provides a clear quantitative genetic basis for the clustering of comorbidities with hyperuricemia.

9.
Am J Kidney Dis ; 2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33400963

RESUMO

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.

10.
Artigo em Inglês | MEDLINE | ID: mdl-33211886

RESUMO

OBJECTIVES: To compare the efficacy and safety of citrate mixture and sodium bicarbonate on urine alkalization in gout patients under benzbromarone treatment. METHODS: A prospective, randomized, parallel controlled trial was conducted among 200 gout patients in the dedicated gout clinic of the Affiliated Hospital of Qingdao University. The participants were randomly divided into two groups (1:1), sodium bicarbonate group (3 g/day) and citrate mixture group (7 g/day). All patients were prescribed with 25 mg/day benzbromarone at initiation and maintained at a dose of 50 mg/day. Clinical and biochemical data were collected at each follow-up time point (baseline, weeks 2, 4, 8 and 12). RESULTS: A total of 182 patients completed the 12-week urine alkalization study. The urine pH value of both groups increased significantly from the baseline to the final follow-up time point (sodium bicarbonate group, 5.50-6.00, P < 0.05; citrate mixture group, 5.53-5.93, P < 0.05). While the comparisons regarding urine pH between treatment groups showed no significant differences for each time point. The estimated glomerular filtration rate (eGFR) dropped significantly after 12 weeks' trial in the sodium bicarbonate group (P < 0.01), while it was comparable between baseline and the last follow-up (P > 0.05) in the citrate mixture group. Results of urine analysis showed that the incident rate of occult blood in the sodium bicarbonate group was higher than that in the citrate mixture group (38 vs 24%, P < 0.05), accompanied by a similar occurrence of kidney stones. After 12-week follow-up, the frequency of twice gout flare in the citrate mixture group was significantly lower than that in sodium bicarbonate group (4 vs 12%, P = 0.037). No treatment-emergent adverse events occurred. CONCLUSION: The efficacy of citrate mixture on urine alkalization is comparable to sodium bicarbonate under benzbromarone treatment without significant adverse events. Citrate mixture is superior to sodium bicarbonate in lowering the incidence of urine occult blood and the frequency of gout attacks. TRIAL REGISTRATION: Registered with ChiCTR (http://www.chictr.org.cn), No. ChiCTR1800018518.

11.
Arthritis Res Ther ; 22(1): 259, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33148335

RESUMO

BACKGROUND: High body mass index (BMI) is strongly associated with hyperuricaemia. It is unknown whether overweight and obesity influences serum urate primarily through increased urate production or reduced renal clearance of uric acid. The aim of this study was to determine the influence of BMI on the response to inosine, a purine nucleoside that functions as an intermediate in the purine salvage and degradation pathways. METHODS: Following an overnight fast, 100 healthy participants without gout attended a study visit. Blood and urine samples were taken prior to and over 180 min after 1.5 g oral inosine. Serum urate and fractional excretion of uric acid (FEUA) were analysed according to high BMI (≥ 25 kg/m2) and low/normal BMI (< 25 kg/m2) groups, and according to BMI as a continuous variable. RESULTS: Participants in the high BMI group (n = 52, mean BMI 30.8 kg/m2) had higher serum urate concentrations at baseline (P = 0.002) compared to those with low/normal BMI (mean BMI 21.8 kg/m2). However, the high BMI group had a smaller increase in serum urate following the inosine load (P = 0.0012). The two BMI groups had a similar FEUA at baseline (P = 0.995), but those in the high BMI group had a smaller increase in FEUA following the inosine (P = 0.0003). Similar findings were observed when analysing BMI as a continuous variable. Those with high BMI had a smaller increase in FEUA per increase in serum urate, compared to those with low BMI (P = 0.005). CONCLUSIONS: In a fasting state, people with high BMI have elevated serum urate levels but similar FEUA values compared with those with low/normal BMI. Following a purine load, those with high BMI have an attenuated renal excretion of uric acid. These data, using an experimental method to dynamically assess human urate handling, suggest that people with high BMI have a higher renal capacity for uric acid reabsorption when fasted and following a dietary purine intake have reduced renal clearance. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry, ACTRN12615001302549 , date of registration 30 November 2015.

12.
Semin Arthritis Rheum ; 50(5): 1089-1100, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32916560

RESUMO

Gout, the most common inflammatory arthritis, is the result of hyperuricemia and inflammation induced by monosodium urate (MSU) crystal deposition. However, most people with hyperuricemia will never develop gout, implying a molecular-genetic contribution to the development of gout. Recent genomic studies reveal links between certain genetic variations and gout. We highlight recent advances in our understanding of gout as an auto-inflammatory disease. We review the auto-inflammatory aspects of gout, including the inflammasome and thirteen gout-associated inflammatory-pathway genes and associated comorbidities. This information provides important insights into emerging immune-modulating targets in the management of gout, and future novel therapeutic targets in gout treatment. Cumulatively, this has important implications for treating gout as an auto-inflammatory disease, as opposed to a purely metabolic disease.

13.
Sci Rep ; 10(1): 15575, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968167

RESUMO

Urate in the fingernails of gout patients and healthy volunteers was successfully detected by high-performance liquid chromatography (HPLC) with ultraviolet (UV) in our previous research. This study aimed to further investigate whether nail urate could be a proxy for the burden of monosodium urate (MSU) crystals deposits in gout. To this end, we conducted a study in two parts. Firstly, we successfully detected urate in the nail by HPLC-UV and evaluated nail urate concentrations in control subjects and patients with gout. As expected, we found that levels of nail urate were significantly higher in patients with gout than in healthy controls, and the nail urate level was significantly correlated with the volume of MSU crystals deposits measured by dual-energy CT (DECT). Secondly, we found that nail urate can reflect changes in urate levels in the body during urate lowering therapy through a 3-month follow-up study. Our results provide the possibility of quantification of urate in human fingernails as a non-invasive alternative for assessing MSU crystals deposits in gout.

14.
Joint Bone Spine ; : 105078, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32950704

RESUMO

OBJECTIVE: The prevalence of gout is increasing but studies of its clinical features in large samples are lacking. This study aimed to clarify changes in the clinical manifestations of gout in China over the last decade and investigate the clinical features and risk factors of early-onset gout. METHODS: Clinical manifestations were compared between 9754 gout patients who first presented at our clinic with gout in 2008-2012 (earlier group) or 2013-2018 (later group). Gout onset≤30 years old was defined as early-onset and>30 years as late-onset. Clinical features and risk factors were compared between the groups. RESULTS: The gout-onset age was 4.14 years younger and the percentage of early-onset gout (3827 patients) was higher in the later 2013-2018 group (5979 patients). The disease duration was significantly shorter (5.72±0.09 vs. 6.01±0.11 years P < 0,05) and the ratio of patients with tophi was correspondingly lower in the later group (22.0% vs. 20.0%, P < 0,05). More patients were obese (32.6% vs. 37.7%, P<0.001) and serum urate levels (465.0±1.9µmol/L vs. 485.5±1.5µmol/L) were significantly higher in the later group. As the age of gout-onset became younger, we did the multivariate logistic regression and identified a positive family history, male sex, obesity, elevated serum urate, and sugar-sweetened soft drinks as independent predictors of early-onset gout. CONCLUSION: The manifestations of gout in China have changed over the last decade, associated with a trend towards younger onset.

16.
BMJ Open ; 10(9): e036518, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873667

RESUMO

INTRODUCTION: There is emerging evidence for stratified glucose-lowering responses to certain oral medications for type 2 diabetes (T2D) by individual characteristics. The objective of this study was to test whether glycaemic response to representative treatments of dipeptidyl peptidase-4 inhibitors (vildagliptin) and thiazolidinediones (pioglitazone) varies according to ethnicity, gender, baseline obesity, triglyceride level or genetic variation. METHODS: This is a multicentre, two-period, two-treatment, open-label, randomised cross-over trial of vildagliptin and pioglitazone as second-line or third-line therapy in patients with T2D who have suboptimal glycaemic control on metformin and/or sulfonylurea therapy. It is conducted in New Zealand with a target of 300 patients (40% with Maori or Pacific ancestry) eligible if aged ≥18 and ≤80 years, with T2D for more than 1 year, on stable doses of metformin and/or sulfonylurea for at least 3 months, with HbA1c between 59 and 110 mmol/mol inclusive. Participants are assigned to complete 4 months of vildagliptin 50 mg per day or pioglitazone 30 mg per day, followed by 4 months of the other medications in randomly allocated sequences. Participant characteristics, including ethnicity, obesity, lipid profile and candidate genotypes are collected at baseline. Primary outcome variable is on treatment HbA1c. Secondary outcomes include weight change, frequency of side effects and patient preference. ETHICS AND DISSEMINATION: Ethical approval of the trial has been obtained from the New Zealand Health and Disability Ethics Committee (18/STH/242). The trial commenced in February 2019 and recruitment is expected to be completed by March 2020. Results will be reported in articles submitted to peer-reviewed journals, as well as in presentations at national and international meetings. TRIAL REGISTRATION NUMBER: ACTRN12618001907235.

17.
Orthod Craniofac Res ; 2020 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-32772440

RESUMO

OBJECTIVE: The aim of this case-control study was to investigate the association between non-syndromic hypodontia and nineteen common variants of candidate genes ectodysplasin A (EDA), paired box 9 (PAX9), msh homeobox 1 (MSX1) and axis inhibition protein 2 (AXIN2). SETTINGS AND SAMPLE POPULATION: Sixty-one hypodontia cases were frequency-matched to 253 controls with no missing teeth (excluding the third molars). MATERIAL AND METHODS: Self-report data and DNA samples were collected from each participant. RESULTS: The sample had a mean age of 16.6 years (SD = 7.3), with most participants being female (59.6%), and of New Zealand European origin (75.4%). Using multiple logistic regression analysis, it was found that the T-allele of rs12853659 (EDA) and the G-allele of rs2428151 (EDA) were both associated with a higher risk of hypodontia (odds ratio, OR = 2.79, 95% CI = 1.11-7.01; and OR = 2.87, 95% CI = 1.04-7.94, respectively). The G-allele of rs2520378 (EDA) showed a protective effect with an OR of 0.61 (95% CI = 0.38-0.99). The EDA SNP findings were consistent with previous reports included in a meta-analysis. No associations were found with the PAX9, AXIN2 and MSX1 genes, after adjusting for sex and ethnicity. CONCLUSIONS: Common variants of the EDA genes are associated with specific phenotypes of non-syndromic hypodontia, thus confirming their role in the regulatory pathways of normal tooth development. However, larger samples are needed to investigate the association further.

18.
J Hum Genet ; 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778763

RESUMO

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.

19.
Diabetologia ; 63(10): 2169-2176, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32654027

RESUMO

AIMS/HYPOTHESIS: The CREBRF rs373863828 minor (A) allele is associated with increased BMI but reduced prevalence of type 2 diabetes in Maori and Pacific people. Given the shared aetiology of type 2 diabetes and gestational diabetes mellitus (GDM), we tested for an association between the CREBRF rs373863828 variant and GDM. METHODS: We conducted a prospective cohort study of Maori and Pacific women nested within a nutritional intervention study for pregnant women with obesity. Women were enrolled at 12-17 weeks' gestation and underwent anthropometry and collection of buffy coats for later genetic testing. GDM was diagnosed by 75 g OGTT at 24-28 weeks' gestation using the International Association of Diabetes and Pregnancy Study Groups criteria. Genotyping was performed by real-time PCR with a custom CREBRF rs373863828 probe-set. The association between CREBRF rs373863828 and GDM was analysed separately by ethnic group using logistic regression, with effect estimates combined in a meta-analysis. RESULTS: Of 112 Maori and Pacific pregnant women with obesity, 31 (28%) carried the CREBRF rs373863828 A allele (A/G or A/A) and 35 (31%) developed GDM. Women who carried the CREBRF rs373863828 A allele did not differ in BMI when compared with non-carriers (G/G). There was a fivefold reduction in the likelihood of GDM per CREBRF rs373863828 A allele (OR 0.19 [95% CI 0.05, 0.69], p = 0.01), independent of age, BMI and family history of diabetes (adjusted OR 0.13 [95% CI 0.03, 0.53], p = 0.004). GDM was diagnosed in 10% and 40% of women with and without the CREBRF rs373863828 A allele, respectively (no woman with the A/A genotype developed GDM). CONCLUSIONS/INTERPRETATION: The CREBRF rs373863828 (A) allele is associated with reduced likelihood of GDM in Maori and Pacific women with obesity and may improve GDM risk prediction. Graphical abstract.

20.
Nat Commun ; 11(1): 2767, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488095

RESUMO

The pathophysiological nature of the common ABCG2 gout and hyperuricemia associated variant Q141K (rs2231142) remains undefined. Here, we use a human interventional cohort study (ACTRN12615001302549) to understand the physiological role of ABCG2 and find that participants with the Q141K ABCG2 variant display elevated serum urate, unaltered FEUA, and significant evidence of reduced extra-renal urate excretion. We explore mechanisms by generating a mouse model of the orthologous Q140K Abcg2 variant and find male mice have significant hyperuricemia and metabolic alterations, but only subtle alterations of renal urate excretion and ABCG2 abundance. By contrast, these mice display a severe defect in ABCG2 abundance and function in the intestinal tract. These results suggest a tissue specific pathobiology of the Q141K variant, support an important role for ABCG2 in urate excretion in both the human kidney and intestinal tract, and provide insight into the importance of intestinal urate excretion for serum urate homeostasis.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Gota/metabolismo , Hiperuricemia/metabolismo , Ácido Úrico/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Alelos , Animais , Modelos Animais de Doenças , Epitélio/metabolismo , Epitélio/patologia , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Gota/genética , Gota/patologia , Homeostase , Humanos , Intestinos/patologia , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Neoplasias , Fenótipo , Ácido Úrico/sangue
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...