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1.
DNA Cell Biol ; 38(10): 1155-1165, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31433201

RESUMO

Our previous genome-wide association study has identified a suggestive association at rs11264799 within FCRL3 (Fc receptor-like 3) locus on 1q23.1 for IgA nephropathy (IgAN) in a Chinese Han population. This study aims to investigate the association of FCRL3 variants with the susceptibility, clinicopathological phenotypes and prognosis of IgAN. Eleven FCRL3 single-nucleotide polymorphisms (SNPs) were selected and analyzed in this two-stage case/control study with a total of 1750 IgAN cases and 2500 healthy controls in a Chinese Han population. Unconditional logistic regression models were used to estimate odds ratios and 95% confidence intervals (CIs) as implemented in the PLINK software. Luciferase assays were applied to detect the allelic effect of rs11264794 on gene expression regulation. We found that four SNPs (rs11264794, rs7865684, rs11264799, and rs6691569) were significantly associated with IgAN susceptibility after Bonferroni correction in the combined samples. Genotype/phenotype association analysis observed that two SNPs (rs11264794 and rs11264793) were associated with less disease severity. After adjusting for confounders, rs11264794 was independently correlated with renal outcome in IgAN patients (hazard ratio = 0.64, 95% CI = 0.43-0.97, p = 0.033). In addition, the protective allele A of rs11264794 was significantly associated with higher FCRL3 gene expression. Furthermore, luciferase reporter gene assays demonstrated that the minor allele of rs11264794 obviously reduced the specific binding between miR-183-5p.1 and FCRL3 3'-untranslated region. Our results indicate that FCRL3 gene polymorphisms are associated with the development and progression of IgAN, and the rs11264794-A allele showed a protective role for IgAN.


Assuntos
Predisposição Genética para Doença , Glomerulonefrite por IGA/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Receptores Imunológicos/genética , Regiões 3' não Traduzidas , Alelos , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Feminino , Expressão Gênica , Genes Reporter , Estudos de Associação Genética , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/etnologia , Glomerulonefrite por IGA/patologia , Humanos , Modelos Logísticos , Luciferases/genética , Luciferases/metabolismo , Masculino , MicroRNAs/metabolismo , Razão de Chances , Fenótipo , Prognóstico , Receptores Imunológicos/metabolismo , Índice de Gravidade de Doença
2.
Int Urol Nephrol ; 51(10): 1883-1892, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31359358

RESUMO

BACKGROUND: Diabetic nephropathy (DN) is one of the most serious chronic complications of diabetes mellitus (DM). Autophagy is an important physiological function for podocytes to maintain stability of intracellular environment. In this study, we planned to clarify the effect of Cordycepin, a traditional Chinese medicine, on DN and the related mechanisms. METHODS: All rats were randomly divided into normal control group, diabetic controls, low-dose group (10 mg/kg), medium-dose group (100 mg/kg), and high-dose group (500 mg/kg). The level of cholesterol, blood sugar, triglyceride, creatinine, and urine protein was examined through an automatic biochemistry analyser. Enzyme-linked immunosorbent assay (Elisa) was used to detect the level of IL-1ß, IL-6, and IL-18. HE staining was used to examine histopathologic changes. TUNEL staining was used to detected cell apoptosis. The expression of fibrosis markers α-SMA, t-TG, and TIMP-1, apoptosis-related proteins cleaved-caspase3, Bax and Bcl-2, autophagy markers Beclin1, light chain 3 (LC3)I/II, and p62 were evaluated by western blot. RESULTS: The level of cholesterol, blood sugar, triglyceride, creatinine, and urine protein in the diabetic controls was much higher than that in the normal control group. Obvious histopathology injuries were also found in DN model group. After Cordycepin treatment, all the above indexes were improved compared with the DN group and tissue damages were also alleviated. Further studies showed that Cordycepin suppressed cell apoptosis and renal fibrosis and rescued cell autophagy in DN rat model. Moreover, the results of our in vitro experiments showed that the addition of 3-methyladenine (3-MA, specific autophagy inhibitor) successfully abolished the protective effect of Cordycepin on renal fibrosis through inducing apoptosis and renal fibrosis. The above protective effects of Cordycepin were exhibited in a dose-dependent manner. CONCLUSION: Cordycepin participated in the modulation of cell apoptosis, fibrosis, and autophagy induction in DN. Our study for the first time revealed that Cordycepin had a certain therapeutic effect on DN in rats through autophagy induction.

3.
J Hum Genet ; 64(9): 927-935, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31227791

RESUMO

Previous genome-wide association studies have discovered significant association at ITGAX-ITGAM on 16p11.2 for IgA nephropathy (IgAN). In this study, we performed a two-stage association study that enrolled 1700 IgAN cases and 2400 controls to further investigate the relationship of ITGAX and ITGAM gene polymorphisms with IgAN. Seven single-nucleotide polymorphisms (SNPs) were selected for genotyping in 1000 IgAN cases and 1000 healthy controls in the discovery stage, and the significant SNP was further validated in additional 700 IgAN cases and 1400 healthy controls. We found that four SNPs (rs11150619, rs11150614, rs7190997, and rs4597342) showed potential associations with IgAN susceptibility in the discovery stage, but only SNP rs11150619 was further genotyped in the validation stage after multiple testing. The results indicated that rs11150619 was significantly associated with IgAN in the combined samples (OR = 0.81, 95%CI = 0.71-0.91, and dominant P = 6.68 × 10-4). Moreover, patients with TT genotype of rs11150619 exhibited increased estimated glomerular filtration rate levels and a reduced proportion of global sclerosis compared with those with TC and CC genotypes. Our results suggested that ITGAX and ITGAM gene polymorphisms were associated with IgAN in a Chinese Han population, and the rs11150619-T allele showed a potential protective role for IgAN.

4.
J Hum Hypertens ; 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30209305

RESUMO

The association of body mass index (BMI) and blood pressure (BP) control and their interaction with cardiovascular (CV) mortality in continuous ambulatory peritoneal dialysis (CAPD) patients is unclear. We retrospectively analyzed a consecutive series of 1595 incident CAPD patients with hypertension from 2006 to 2013, and followed up through December 2015. The BMI was categorized according to the World Health Organization classification for Asian population. Binary logistic regression was used to assess the relationship between BMI and BP control. Cox's proportional hazards models and competing risk analyses were performed to examine the nassociation of BMI and BP control with CV mortality. In the entire cohort, obesity was unlikely related to increased risk of uncontrolled BP. However, the adjusted hazard ratio (AHR) of CV mortality was increased in individuals with obesity when compared to those with normal weight (AHR 1.56; 95% confidence interval (CI) 1.04-2.34) and in individuals with uncontrolled BP when compared to those with controlled BP (AHR 1.39; (1.02-1.89)). Subgroup analyses showed that the combination of obesity and uncontrolled BP was associated with an increased risk for CV death, when compared to normal weight subjects with uncontrolled BP (AHR 2.35; (1.43-3.86)). Further, subjects with obesity and uncontrolled BP had a nearly threefold increase in risk (AHR 2.57; (1.57-4.20)) for CV death compared to subjects with neither risk factor. These associations persisted in competing risk analyses. In conclusion, the association of obesity with CV mortality was likely to vary with hypertension status among CAPD patients.

5.
J Am Soc Nephrol ; 28(11): 3383-3394, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28754791

RESUMO

Lupus nephritis (LN) is one of the most prevalent and serious complications of SLE, with significant effects on patient and renal survival. Although a large number of genetic variants associated with SLE have been identified, biomarkers that correlate with LN are extremely limited. In this study, we performed a comprehensive sequencing analysis of the whole MHC region in 1331 patients with LN and 1296 healthy controls and validated the independent associations in another 950 patients with LN and 1000 controls. We discovered five independent risk variants for LN within the MHC region, including HLA-DRß1 amino acid 11 (Pomnibus<0.001), HLA-DQß1 amino acid 45 (P<0.001; odds ratio, 0.58; 95% confidence interval, 0.52 to 0.65), HLA-A amino acid 156 (Pomnibus<0.001), HLA-DPß1 amino acid 76 (Pomnibus<0.001), and a missense variant in PRRC2A (rs114580964; P<0.001; odds ratio, 0.38; 95% confidence interval, 0.30 to 0.49) at genome-wide significance. These data implicate aberrant peptide presentation by MHC classes 1 and 2 molecules and sex hormone modulation in the development of LN.


Assuntos
Estudo de Associação Genômica Ampla , Nefrite Lúpica/genética , Complexo Principal de Histocompatibilidade/genética , Adulto , Feminino , Humanos , Masculino
6.
J Gene Med ; 19(6-7)2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28636766

RESUMO

BACKGROUND: Our previous genome-wide association study of IgA nephropathy (IgAN) in a Chinese Han population suggested that the TNFSF13 gene may be a novel susceptibility gene for IgAN. In the present study, we aimed to further evaluate the associations of single-nucleotide polymorphisms (SNPs) and expression level of the TNFSF13 gene with the risk and clinical parameters of IgAN. METHODS: Six candidate SNPs were selected for genotyping by Sequenom MassARRAY iPLEX in 1000 IgAN cases and 1000 controls. Unconditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (95% CI) with adjustment for age and sex. Serum APRIL (encoded by the TNFSF13 gene) level was detected by an enzyme-linked immunosorbent assay. RESULTS: We found that rs3803800 was significantly associated with the susceptibility of IgAN after Bonferroni correction [padditive  = 0.0009, OR (95% CI) = 1.25 (1.09-1.42); precessive  = 0.0006, OR (95% CI) = 1.54 (1.20-1.96)]; however, the association remained only in women after further sex-stratified analysis. Genotype-phenotype correlation analysis showed significant associations of rs3803800 with severe clinicopathological manifestations in IgAN patients after adjusting for age and sex, as well as the other two SNPs (rs4246413 and rs4968210) that were also associated with specific clinical phenotypes. Compared with healthy controls, serum APRIL levels were significantly higher in IgAN patients (p = 0.0001) and associated with severity of disease. CONCLUSIONS: The results of the present study indicate that the genetic variations and gene expression level of TNFSF13 are associated with the susceptibility and severity of IgAN in a Han Chinese population.


Assuntos
Glomerulonefrite por IGA/genética , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Estudos de Casos e Controles , China , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Glomerulonefrite por IGA/fisiopatologia , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores Sexuais
7.
Sci Transl Med ; 8(345): 345ra88, 2016 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-27358498

RESUMO

Although a major source of genetic variation, copy number variations (CNVs) and their involvement in disease development have not been well studied. Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. We performed association analysis of the DEFA1A3 CNV locus in two independent IgAN cohorts of southern Chinese Han (total of 1189 cases and 1187 controls). We discovered three independent copy number associations within the locus: DEFA1A3 [P = 3.99 × 10(-9); odds ratio (OR), 0.88], DEFA3 (P = 6.55 × 10(-5); OR, 0.82), and a noncoding deletion variant (211bp) (P = 3.50 × 10(-16); OR, 0.75) (OR per copy, fixed-effects meta-analysis). While showing strong association with an increased risk for IgAN (P = 9.56 × 10(-20)), low total copy numbers of the three variants also showed significant association with renal dysfunction in patients with IgAN (P = 0.03; hazards ratio, 3.69; after controlling for the effects of known prognostic factors) and also with increased serum IgA1 (P = 0.02) and galactose-deficient IgA1 (P = 0.03). For replication, we confirmed the associations of DEFA1A3 (P = 4.42 × 10(-4); OR, 0.82) and DEFA3 copy numbers (P = 4.30 × 10(-3); OR, 0.74) with IgAN in a Caucasian cohort (531 cases and 198 controls) and found the 211bp variant to be much rarer in Caucasians. We also observed an association of the 211bp copy number with membranous nephropathy (P = 1.11 × 10(-7); OR, 0.74; in 493 Chinese cases and 500 matched controls), but not with diabetic kidney disease (in 806 Chinese cases and 786 matched controls). By explaining 4.96% of disease risk and influencing renal dysfunction in patients with IgAN, the DEFA1A3 CNV locus may be a potential therapeutic target for developing treatments for this disease.


Assuntos
Dosagem de Genes/genética , alfa-Defensinas/genética , Estudos de Casos e Controles , Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Genótipo , Glomerulonefrite por IGA/sangue , Humanos , Nefropatias/genética , Razão de Chances , Peptídeos Cíclicos/genética , Fenótipo
8.
Clin Nephrol ; 86(7): 35-41, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27251340

RESUMO

AIMS: To investigate the clinicopathologic features of IgA nephropathy (IgAN) patients with different levels of proteinuria and its clinical significance. METHODS: This was a single-center retrospective cohort study. Patients with biopsy-proven primary IgAN were enrolled from January 2006 to December 2011 in The First Affiliated Hospital of Sun Yat-sen University, divided into six groups based on proteinuria at biopsy (≤ 0.30 g/d, 0.31 - 0.50 g/d, 0.51 - 1.00 g/d, 1.01 - 2.00 g/d, 2.01 - 3.00 g/d, and > 3.00 g/d). Demographic and clinicopathologic data were collected and analyzed. RESULTS: 1,413 patients were enrolled in this study, with the median proteinuria being 0.61 g/d (interquartile range 0.30 - 1.29). Patients with proteinuria > 0.50 g/d showed significant differences in their clinicopathologic characteristics with higher prevalence of hypertension, hypoalbuminemia, hyperuricemia, hypercholesterolemia and hypertriglyceridemia, worse renal function, higher proportions of segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, and interstitial inflammation. Even the patients with proteinuria 0.31 - 0.50 g/d exhibited higher uric acid, lower total serum protein and albumin, higher proportions of crescents, and global glomerulosclerosis. Furthermore, multiple risk factors linear regression analysis has shown that there were significant associations between proteinuria and serum albumin, uric acid, total cholesterol, triglyceride, systolic blood pressure, degrees of segmental glomerulosclerosis, proportions of crescents, and global glomerulosclerosis. CONCLUSION: Clinicopathologic features were significantly worse in IgAN patients with increasing of proteinuria.


Assuntos
Glomerulonefrite por IGA/patologia , Glomerulonefrite por IGA/fisiopatologia , Túbulos Renais/patologia , Proteinúria/etiologia , Proteinúria/fisiopatologia , Adulto , Atrofia/patologia , Biópsia , Feminino , Fibrose , Taxa de Filtração Glomerular , Glomerulonefrite por IGA/complicações , Glomerulosclerose Segmentar e Focal/etiologia , Humanos , Hipercolesterolemia/etiologia , Hipertensão/etiologia , Hipertrigliceridemia/etiologia , Hiperuricemia/etiologia , Hipoalbuminemia/etiologia , Masculino , Estudos Retrospectivos , Fatores de Risco , Albumina Sérica/metabolismo , Ácido Úrico/sangue
9.
Nat Genet ; 48(7): 740-6, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27213287

RESUMO

The human major histocompatibility complex (MHC) region has been shown to be associated with numerous diseases. However, it remains a challenge to pinpoint the causal variants for these associations because of the extreme complexity of the region. We thus sequenced the entire 5-Mb MHC region in 20,635 individuals of Han Chinese ancestry (10,689 controls and 9,946 patients with psoriasis) and constructed a Han-MHC database that includes both variants and HLA gene typing results of high accuracy. We further identified multiple independent new susceptibility loci in HLA-C, HLA-B, HLA-DPB1 and BTNL2 and an intergenic variant, rs118179173, associated with psoriasis and confirmed the well-established risk allele HLA-C*06:02. We anticipate that our Han-MHC reference panel built by deep sequencing of a large number of samples will serve as a useful tool for investigating the role of the MHC region in a variety of diseases and thus advance understanding of the pathogenesis of these disorders.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Complexo Principal de Histocompatibilidade/genética , Polimorfismo de Nucleotídeo Único/genética , Psoríase/genética , Butirofilinas/genética , Estudos de Casos e Controles , China/epidemiologia , Predisposição Genética para Doença , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Cadeias beta de HLA-DP/genética , Humanos , Psoríase/epidemiologia
10.
Nat Commun ; 6: 7270, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-26028593

RESUMO

IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis. Previously identified genome-wide association study (GWAS) loci explain only a fraction of disease risk. To identify novel susceptibility loci in Han Chinese, we conduct a four-stage GWAS comprising 8,313 cases and 19,680 controls. Here, we show novel associations at ST6GAL1 on 3q27.3 (rs7634389, odds ratio (OR)=1.13, P=7.27 × 10(-10)), ACCS on 11p11.2 (rs2074038, OR=1.14, P=3.93 × 10(-9)) and ODF1-KLF10 on 8q22.3 (rs2033562, OR=1.13, P=1.41 × 10(-9)), validate a recently reported association at ITGAX-ITGAM on 16p11.2 (rs7190997, OR=1.22, P=2.26 × 10(-19)), and identify three independent signals within the DEFA locus (rs2738058, P=1.15 × 10(-19); rs12716641, P=9.53 × 10(-9); rs9314614, P=4.25 × 10(-9), multivariate association). The risk variants on 3q27.3 and 11p11.2 show strong association with mRNA expression levels in blood cells while allele frequencies of the risk variants within ST6GAL1, ACCS and DEFA correlate with geographical variation in IgAN prevalence. Our findings expand our understanding on IgAN genetic susceptibility and provide novel biological insights into molecular mechanisms underlying IgAN.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Glomerulonefrite por IGA/genética , Adulto , Antígenos CD/genética , Antígeno CD11b/genética , Antígeno CD11c/genética , Estudos de Casos e Controles , China , Proteína DEFICIENS/genética , Fatores de Transcrição de Resposta de Crescimento Precoce/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Proteínas de Choque Térmico/genética , Humanos , Fatores de Transcrição Kruppel-Like/genética , Liases/genética , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Sialiltransferases/genética , Adulto Jovem
11.
Perit Dial Int ; 35(1): 70-7, 2015 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24293666

RESUMO

BACKGROUND: The effect of high peritoneal dialysate glucose concentration (PDGC) on all-cause and cardiovascular disease (CVD) mortality in peritoneal dialysis (PD) patients is unclear. OBJECTIVE: Our study aimed to investigate the effect of high PDGC on all-cause and CVD mortality in continuous ambulatory PD (CAPD) patients. METHODS: The study enrolled 716 patients newly initiated on CAPD therapy between January 2006 and December 2010. We allocated the patients to low (< 1.56%), medium (≥ 1.56% to < 1.74%), and high (≥ 1.74%) average PDGC groups according to the tertile of average PDGC in the first 6 months after PD initiation. Cox regression and ordinal logistic regression were used to analyze determinants of mortality and of PDGC use respectively. RESULTS: Mean follow-up in the study cohort was 31 ± 15 months. The all-cause mortality was 4.7 events per 100 patient-years, and the leading cause of death was CVD. Patients with a higher PDGC had significantly higher cumulative rates of all-cause (log-rank p < 0.001) and CVD mortality (log-rank p < 0.001). In Cox regression analysis, high PDGC independently predicted higher all-cause (hazard ratio: 2.63; p = 0.004) and CVD mortality (hazard ratio: 2.78; p = 0.01). Compared with a lower PDGC, a higher PDGC was significantly associated with older age [odds ratio (OR): 1.02; p < 0.001], low residual renal function (OR: 0.91; p < 0.001), and high dialysate-to-plasma ratio of creatinine (OR: 28.61; p < 0.001) in ordinal logistic regression. CONCLUSIONS: Higher PDGC is associated with higher allcause and CVD mortality in CAPD patients.


Assuntos
Doenças Cardiovasculares/mortalidade , Causas de Morte , Soluções para Diálise/efeitos adversos , Glucose/efeitos adversos , Falência Renal Crônica/terapia , Diálise Peritoneal Ambulatorial Contínua/mortalidade , Adulto , Idoso , Doenças Cardiovasculares/etiologia , Estudos de Coortes , Feminino , Glucose/análise , Humanos , Estimativa de Kaplan-Meier , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/mortalidade , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Diálise Peritoneal Ambulatorial Contínua/métodos , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Taxa de Sobrevida , Resultado do Tratamento
12.
PLoS One ; 9(10): e110445, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25329459

RESUMO

BACKGROUND: Continuous ambulatory peritoneal dialysis (CAPD) patients with diabetes are at increased risk of mortality and high peritoneal transporters appear to contribute to poor survival. However, little is known about the combined impacts of high peritoneal transporters and diabetes on mortality. METHODS: This was a prospective observational cohort study. 776 incident CAPD patients were enrolled. Unadjusted and adjusted Cox proportional regression models were used to evaluate the association and interaction of peritoneal transport and diabetic status with mortality. RESULTS: In the entire cohort, high peritoneal transport status was associated with an increased risk of all-cause mortality in unadjusted model [hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.30 to 4.25, P = 0.01], but this association was not significant in multivariable model. There was an interaction between peritoneal membrane transport status and diabetes (P = 0.028). Subgroup analyses showed that compared to low and low average transporters, high transporters was associated with a higher risk of all-cause mortality (adjusted HR 1.78, 95% CI 1.07 to 4.70, P = 0.04) in CAPD patients without diabetes, but not in those with diabetes (adjusted HR 0.79, 95%CI 0.33 to 1.89, P = 0.59). Results were similar when transport status was assessed as a continuous variable. CONCLUSIONS: The association between high peritoneal transport and all-cause mortality was likely to vary with diabetes status. High peritoneal transport was associated with an elevated risk of death among CAPD patients without diabetes, but not in those with diabetes.


Assuntos
Doenças Cardiovasculares/terapia , Diabetes Mellitus/terapia , Falência Renal Crônica/terapia , Diálise Peritoneal Ambulatorial Contínua/efeitos adversos , Adolescente , Adulto , Idoso , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/patologia , Estudos de Coortes , Diabetes Mellitus/mortalidade , Diabetes Mellitus/patologia , Feminino , Humanos , Falência Renal Crônica/mortalidade , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Mortalidade , Modelos de Riscos Proporcionais , Estudos Prospectivos
13.
Hum Genet ; 133(10): 1299-309, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25024040

RESUMO

Our recent genome-wide association study (GWAS) had discovered a new locus at 8p23 (rs2738048) associated with IgA nephropathy (IgAN) in Chinese Han patients, implicating the DEFA gene family within this locus as susceptibility genes. However, it is still unknown whether there are additional variations within these genes associated with the disease susceptibility. The aim of this study is to investigate the polymorphisms of DEFA genes in the susceptibility to IgAN and explore possible disease mechanisms. Sixteen tag single-nucleotide polymorphisms (tag SNPs) were selected for association study in 1,000 IgAN cases and 1,000 controls by using Sequenom MassArray system or TaqMan SNP genotyping assays. We found seven SNPs within DEFA genes that were significantly associated with IgAN, including rs2738048 discovered in our previous GWAS (p = 0.0007, OR = 0.77) and additional 6 SNPs (rs2615787, p = 0.0001, OR = 0.74; rs2738081, p = 0.0003, OR = 0.72; rs2738058, p = 0.0001, OR = 0.73; rs4288398, p = 0.0008, OR = 0.78; rs6984215, p = 0.002, OR = 0.63; rs12716641, p = 0.00002, OR = 0.71). Electrophoretic mobility shift assays and luciferase assays demonstrated that fragments containing rs2738048, rs2738081 and rs6984215 were transcription factor binding sites for CTF, SP1 and CdxA, respectively, and the allele status of rs2738048 and rs6984215 could significantly change the luciferase activity. These results suggest that polymorphisms within DEFA genes are involved in gene transcriptional regulation, and this may have some effect in mediating susceptibility to IgAN in southern Chinese.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Glomerulonefrite por IGA/genética , Polimorfismo de Nucleotídeo Único , alfa-Defensinas/genética , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Glomerulonefrite por IGA/epidemiologia , Células HEK293 , Humanos , Desequilíbrio de Ligação , Masculino , Família Multigênica
14.
Int J Mol Sci ; 15(1): 1162-75, 2014 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-24441570

RESUMO

Peritoneal dialysis effluent (PDE) potentially carries an archive of peptides relevant to pathological processes in abdominal and surrounding tissues. Magnetic beads and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry is one such approach that offers a unique tool for profiling of peptides, but this approach has not been used in the PDE analysis. In this study, we developed a strategy for screening PDE proteins <15 kDa and applied this technique to identify potential biomarkers for peritonitis. We examined four kinds of magnetic beads, including a carbon series (C3, C8), weak cation exchange (WCX) and immobilized metal-affinity chromatography (IMAC-Cu) beads. Samples processed with IMAC-Cu magnetic beads consistently showed more MS signals across all beads within the measured mass range. Moreover, there was no difference in the number and morphology of MS signals between concentrated and unconcentrated samples. The PDE peptidome pattern, based on a panel of 15 peaks, accurately recognized peritonitis PD patients from peritonitis-free patients with sensitivity of 90.5% and specificity of 94.7% respectively. Therefore, IMAC-Cu magnetic beads and unconcentrated samples can be used as a fast and cost-effective approach for sample preparation prior to more in-depth discovery of predictive biomarkers of disease in patients on dialysis.


Assuntos
Líquido Ascítico/química , Separação Imunomagnética/métodos , Diálise Peritoneal/métodos , Proteoma/análise , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Humanos , Sensibilidade e Especificidade
15.
PLoS One ; 8(8): e70767, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23951003

RESUMO

BACKGROUND: Periodontal disease is common among adults and is associated with an increasing risk of chronic kidney disease (CKD). We aimed to investigate the prevalence and risk factors of CKD in patients with periodontal disease in China. METHODS: In the current cross-sectional study, patients with periodontal disease were included from Guangdong Provincial Stomatological Hospital between March 2011 and August 2011. CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2), the presence of albuminuria, or hematuria. All patients with periodontal disease underwent a periodontal examination, including periodontal probing pocket depth, gingival recession, and clinical attachment level by Florida Probe. They completed a questionnaire and had blood and urine samples taken. The adjusted prevalence of indicators of kidney damage was calculated and risk factors associated with CKD were analyzed. RESULTS: A total of 1392 patients with periodontal disease were invited to participate this study and 1268 completed the survey and examination. After adjusting for age and sex, the prevalence of reduced eGFR, albuminuria, and hematuria was 2.7% (95% CI 1.7-3.7), 6.7% (95% CI 5.5-8.1) and 10.9% (95% CI 9.2-12.5), respectively. The adjusted prevalence of CKD was 18.2% (95% CI 16.2-20.3). Age, male, diabetes, hypertension, history of CKD, hyperuricemia, and interleukin-6 levels (≥7.54 ng/L) were independent risk factors for reduced eGFR. Female, diabetes, hypertension, history of CKD, hyperuricemia, high level of cholesterol, and high sensitivity C-reactive protein (hsCRP) (≥ 1.03 mg/L) and TNF-α levels (≥ 1.12 ng/L) were independently associated with an increased risk of albuminuria. Female, lower education (

Assuntos
Grupo com Ancestrais do Continente Asiático , Doenças Periodontais/complicações , Insuficiência Renal Crônica/complicações , Adulto , Idoso , Proteína C-Reativa/metabolismo , China/epidemiologia , Colesterol/sangue , Estudos Transversais , Feminino , Taxa de Filtração Glomerular , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Doenças Periodontais/epidemiologia , Doenças Periodontais/etnologia , Prevalência , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etnologia , Fatores de Risco , Fator de Necrose Tumoral alfa/sangue
16.
Am J Nephrol ; 36(2): 114-20, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22776760

RESUMO

BACKGROUND: Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal dominant disorder characterized by early onset of hyperuricemia, decreased fractional renal urate excretion and progressive interstitial nephropathy. Mutations in the uromodulin (UMOD) gene encoding uromodulin/Tamm-Horsfall, a glycosylphosphatidylinositol (GPI)-anchored protein, cause this disease. METHODS: One Chinese family with 13 FJHN-affected individuals is described. Clinical data, blood and urine samples of 7 affected members (all alive patients in this family) and 15 unaffected members were collected. Mutation analysis of the UMOD gene was performed by polymerase chain reaction and direct sequencing. Urinary uromodulin from affected or unaffected members of this family and healthy controls was examined by enzyme-linked immunosorbent assay kit. Expression of uromodulin in renal tissue was shown with immunofluorescence. RESULTS: A novel mutation (p.T605G) within the uromodulin GPI anchor signal segment was identified in the affected individuals of this FJHN family. There was a markedly increased expression of uromodulin in renal tissue and significantly decreased urinary excretion of uromodulin in affected patients with an estimated glomerular filtration rate <60 ml/min/1.73 m(2). CONCLUSIONS: The present study reported a novel mutation in exon 9 of UMOD in the Chinese Han population, within the GPI anchor signal segment of uromodulin. Since the GPI anchor is linked with the release or secretion of proteins, our finding may provide further evidence for the underlying mechanism of decreased urinary excretion of uromodulin in FJHN.


Assuntos
Gota/genética , Hiperuricemia/genética , Nefropatias/genética , Mutação de Sentido Incorreto/genética , Uromodulina/genética , Adolescente , Adulto , Sequência de Bases , Criança , Éxons/genética , Saúde da Família , Feminino , Gota/patologia , Humanos , Hiperuricemia/patologia , Rim/metabolismo , Rim/patologia , Nefropatias/patologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Uromodulina/metabolismo , Adulto Jovem
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