Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 171
Filtrar
1.
Nat Commun ; 10(1): 1847, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015462

RESUMO

Chronic kidney disease (CKD) is a growing health burden currently affecting 10-15% of adults worldwide. Estimated glomerular filtration rate (eGFR) as a marker of kidney function is commonly used to diagnose CKD. We analyze eGFR data from the Nord-Trøndelag Health Study and Michigan Genomics Initiative and perform a GWAS meta-analysis with public summary statistics, more than doubling the sample size of previous meta-analyses. We identify 147 loci (53 novel) associated with eGFR, including genes involved in transcriptional regulation, kidney development, cellular signaling, metabolism, and solute transport. Additionally, sex-stratified analysis identifies one locus with more significant effects in women than men. Using genetic risk scores constructed from these eGFR meta-analysis results, we show that associated variants are generally predictive of CKD with only modest improvements in detection compared with other known clinical risk factors. Collectively, these results yield additional insight into the genetic factors underlying kidney function and progression to CKD.


Assuntos
Loci Gênicos , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular/genética , Insuficiência Renal Crônica/genética , Feminino , Carga Global da Doença , Humanos , Rim/fisiopatologia , Masculino , Prognóstico , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/fisiopatologia , Medição de Risco/métodos , Fatores de Risco , Fatores Sexuais
2.
Med Sci Monit ; 25: 1699-1708, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30835718

RESUMO

BACKGROUND Diabetic kidney disease (DKD) can result in end-stage kidney disease and renal failure. This study aimed to examine the expression of serum microRNAs (miRNAs), miR-20a, miR-99b, miR-122-5p, and miR-486-5p, and to use bioinformatics data to investigate the pathways involved in DKD. MATERIAL AND METHODS Serum miRNAs were obtained from 25 healthy volunteers, 50 patients with non-complicated type 2 diabetes mellitus (T2DM), and 42 patients with T2DM and DKD. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of serum miRNAs. Specificity and sensitivity of the association between serum miRNAs in DKD were evaluated by analysis of the receiver operating characteristic (ROC) area under the curve (AUC). Serum miRNAs and clinical parameters of the patients were compared. Bioinformatics data analysis accessed the miRNA targets involved in the pathways related to the pathogenesis of DKD. RESULTS Serum levels of miR-99b and miR-122 significantly increased, and mir-20a and miR-486 decreased in the DKD group compared with healthy controls. Serum levels of miR-20a, miR-99b, miR-486-5p, and miR-122-5p were significantly correlated with albuminuria, estimated glomerular filtration rate (eGFR), blood glucose and lipid profiles. ROC curve analysis showed that diagnostic accuracy of serum levels of miR-99b for DKD was superior to miR-486-5p, miR-122-5p, and miR-20a, resulting in AUCs of 0.895, 0.853, 0.80, and 0.697, respectively. These four miRNAs regulate several genes affecting oxidative stress, inflammation, and apoptosis. CONCLUSIONS Serum miR-99b, miR-486-5p, miR-122-5p, and miR-20a were differentially expressed in patients with T2DM and DKD and should be evaluated further as potential biomarkers for DKD.


Assuntos
Nefropatias Diabéticas/genética , MicroRNAs/genética , Adulto , Albuminúria/sangue , Albuminúria/genética , Área Sob a Curva , Biomarcadores/sangue , Glicemia/análise , Estudos de Casos e Controles , Biologia Computacional/métodos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/sangue , Feminino , Perfilação da Expressão Gênica/métodos , Taxa de Filtração Glomerular/genética , Humanos , Lipídeos/análise , Lipídeos/sangue , Masculino , MicroRNAs/análise , MicroRNAs/sangue , Pessoa de Meia-Idade , Curva ROC
3.
PLoS Med ; 16(1): e1002725, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30645594

RESUMO

BACKGROUND: Studies have shown strong positive associations between serum urate (SU) levels and chronic kidney disease (CKD) risk; however, whether the relation is causal remains uncertain. We evaluate whether genetic data are consistent with a causal impact of SU level on the risk of CKD and estimated glomerular filtration rate (eGFR). METHODS AND FINDINGS: We used Mendelian randomization (MR) methods to evaluate the presence of a causal effect. We used aggregated genome-wide association data (N = 110,347 for SU, N = 69,374 for gout, N = 133,413 for eGFR, N = 117,165 for CKD), electronic-medical-record-linked UK Biobank data (N = 335,212), and population-based cohorts (N = 13,425), all in individuals of European ancestry, for SU levels and CKD. Our MR analysis showed that SU has a causal effect on neither eGFR level nor CKD risk across all MR analyses (all P > 0.05). These null associations contrasted with our epidemiological association findings from the 4 population-based cohorts (change in eGFR level per 1-mg/dl [59.48 µmol/l] increase in SU: -1.99 ml/min/1.73 m2; 95% CI -2.86 to -1.11; P = 8.08 × 10(-6); odds ratio [OR] for CKD: 1.48; 95% CI 1.32 to 1.65; P = 1.52 × 10(-11)). In contrast, the same MR approaches showed that SU has a causal effect on the risk of gout (OR estimates ranging from 3.41 to 6.04 per 1-mg/dl increase in SU, all P < 10-3), which served as a positive control of our approach. Overall, our MR analysis had >99% power to detect a causal effect of SU level on the risk of CKD of the same magnitude as the observed epidemiological association between SU and CKD. Limitations of this study include the lifelong effect of a genetic perturbation not being the same as an acute perturbation, the inability to study non-European populations, and some sample overlap between the datasets used in the study. CONCLUSIONS: Evidence from our series of causal inference approaches using genetics does not support a causal effect of SU level on eGFR level or CKD risk. Reducing SU levels is unlikely to reduce the risk of CKD development.


Assuntos
Insuficiência Renal Crônica/etiologia , Ácido Úrico/sangue , Adulto , Fatores Etários , Feminino , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular/genética , Humanos , Masculino , Análise da Randomização Mendeliana , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/genética , Fatores Sexuais , Adulto Jovem
4.
Nat Commun ; 10(1): 29, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30604766

RESUMO

Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.


Assuntos
Taxa de Filtração Glomerular/genética , Hipertensão/genética , Cálculos Renais/genética , Rim/fisiopatologia , Insuficiência Renal Crônica/genética , Adulto , Idoso , Pressão Sanguínea/genética , Grupos Étnicos/genética , Feminino , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Código das Histonas/genética , Histonas/metabolismo , Humanos , Hipertensão/etnologia , Hipertensão/fisiopatologia , Cálculos Renais/etnologia , Cálculos Renais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/etnologia , Insuficiência Renal Crônica/fisiopatologia
5.
PLoS One ; 13(3): e0194044, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29558500

RESUMO

Chronic kidney disease (CKD) is an important social health problem characterized by a decrease in the kidney glomerular filtration rate (GFR). In this study, we analyzed genome-wide association studies for kidney disease-related traits using data from a Korean adult health screening cohort comprising 7,064 participants. Kidney disease-related traits analyzed include blood urea nitrogen (BUN), serum creatinine, estimated GFR, and uric acid levels. We detected two genetic loci (SLC14A2 and an intergenic region) and 8 single nucleotide polymorphisms (SNPs) associated with BUN, 3 genetic loci (BCAS3, C17orf82, ALDH2) and 6 SNPs associated with serum creatinine, 3 genetic loci (BCAS3, C17orf82/TBX2, LRP2) and 7 SNPs associated with GFR, and 14 genetic loci (3 in ABCG2/PKD2, 2 in SLC2A9, 3 in intergenic regions on chromosome 4; OTUB1, NRXN2/SLC22A12, CDC42BPG, RPS6KA4, SLC22A9, and MAP4K2 on chromosome 11) and 84 SNPs associated with uric acid levels. By comparing significant genetic loci associated with serum creatinine levels and GFR, rs9895661 in BCAS3 and rs757608 in C17orf82 were simultaneously associated with both traits. The SNPs rs11710227 in intergenic regions on chromosome 3 showing significant association with BUN is newly discovered. Genetic variations of multiple gene loci are associated with kidney disease-related traits, and differences in associations between kidney disease-related traits and genetic variation are dependent on the population. The meanings of the mutations identified in this study will need to be reaffirmed in other population groups in the future.


Assuntos
Loci Gênicos/genética , Predisposição Genética para Doença/genética , Insuficiência Renal Crônica/genética , Adulto , Nitrogênio da Ureia Sanguínea , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 4/genética , Creatinina/sangue , Feminino , Estudo de Associação Genômica Ampla/métodos , Taxa de Filtração Glomerular/genética , Humanos , Rim/patologia , Testes de Função Renal/métodos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Insuficiência Renal Crônica/sangue , Seul , Ácido Úrico/sangue
6.
Int Urol Nephrol ; 50(4): 715-723, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29404926

RESUMO

PURPOSE: Since altered sympathetic nerve activity and insulin resistance are implicated in the pathogenesis of type 2 diabetic nephropathy, we investigated the effect of polymorphic Arg16Gly and Gln27Glu in the ß2 adrenoceptor gene and Ala54Thr in the fatty acid binding protein 2 gene on the estimated glomerular filtration rate (eGFR) in Chinese patients with the above disease. METHODS: A total of 552 diabetic subjects recruited from annual health examinations were studied. The eGFR was calculated from the Modification of Diet in Renal Disease equation for the Chinese. Plasma norepinephrine level and genotype were determined by high-performance liquid chromatography-tandem mass spectrometry and TaqMan method, respectively. Holter-derived heart rate viability (HRV) and the MRI-generated renal apparent diffusion coefficient (ADC) were evaluated. RESULTS: The Gly16Gly and Thr54Thr homozygotes had significantly higher microalbuminuria and lower eGFR against other genotypes in their individual polymorphism. Besides, the Gly16Gly variant exhibited markedly elevated norepinephrine level, whereas indicative of insulin resistance was increased in the Thr54Thr one. Multiple linear regression analysis further confirmed the independent genetic effect on the eGFR. Moreover, multifactor dimensionality reduction method detected a gene-gene synergistic action that subjects with the Gly16Gly/Thr54Thr genotype were exposed to higher risk of eGFR loss. Finally, these findings were accompanied by lower HRV and ADC, indicating sympathetically mediated hemodynamic changes. CONCLUSIONS: By uncovering the genetic component of the coherent interplay between the elevated sympathetic nerve activity and metabolic disorders, our observations might promote the development of novel personalized prevention and management strategies against the diabetic nephropathy, especially in the genetically susceptible individuals.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/genética , Proteínas de Ligação a Ácido Graxo/genética , Taxa de Filtração Glomerular/genética , Receptores Adrenérgicos beta 2/genética , Grupo com Ancestrais do Continente Asiático/genética , China , Nefropatias Diabéticas/fisiopatologia , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
7.
Mol Genet Genomics ; 293(1): 225-235, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29038864

RESUMO

Genome-wide association studies (GWAS) have been shown to have the potential of explaining more of the "missing heritability" of complex human phenotypes by improving statistical approaches. Here, we applied a genetic-pleiotropy-informed conditional false discovery rate (cFDR) to capture additional polygenic effects associated with estimated glomerular filtration rate (creatinine) (eGFRcrea) and type 2 diabetes (T2D). The cFDR analysis improves the identification of pleiotropic variants by incorporating potentially shared genetic mechanisms between two related traits. The Q-Q and fold-enrichment plots were used to assess the enrichment of SNPs associated with eGFRcrea or T2D, and Manhattan plots were used for showing chromosomal locations of the significant loci detected. By applying the cFDR method, we newly identified 74 loci for eGFRcrea and 3 loci for T2D with the cFDR criterion of 0.05 compared with previous related GWAS studies. Four shared SNPs were detected to be associated with both eGFRcrea and T2D at the significant conjunction cFDR level of 0.05, and these shared SNPs had not been reported in previous studies. In addition, we used DAVID analysis to perform functional analysis of the shared SNPs' annotated genes and found their potential hidden associations with eGFRcrea and T2D. In this study, the cFDR method shows the feasibility to detect more genetic variants underlying the heritability of eGFRcrea and T2D, and the overlapping SNPs identified could be regarded as candidate loci that provide a thread of genetic mechanisms between eGFRcrea and T2D in future research.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Taxa de Filtração Glomerular/genética , Diabetes Mellitus Tipo 2/patologia , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único
8.
Gene ; 644: 93-100, 2018 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-29101067

RESUMO

AIM: The present study was conducted to determine the effect of FOXP3 single nucleotide polymorphisms (SNPs) on clinical outcomes in CsA-treated renal transplant patients. METHODS: A total of 166 renal transplant patients with at least 5years of follow-up were included. SNPs of FOXP3 gene (rs3761547, rs3761548, rs3761549, rs2232365 and rs2280883) were detected by Taqman probe technique. The associations of SNPs with acute rejection, CsA-induced nephrotoxicity, pneumonia and post-transplantation estimated glomerular filtration rate (eGFR) were explored. RESULTS: Patients with rs3761549 T/TT genotype showed a more rapid decline in the eGFR level during the 5years following transplantation than those with the C/CC genotype (24.0% vs. 6.3%, P=0.004). All the SNPs and site-site interaction were not related to the occurrence of acute rejection, nephrotoxicity, and pneumonia. CONCLUSIONS: FOXP3 rs3761549 was significantly correlated with the renal allograft function. It could be used to predict and improve the outcome of renal transplant patients taking CsA as an immunosuppressant.


Assuntos
Ciclosporina/uso terapêutico , Fatores de Transcrição Forkhead/genética , Rejeição de Enxerto/genética , Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Adulto , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/genética , Humanos , Transplante de Rim/métodos , Masculino
9.
Discov Med ; 26(145): 251-260, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30695674

RESUMO

To determine whether -344T/C CYP11B2 promoter polymorphism affects serum aldosterone levels and whether this polymorphism is an indicator of eGFR decline in patients with chronic kidney disease. -344 C/T CYP11B2 gene polymorphism analysis was performed in 96 adults with stages 1-5 CKD by using polymerase chain reaction. Serum aldosterone levels were measured at baseline and at 1.5-year follow-up. The primary outcome was the annual eGFR decline and the secondary outcome was the occurrence of cardio-cerebrovascular events. The genotype distribution of -344T/C SNP in the patients with CKD was: CC (9.4%), CT (53.1%), and TT (37.5%), nearly similar to the healthy non-CKD individuals as reported. Mean aldosterone levels were highest in the TT group and lowest in CC group (p = 0.036). Serum aldosterone level also showed a negative correlation with baseline eGFR in patients with eGFR >60 mL/min (r = -0.403, p < 0.001). The mean annual eGFR decline ratio was highest in the TT group and lowest in the CC group (p = 0.011). The incidence of cardio-cerebrovascular accidents was significantly higher in the TT group than in the CC and CT groups (p = 0.033). -344T/C promoter polymorphism of CYP11B2 modulated aldosterone levels in patients with all stages of CKD and was predictive of annual eGFR decline in CKD stages 3-4. In addition, the -344 T allele appeared to be an independent predictor of cardio-cerebrovascular events.


Assuntos
Aldosterona/metabolismo , Citocromo P-450 CYP11B2/genética , Taxa de Filtração Glomerular , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Insuficiência Renal Crônica , Adulto , Idoso , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Transtornos Cerebrovasculares/etiologia , Transtornos Cerebrovasculares/genética , Transtornos Cerebrovasculares/fisiopatologia , Citocromo P-450 CYP11B2/metabolismo , Progressão da Doença , Regulação para Baixo , Feminino , Seguimentos , Taxa de Filtração Glomerular/genética , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/fisiopatologia
10.
Clin J Am Soc Nephrol ; 12(12): 1974-1983, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29146700

RESUMO

BACKGROUND AND OBJECTIVES: Genetic heterogeneity and phenotypic variability are major challenges in familial nephronophthisis and related ciliopathies. To date, mutations in 20 different genes (NPHP1 to -20) have been identified causing either isolated kidney disease or complex multiorgan disorders. In this study, we provide a comprehensive and detailed characterization of 152 children with a special focus on extrarenal organ involvement and the long-term development of ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We established an online-based registry (www.nephreg.de) to assess the clinical course of patients with nephronophthisis and related ciliopathies on a yearly base. Cross-sectional and longitudinal data were collected. Mean observation time was 7.5±6.1 years. RESULTS: In total, 51% of the children presented with isolated nephronophthisis, whereas the other 49% exhibited related ciliopathies. Monogenetic defects were identified in 97 of 152 patients, 89 affecting NPHP genes. Eight patients carried mutations in other genes related to cystic kidney diseases. A homozygous NPHP1 deletion was, by far, the most frequent genetic defect (n=60). We observed a high prevalence of extrarenal manifestations (23% [14 of 60] for the NPHP1 group and 66% [61 of 92] for children without NPHP1). A homozygous NPHP1 deletion not only led to juvenile nephronophthisis but also was able to present as a predominantly neurologic phenotype. However, irrespective of the initial clinical presentation, the kidney function of all patients carrying NPHP1 mutations declined rapidly between the ages of 8 and 16 years, with ESRD at a mean age of 11.4±2.4 years. In contrast within the non-NPHP1 group, there was no uniform pattern regarding the development of ESRD comprising patients with early onset and others preserving normal kidney function until adulthood. CONCLUSIONS: Mutations in NPHP genes cause a wide range of ciliopathies with multiorgan involvement and different clinical outcomes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Ciliopatias/genética , Doenças Renais Císticas/congênito , Falência Renal Crônica/genética , Proteínas de Membrana/genética , Fenótipo , Adolescente , Anemia/genética , Antígenos de Neoplasias/genética , Proteínas de Ligação a Calmodulina/genética , Proteínas de Transporte/genética , Criança , Ciliopatias/complicações , Estudos Transversais , Feminino , Taxa de Filtração Glomerular/genética , Homozigoto , Humanos , Rim/diagnóstico por imagem , Doenças Renais Císticas/complicações , Doenças Renais Císticas/diagnóstico por imagem , Doenças Renais Císticas/genética , Falência Renal Crônica/fisiopatologia , Cinesina/genética , Estudos Longitudinais , Masculino , Proteínas de Neoplasias/genética , Doenças do Sistema Nervoso/genética , Poliúria/genética , Proteínas/genética , Ultrassonografia , Adulto Jovem
11.
Nat Commun ; 8(1): 1286, 2017 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-29097680

RESUMO

Chronic kidney disease (CKD) is defined by reduced estimated glomerular filtration rate (eGFR). Previous genetic studies have implicated regulatory mechanisms contributing to CKD. Here we present epigenome-wide association studies of eGFR and CKD using whole-blood DNA methylation of 2264 ARIC Study and 2595 Framingham Heart Study participants to identify epigenetic signatures of kidney function. Of 19 CpG sites significantly associated (P < 1e-07) with eGFR/CKD and replicated, five also associate with renal fibrosis in biopsies from CKD patients and show concordant DNA methylation changes in kidney cortex. Lead CpGs at PTPN6/PHB2, ANKRD11, and TNRC18 map to active enhancers in kidney cortex. At PTPN6/PHB2 cg19942083, methylation in kidney cortex associates with lower renal PTPN6 expression, higher eGFR, and less renal fibrosis. The regions containing the 243 eGFR-associated (P < 1e-05) CpGs are significantly enriched for transcription factor binding sites of EBF1, EP300, and CEBPB (P < 5e-6). Our findings highlight kidney function associated epigenetic variation.


Assuntos
Metilação de DNA/genética , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Idoso , Sítios de Ligação/genética , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Ilhas de CpG , Progressão da Doença , Proteína p300 Associada a E1A/genética , Proteína p300 Associada a E1A/metabolismo , Epigênese Genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular/genética , Humanos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
12.
Clin J Am Soc Nephrol ; 12(11): 1771-1777, 2017 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-29051146

RESUMO

BACKGROUND AND OBJECTIVES: The natural history of kidney disease among blacks who carry the APOL1 high-risk variants varies, with only a subgroup progressing to ESRD. We aimed to determine whether the APOL1 risk variants are associated with incident proteinuria in the context of hypertension-attributed CKD, and whether subsequent kidney function decline after the onset of proteinuria differs by APOL1 risk status. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using Cox models, we studied the association between APOL1 risk status and incident proteinuria (defined as a doubling of urine protein-to-creatinine ratio to a level ≥0.22 g/g creatinine) among African-American Study of Kidney Disease and Hypertension (AASK) trial participants with APOL1 genotyping and without proteinuria at baseline. RESULTS: Of the 480 participants in our study, 82 (17%) had the high-risk genotypes (2 alleles), and 254 (53%) developed proteinuria over a median follow-up of 6.8 years. At baseline, mean eGFR was lower in the APOL1 high-risk group compared with the low-risk group (0 or 1 allele; 49.6 versus 53.2 ml/min per 1.73 m2, respectively; P=0.02), but median proteinuria was similar (0.04 g/g creatinine for both groups; P=0.43). Individuals with the high-risk genotypes were 1.72-fold more likely to develop incident proteinuria compared with those with the low-risk genotypes (95% confidence interval, 1.27 to 2.32), independent of age, sex, ancestry, baseline eGFR, baseline systolic BP, and randomized treatment groups. Although eGFR declined faster after the onset of proteinuria, this rate did not differ significantly by APOL1 risk status. CONCLUSIONS: Among blacks with established moderate CKD, the APOL1 high-risk variants are associated with greater risk of incident proteinuria. After proteinuria onset, kidney function declines more rapidly but does not differ by APOL1 risk status. This suggests that factors that lead to proteinuria, beyond APOL1, may additionally drive CKD progression.


Assuntos
Afro-Americanos/genética , Apolipoproteína L1/genética , Proteinúria/genética , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Idoso , Creatinina/urina , Feminino , Seguimentos , Genótipo , Taxa de Filtração Glomerular/genética , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Proteinúria/urina , Insuficiência Renal Crônica/etiologia , Fatores de Risco
13.
Neuromuscul Disord ; 27(11): 1038-1042, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29029879

RESUMO

Myotonic dystrophy type 1 (DM1) affects several organs. Disease severity and age at onset are correlated to the CTG repeat expansion. The aim of this study was to assess renal function and the association to numbers of CTG repeat expansion in patients with DM1. Ninety-eight patients with DM1 were included. Glomerular filtration rate (measured GFR) was measured using iohexol clearance. Data on CTG repeats were available in 83/98 (85%) patients. The overall mGFR was 74 (16) ml/min/1.73 m2 (range 38-134). Sixty-four patients (69%) had a mild and sixteen patients (17%) a moderate decrease in renal function (mGFR 60-89 and 30-59 ml/min/1.73 m2, respectively). No correlations were found between CTG repeats and mGFR (r = 0.10, p = 0.4) or between CTG repeats and serum cystatin C (r = 0.12, p = 0.29). CTG repeats was positively correlated to creatinine-based estimates of GFR (eGFR) (modified diet in renal disease r = 0.49, p < 0.001, CKD-EPI creatinine equation; r = 0.50, p < 0.001), but analyses using Structural Equation Modeling showed no correlation. The correlation was explained by an indirect effect via serum creatinine and skeletal muscle mass index. In conclusion, patients with DM1 seem to have a slight decrease in renal function but there is no association between renal function and the number of CTG repeats, a marker of disease severity.


Assuntos
Rim/fisiopatologia , Distrofia Miotônica/genética , Distrofia Miotônica/fisiopatologia , Miotonina Proteína Quinase/genética , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Albuminúria/epidemiologia , Albuminúria/genética , Albuminúria/fisiopatologia , Biomarcadores/sangue , Estudos de Coortes , Creatinina/sangue , Cistatina C/sangue , Feminino , Taxa de Filtração Glomerular/genética , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Distrofia Miotônica/epidemiologia , Tamanho do Órgão , Insuficiência Renal Crônica/epidemiologia , Fatores de Risco , Índice de Gravidade de Doença , Expansão das Repetições de Trinucleotídeos
14.
J Pharmacol Exp Ther ; 363(3): 412-418, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28912346

RESUMO

20-Hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) has been linked to pro-hypertensive and anti-hypertensive actions through its ability to promote vasoconstriction and inhibit Na transport in the ascending limb of the loop of Henle, respectively. In this study, we assessed the effects of 20-HETE blockade on blood pressure, renal hemodynamics, and urinary sodium excretion in Cyp4a14(-/-) male mice, which display androgen-driven 20-HETE-dependent hypertension. Administration of 2,5,8,11,14,17-hexaoxanonadecan-19-yl 20-hydroxyicosa-6(Z),15(Z)-dienoate (20-SOLA), a water-soluble 20-HETE antagonist, in the drinking water normalized the blood pressure of male Cyp4a14(-/-) hypertensive mice (±124 vs. ±153 mmHg) while having no effect on age-matched normotensive wild-type (WT) male mice. Hypertension in Cyp4a14(-/-) male mice was accompanied by decreased renal perfusion and reduced glomerular filtration rates, which were corrected by treatment with 20-SOLA. Interestingly, Cyp4a14(-/-) male mice treated with 20-SOLA displayed increased urinary sodium excretion that was paralleled by the reduction of blood pressure suggestive of an antinatriuretic activity of endogenous 20-HETE in the hypertensive mice. This interpretation is in line with the observation that the natriuretic response to acute isotonic saline loading in hypertensive Cyp4a14(-/-) male mice was significantly impaired relative to that in WT mice; this impairment was corrected by 20-SOLA treatment. Hence, endogenous 20-HETE appears to promote sodium conservation in hypertensive Cyp4a14(-/-) male mice, presumably, as a result of associated changes in renal hemodynamics and/or direct stimulatory action on tubular sodium reabsorption.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Família 4 do Citocromo P450/genética , Ácidos Hidroxieicosatetraenoicos/antagonistas & inibidores , Natriurese/efeitos dos fármacos , Animais , Anti-Hipertensivos/farmacologia , Feminino , Taxa de Filtração Glomerular/genética , Túbulos Renais/metabolismo , Masculino , Camundongos , Camundongos Knockout , Polietilenoglicóis , Circulação Renal/genética , Siloxanas , Sódio/urina
15.
Br J Haematol ; 178(4): 629-639, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28466968

RESUMO

Micro-albuminuria and glomerular hyperfiltration are primary indicators of renal dysfunctions in Sickle Cell Disease (SCD), with more severe manifestations previously associated with variants in APOL1 and HMOX1 among African Americans. We have investigated 413 SCD patients from Cameroon. Anthropometric variables, haematological indices, crude albuminuria, albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were measured. Patients were genotyped for 3·7 kb alpha-globin gene (HBA1/HBA2) deletion, and for variants in APOL1 (G1/G2; rs60910145, rs73885319, rs71785313) and HMOX1 (rs3074372, rs743811). The median age was 15 years; the majority presented with micro-albuminuria (60·9%; n = 248), and approximately half with glomerular hyperfiltration (49·5%; n = 200). Age, male sex, haemoglobin level, leucocyte count, mean corpuscular volume, blood pressure, body mass index and creatinine levels significantly affected albuminuria and/or eGFR. Co-inheritance of alpha-thalassaemia was protective against macro-albuminuria (P = 0·03). APOL1 G1/G2 risk variants were significantly associated with the ACR (P = 0·01) and borderline with eGFR (P = 0·07). HMOX1 - rs743811 was borderline associated with micro-albuminuria (P = 0·07) and macro-albuminuria (P = 0·06). The results revealed a high proportion of micro-albuminuria and glomerular hyperfiltration among Cameroonian SCD patients, and support the possible use of targeted genetic biomarkers for risks assessment.


Assuntos
Anemia Falciforme/complicações , Insuficiência Renal/etiologia , Adolescente , Adulto , Albuminúria/epidemiologia , Albuminúria/etiologia , Albuminúria/genética , Anemia Falciforme/epidemiologia , Anemia Falciforme/genética , Antropometria/métodos , Apolipoproteína L1 , Apolipoproteínas/genética , Camarões/epidemiologia , Criança , Pré-Escolar , Feminino , Deleção de Genes , Predisposição Genética para Doença , Variação Genética , Taxa de Filtração Glomerular/genética , Hemoglobina A Glicada/genética , Heme Oxigenase-1/genética , Humanos , Lipoproteínas HDL/genética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Insuficiência Renal/epidemiologia , Insuficiência Renal/genética , Fatores de Risco
16.
PLoS One ; 12(1): e0170815, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28135296

RESUMO

Genome-wide association studies (GWAS) using single nucleotide polymorphisms (SNPs) have identified more than 50 loci associated with estimated glomerular filtration rate (eGFR), a measure of kidney function. However, significant SNPs account for a small proportion of eGFR variability. Other forms of genetic variation have not been comprehensively evaluated for association with eGFR. In this study, we assess whether changes in germline DNA copy number are associated with GFR estimated from serum creatinine, eGFRcrea. We used hidden Markov models (HMMs) to identify copy number polymorphic regions (CNPs) from high-throughput SNP arrays for 2,514 African (AA) and 8,645 European ancestry (EA) participants in the Atherosclerosis Risk in Communities (ARIC) study. Separately for the EA and AA cohorts, we used Bayesian Gaussian mixture models to estimate copy number at regions identified by the HMM or previously reported in the HapMap Project. We identified 312 and 464 autosomal CNPs among individuals of EA and AA, respectively. Multivariate models adjusted for SNP-derived covariates of population structure identified one CNP in the EA cohort near genome-wide statistical significance (Bonferroni-adjusted p = 0.067) located on chromosome 5 (876-880kb). Overall, our findings suggest a limited role of CNPs in explaining eGFR variability.


Assuntos
Variações do Número de Cópias de DNA/genética , Estudo de Associação Genômica Ampla , Rim/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Grupo com Ancestrais do Continente Africano/genética , Aterosclerose/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Taxa de Filtração Glomerular/genética , Humanos , Testes de Função Renal , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Fatores de Risco
17.
Clin Exp Nephrol ; 21(3): 474-480, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27339447

RESUMO

BACKGROUND: This study aimed to evaluate genetic and environmental relations between change in estimated glomerular filtration rate (eGFR) and changes in cardiometabolic factors. METHODS: In 1772 Korean adults without diabetes and chronic kidney disease at baseline, changes in eGFR using the Chronic Kidney Disease Epidemiology Collaboration equation, blood pressure (BP), fasting serum glucose (FSG), insulin, homeostasis model assessment of insulin resistance index (HOMA-IR), hemoglobin A1c, triglycerides, high and low density lipoprotein cholesterol (HDL and LDL), uric acid, white blood cell (WBC) count, and body mass index (BMI) were calculated as follows: (value at follow-up - value at baseline) × 100/[value at baseline × follow-up interval (years)]. RESULTS: eGFR change was associated with 10 % changes in FSG (Odds ratio, OR = 1.36), uric acid (OR = 2.49), HDL (OR = 0.69), LDL (OR = 1.26), and WBC (OR = 1.15) after adjusting for age, sex, intra-familial and twin correlations, smoking, alcohol use, and physical activity at baseline, and BMI change using a generalized estimating equation. In bivariate variance-component analysis, eGFR change had additive genetic correlations ([Formula: see text]) with changes in insulin (-0.26), HOMA-IR (-0.24), diastolic BP (-0.15), uric acid (-0.45), triglycerides (-0.30), WBC (-0.46), and HDL (0.41), and environmental correlations ([Formula: see text]) with changes in FSG (-0.11), uric acid (-0.32), LDL (-0.14), and WBC (0.10). In co-twin control analyses in 319 monozygotic twin pairs, the ORs for having a greater eGFR decline with a 1 % increase in diastolic BP, uric acid, and LDL were 1.04, 1.09, and 1.03, respectively after adjusting for change in BMI and health behaviors at baseline. CONCLUSIONS: In these Korean twins and families, additive genetic influences and environmental effects play significant roles in the associations between eGFR change and changes in cardiometabolic factors.


Assuntos
Interação Gene-Ambiente , Taxa de Filtração Glomerular/genética , Rim/fisiopatologia , Síndrome Metabólica/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores/sangue , Glicemia/metabolismo , Distribuição de Qui-Quadrado , Feminino , Pleiotropia Genética , Predisposição Genética para Doença , Hemoglobina A Glicada/metabolismo , Humanos , Insulina/sangue , Estilo de Vida , Lipídeos/sangue , Modelos Logísticos , Masculino , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/genética , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Fenótipo , Prognóstico , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia , República da Coreia , Fatores de Risco , Fatores de Tempo , Ácido Úrico/sangue
18.
J Am Soc Nephrol ; 28(3): 981-994, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27920155

RESUMO

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10-7), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10-8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.


Assuntos
Exoma/genética , Taxa de Filtração Glomerular/genética , Rim/embriologia , Proteínas Tirosina Fosfatases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Son Of Sevenless/genética , Animais , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Peixe-Zebra
19.
Nephrology (Carlton) ; 22(10): 811-817, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27450519

RESUMO

AIM: Meta-analysis of data from a genome-wide association study (GWAS) identified seven single nucleotide polymorphisms (SNPs) as strong predictors of IgA nephropathy (IgAN). To replicate the association of these seven SNPs and understand whether they influence the clinical characteristics of IgAN, a case-control study including 521 IgAN patients and 535 controls was conducted in a Western Han cohort. METHODS: Data were analyzed using logistic regression and multifactor dimensionality reduction (MDR). Clinical data collected from 459 IgAN patients were investigated to estimate the relationship between the genotype and phenotype of IgAN. A retrospective cohort study of 315 IgAN patients was conducted to investigate the relationship between genotype and progression of renal disease over a mean period of 44.49 ± 19.94 months. RESULTS: Upon Bonferroni correction, none of the seven SNPs were associated with IgAN (corrected P-value [Pc], >0.05). A combination of the rs2856717T/C, rs9275596C/T, and rs2412971A/G had effects on the susceptibility of IgAN (P = 0.001). Marginally significant association of rs2856717 T/C recessive model for the T allele was significantly associated with estimated glomerular filtration rate (eGFR) (<60 mL/min per 1.73 m2 ) in IgAN patients (P = 0.008, Pc = 0.056, odds ratio [OR] = 1.527). The T allele at rs9275596 was significantly associated with macroscopic haematuria of IgAN patients under the dominant and additive models of inheritance, (P < 0.001, Pc = 0.007, OR = 2.983) and (P < 0.001, Pc = 0.007, OR = 2.17), respectively. Kaplan-Meier survival analysis showed that patients carrying the TT + TC genotype for rs2856717 had reduced renal survival rate than those carrying the CC genotype (85.1% vs. 92.7%, P = 0.046). CONCLUSION: rs2856717 may influence the clinical characteristics and poor outcome of IgAN. Further studies are warranted to explore the mechanisms for such genotype-disease phenotype association.


Assuntos
Taxa de Filtração Glomerular/genética , Glomerulonefrite por IGA/genética , Rim/fisiopatologia , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Distribuição de Qui-Quadrado , China/epidemiologia , Progressão da Doença , Feminino , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/fisiopatologia , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Razão de Chances , Fenótipo , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Adulto Jovem
20.
J Cell Biochem ; 118(7): 1803-1809, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27996163

RESUMO

To explore the associations between potential functional promoter polymorphisms in pro-inflammatory and anti-inflammatory (IL-4(-590C/T) and IL-6(-174G/C) cytokine genes, and kidney dysfunction in North Indian type 2 diabetic subjects with chronic kidney disease. A total of 150 subjects aged 25-75 year were included in this study. The glomerular filtration rate (GFR) and serum creatinine were estimated. PCR was performed to analyse genotype distribution in IL-4 (-590T/C) and IL-6 (-174G/C) among healthy, type 2 diabetic patients with or without CKD. The genotype distributions were determined by Hardy-Weinberg equilibrium. CKD patients showed lower GFR (59.36 ± 1.33 ml/min/1.73 m2 ) and higher serum creatinine (1.93 ± 0.99% mg) level in comparison to diabetic patients without CKD and healthy subjects. Genotypic distribution of the different genotypes among the study groups in IL-4 gene was genotype CC = 30, TC = 12, and TT = 8 in CKD patients. In type 2 diabetic patients without CKD, genotype distribution was CC = 38, TC = 10, and TT = 2. In healthy subjects, distribution of genotype was CC = 35, TC = 14, and TT = 1. The distribution of different genotype among the study groups for IL-6 gene was GG = 27, GC = 20, and CC = 3 in healthy subjects; GG = 28, GC = 19, and CC = 3 in diabetic patients without CKD and GG = 38, GC = 11, and CC = 1 in diabetic patients with CKD. There was no significant difference in the distribution of genotype frequencies between healthy subjects and diabetic patients without CKD but a significant difference was found in diabetic patients with CKD. The functional promoter polymorphisms IL4-590C/T and IL6-174G/C, which affect the IL-4 and IL-6 levels in north Indian subjects, were associated with kidney dysfunction and CKD. J. Cell. Biochem. 118: 1803-1809, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Predisposição Genética para Doença/genética , Interleucina-4/genética , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Insuficiência Renal Crônica/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , Creatinina/sangue , Diabetes Mellitus Tipo 2 , Eletroforese em Gel de Ágar , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Genótipo , Taxa de Filtração Glomerular/genética , Taxa de Filtração Glomerular/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA