Dataset Information

Cytosine methylation predicts renal function decline in American Indians.

ABSTRACT: Diabetic nephropathy accounts for most of the excess mortality in individuals with diabetes, but the molecular mechanisms by which nephropathy develops are largely unknown. Here we tested cytosine methylation levels at 397,063 genomic CpG sites for association with decline in the estimated glomerular filtration rate (eGFR) over a six year period in 181 diabetic Pima Indians. Methylation levels at 77 sites showed significant association with eGFR decline after correction for multiple comparisons. A model including methylation level at two probes (cg25799291 and cg22253401) improved prediction of eGFR decline in addition to baseline eGFR and the albumin to creatinine ratio with the percent of variance explained significantly improving from 23.1% to 42.2%. Cg22253401 was also significantly associated with eGFR decline in a case-control study derived from the Chronic Renal Insufficiency Cohort. Probes at which methylation significantly associated with eGFR decline were localized to gene regulatory regions and enriched for genes with metabolic functions and apoptosis. Three of the 77 probes that were associated with eGFR decline in blood samples showed directionally consistent and significant association with fibrosis in microdissected human kidney tissue, after correction for multiple comparisons. Thus, cytosine methylation levels may provide biomarkers of disease progression in diabetic nephropathy and epigenetic variations contribute to the development of diabetic kidney disease.

SUBMITTER: Qiu C

PROVIDER: S-EPMC5973533 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Cytosine methylation predicts renal function decline in American Indians.

Qiu Chengxiang C Hanson Robert L RL Fufaa Gudeta G Kobes Sayuko S Gluck Caroline C Huang Jing J Chen Yong Y Raj Dominic D Nelson Robert G RG Knowler William C WC Susztak Katalin K

Kidney international 20180427 6

Diabetic nephropathy accounts for most of the excess mortality in individuals with diabetes, but the molecular mechanisms by which nephropathy develops are largely unknown. Here we tested cytosine methylation levels at 397,063 genomic CpG sites for association with decline in the estimated glomerular filtration rate (eGFR) over a six year period in 181 diabetic Pima Indians. Methylation levels at 77 sites showed significant association with eGFR decline after correction for multiple comparisons. ...[more]

PMID: 29709239

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Project description:Diabetes is the leading cause of kidney failure in the United States, but early structural determinants of renal function loss in type 2 diabetes are poorly defined. We examined the association between morphometrically determined renal structural variables and loss of renal function in 111 American Indians with type 2 diabetes who volunteered for a research kidney biopsy at the end of a 6-year clinical trial designed to test the renoprotective efficacy of losartan versus placebo. Participants were subsequently followed in an observational study, in which annual measurements of GFR (iothalamate) initiated during the clinical trial were continued.Renal function loss was defined as ?40% loss of GFR from the research examination performed at the time of kidney biopsy. Associations with renal function loss were evaluated by Cox proportional hazards regression. Hazard ratios (HRs) were reported per 1-SD increment for each morphometric variable.Of 111 participants (82% women; baseline mean [±SD] age, 46 years old [±10]; diabetes duration, 16 years [±6]; hemoglobin A1c =9.4% [±2.2]; GFR=147 ml/min [±56]; median albumin-to-creatinine ratio, 41 mg/g [interquartile range, 13-158]), 51 (46%) developed renal function loss during a median follow-up of 6.6 years (interquartile range, 3.1-9.0). Fourteen had baseline GFR <90 ml/min, and three had baseline GFR <60 ml/min. Higher mesangial fractional volume (HR, 2.27; 95% confidence interval [95% CI], 1.58 to 3.26), percentage of global glomerular sclerosis (HR, 1.63; 95% CI, 1.21 to 2.21), nonpodocyte cell number per glomerulus (HR, 1.50; 95% CI, 1.10 to 2.05), glomerular basement membrane width (HR, 1.48; 95% CI, 1.05 to 2.08), mean glomerular volume (HR, 1.42; 95% CI, 1.02 to 1.96), and podocyte foot process width (HR, 1.28; 95% CI, 1.03 to 1.60); lower glomerular filtration surface density (HR, 0.62; 95% CI, 0.41 to 0.94); and fewer endothelial fenestrations (HR, 0.68; 95% CI, 0.48 to 0.95) were each associated with GFR decline after adjustment for baseline age, sex, duration of diabetes, hemoglobin A1c, GFR, and treatment assignment during the clinical trial.Quantitative measures of glomerular structure predict loss of renal function in type 2 diabetes.

Project description:Chronic kidney disease (CKD) is characterized by increased risks of morbidity and mortality. Upper-body subcutaneous fat, which is commonly estimated from the neck circumference (NC), was revealed to be the main reservoir of circulating nonesterified fatty acids in overweight patients. Despite a close association between NC and metabolic complications, the relationship of NC with renal function has not been fully investigated. In this study, the impact of NC on the development of incident CKD was elucidated.The data were retrieved from the Korean Genome and Epidemiology Study cohort. The subjects were followed at 2-year intervals from 2003 to 2011. Overweight was defined as a body mass index of ≥23 kg/m. A total of 4298 cohort subjects were screened. After exclusion, 2268 overweight subjects were included for the final analysis. The primary end point was incident CKD, which was defined as a composite of estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m or the development of proteinuria.The mean patient age was 36.3 ± 3.0 years, and 1285 (56.7%) were men. They were divided into 2 groups according to the median NC in male and female subjects, separately. In both sexes, hypertension (men, P < 0.001; women, P = 0.009) and diabetes (men, P = 0.002; women, P < 0.001) were significantly more prevalent in the big NC group than in the small NC group. In contrast, eGFR was significantly lower only in male subjects of the big NC group (P < 0.001), whereas it was comparable between the small and big NC groups (P = 0.167). In multivariate Cox proportional hazards regression analysis, NC values were independently associated with incident CKD development in female subjects after adjusting for multiple confounding factors (per 1 cm increase, hazard ratio [95% confidence interval] = 1.159 [1.024-1.310], P = 0.019) but not in male subjects.NC is independently associated with the development of CKD in overweight female subjects, suggesting that it could be a practical risk factor for CKD.

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Cytosine methylation predicts renal function decline in American Indians.

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Cytosine methylation predicts renal function decline in American Indians.

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