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UMOD as a susceptibility gene for end-stage renal disease.

ABSTRACT: BACKGROUND: In recent genetic association studies, common variants including rs12917707 in the UMOD locus have shown strong evidence of association with eGFR, prevalent and incident chronic kidney disease and uromodulin urinary concentration in general population cohorts. The association of rs12917707 with end-stage renal disease (ESRD) in a recent case-control study was only nominally significant. METHODS: To investigate whether rs12917707 associates with ESRD, graft failure (GF) and urinary uromodulin levels in an independent cohort, we genotyped 1142 ESRD patients receiving a renal transplantation and 1184 kidney donors as controls. After transplantation, 1066 renal transplant recipients were followed up for GF. Urinary uromodulin concentration was measured at median [IQR] 4.2 [2.2-6.1] yrs after kidney transplantation. RESULTS: The rs12917707 minor allele showed association with lower risk of ESRD (OR 0.89 [0.76-1.03], p = 0.04) consistent in effect size and direction with the previous report (Böger et al, PLoS Genet 2011). Meta-analysis of these findings showed significant association of rs12917707 with ESRD (OR 0.91 [0.85-98], p = 0.008). In contrast, rs12917707 was not associated with incidence of GF. Urinary uromodulin concentration was lower in recipients-carriers of the donor rs12917707 minor allele as compared to non-carriers, again consistent with previous observations in general population cohorts. CONCLUSIONS: Our study thus corroborates earlier evidence and independently confirms the association between UMOD and ESRD.

SUBMITTER: Reznichenko A

PROVIDER: S-EPMC3495046 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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UMOD as a susceptibility gene for end-stage renal disease.

Reznichenko Anna A Böger Carsten A CA Snieder Harold H van den Born Jacob J de Borst Martin H MH Damman Jeffrey J van Dijk Marcory C R F MC van Goor Harry H Hepkema Bouke G BG Hillebrands Jan-Luuk JL Leuvenink Henri G D HG Niesing Jan J Bakker Stephan J L SJ Seelen Marc M Navis Gerjan G

BMC medical genetics 20120905

<h4>Background</h4>In recent genetic association studies, common variants including rs12917707 in the UMOD locus have shown strong evidence of association with eGFR, prevalent and incident chronic kidney disease and uromodulin urinary concentration in general population cohorts. The association of rs12917707 with end-stage renal disease (ESRD) in a recent case-control study was only nominally significant.<h4>Methods</h4>To investigate whether rs12917707 associates with ESRD, graft failure (GF) a ...[more]

PMID: 22947327

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Project description:Background/objectiveRAC1 gene could influence susceptibility to renal failure by altering the activity and expression of Rac1, which is a member of the Rho family of small GTP-binding proteins. In clinical practice, renal transplantation provides the optimal treatment for people with end-stage renal disease (ESRD). The objective of this present study was to determine whether the RAC1 gene polymorphisms were associated with primary ESRD susceptibility in Chinese renal recipients.MethodsSix single nucleotide polymorphisms (SNPs) of RAC1 gene, including rs836488 T>C, rs702482 A>T, rs10951982 G>A, rs702483 A>G, rs6954996 G>A, and rs9374 G>A, were genotyped in 300 renal transplant recipients (cases) and 998 healthy Chinese subjects (controls) by using TaqMan SNP genotyping assay. Allele, genotype, and haplotype frequencies of the six SNPs were compared between cases and controls. Odds ratios (OR) and 95% confidence intervals (CI) were calculated in logistic regression models to evaluate the associations of the six SNPs with ESRD risk.ResultsThe genotype distributions for the six SNPs in controls were consistent with Hardy-Weinberg equilibrium (P > 0.05). Association analysis revealed that three SNPs were significantly associated with ESRD risk. Positive associations with ESRD risk were found for the rs836488, rs702482, and rs702483 in the co-dominant model (minor allele homozygotes versus major allele homozygotes); specifically, the frequencies of the minor allele homozygotes and the minor allele for the three SNPs were higher in the cases than in the controls. In addition, these three SNPs also had associations with increased ESRD risk under the additive model (P < 0.05), and positive associations were also found for the rs836488 in the dominant model (P < 0.05) and for the rs702483 in the recessive model (P < 0.05). All these associations were independent of confounding factors. The other three SNPs (rs10951982, rs6954996, and rs9374), in all comparison models, were not associated with ESRD risk (P > 0.05). In haplotype analysis, carriers with "C-T-G-G-G-G" haplotype had a significantly higher risk of ESRD compared with the most common haplotype "T-A-G-A-G-G" (P = 0.011, OR = 1.46, 95% CI = 1.09-1.94).ConclusionThis study suggested that polymorphisms of RAC1 gene might influence the susceptibility to ESRD in Chinese Han population. Further studies are necessary to confirm our findings.

Project description:BackgroundThe low-density lipoprotein receptor (LDLR) plays a significant role in maintaining the cellular cholesterol homeostasis. Mutations in the LDLR gene can lead to a significant rise in plasma LDL levels that may result in an increased risk of atherosclerosis and coronary heart disease. The purpose of this study was to assess the potential association of the LDLR rs688 polymorphism with cardiovascular disease (CVD) in patients with end-stage kidney disease (ESKD) undergoing hemodialysis.MethodsIn this case-control study the polymorphism was genotyped by the allele specific PCR method in 800 patients with ESKD and 500 healthy controls. The genotype and allele distribution was compared in subgroups of patients with CVD (552) versus those without CVD (248).ResultsA significant difference was observed in genotype distribution among ESKD patients and healthy controls. The frequencies of the T allele and TT genotype in ESKD group were significantly higher, with OR (95% CI) 2.2 (1.87-2.6), p < 0.0001 and 5.84 (3.94-8.65), p < 0.0001, respectively. In the he ESKD cohort the distribution of the rs688 was compared between CVD+ and CVD- subgroups. A strong association of the polymorphism with the CVD risk was observed in this analysis. The frequencies of the T allele and TT genotype were significantly higher in CVD+ subgroup, with OR (95% CI) 3.4 (2.71-4.26), p < 0.0001 and 13.2 (7.87-22.09), p < 0.0001, respectively. A multivariate logistic regression analysis was performed to estimate the association between rs688 T variant and risk of CVD. After adjustment for age, sex, BMI, hypertension and diabetes, both CT and TT genotypes were associated with an increased risk of developing CVD in the dominant, recessive and codominant models of inheritance. No significant differences in serum LDL cholesterol levels were found when compared between genotypes.ConclusionsThe present study is the first to demonstrate the association of the LDLR gene polymorphism with increased susceptibility to cardiovascular disease in ESKD patients. This finding needs further investigation to confirm that LDLR rs688 might be a novel genetic risk factor with some prognostic capacity for CVD in ESKD patients.

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UMOD as a susceptibility gene for end-stage renal disease.

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UMOD as a susceptibility gene for end-stage renal disease.

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