Dataset Information

Urinary Uromodulin Levels and UMOD Variants in Black South Africans with Hypertension-Attributed Chronic Kidney Disease.

ABSTRACT: Uromodulin, the most abundant protein in urine, is synthesized in the thick ascending loop of Henle and distal convoluted tubules. Patients with chronic kidney disease (CKD) have reduced urinary uromodulin levels secondary to tubular damage. Genome wide association studies identified significant single nucleotide polymorphism (SNP) associations with CKD at the uromodulin (UMOD) locus. We examined the association of urinary uromodulin concentrations with CKD and with SNP rs1333226 in the UMOD gene. The study included 71 black South Africans with hypertension-attributed CKD with an eGFR ? 60ml/min/1.73m2, 52 first-degree relatives, and 58 unrelated controls. Urinary uromodulin concentration was measured using Luminex® multiplex kits. After DNA extraction from blood using the Maxwell® automated platform, genotyping of rs13333226 was performed using real-time PCR using TaqMan® genotyping assays. Urinary uromodulin levels were significantly lower in CKD cases compared to both controls and first-degree relatives and correlated negatively with age, serum uric acid, serum creatinine, and systolic BP and positively with CKD-EPI eGFR. For each 1-standard deviation increase in uromodulin level, the multivariable-adjusted odds ratio for CKD was 0.6 (95% CI [0.48 to 0.81]; p <0.01). There were no significant differences in the minor allele frequency between CKD cases and controls (p = 0.59) nor between first-degree relatives and controls (p = 0.98). There were no significant associations between genotype at rs13333226 and urine uromodulin levels (p = 0.43). Higher levels of urinary uromodulin are associated with lower odds of hypertension-attributed CKD. We did not detect associations of genotype at rs13333226 with urinary uromodulin levels in our sample population. Larger sample size studies from ethnically disparate populations are essential to further categorize this association.

SUBMITTER: Nqebelele NU

PROVIDER: S-EPMC6466913 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Urinary Uromodulin Levels and <i>UMOD</i> Variants in Black South Africans with Hypertension-Attributed Chronic Kidney Disease.

Nqebelele Nolubabalo Unati NU Dickens Caroline C Dix-Peek Therese T Duarte Raquel R Naicker Saraladevi S

International journal of nephrology 20190402

Uromodulin, the most abundant protein in urine, is synthesized in the thick ascending loop of Henle and distal convoluted tubules. Patients with chronic kidney disease (CKD) have reduced urinary uromodulin levels secondary to tubular damage. Genome wide association studies identified significant single nucleotide polymorphism (SNP) associations with CKD at the uromodulin (<i>UMOD)</i> locus. We examined the association of urinary uromodulin concentrations with CKD and with SNP rs1333226 in the < ...[more]

PMID: 31065383

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Project description:Recent genome-wide association studies (GWAS) have identified common variants in the UMOD region associated with kidney function and disease in the general population. To identify novel rare variants as well as common variants that may account for this GWAS signal, the exons and 4 kb upstream region of UMOD were sequenced.Individuals (n?=?485) were selected based on presence of the GWAS risk haplotype and chronic kidney disease (CKD) in the ARIC Study and on the extremes of of the UMOD gene product, uromodulin, in urine (Tamm Horsfall protein, THP) in the Framingham Heart Study (FHS). Targeted sequencing was conducted using capillary based Sanger sequencing (3730 DNA Analyzer). Variants were tested for association with THP concentrations and estimated glomerular filtration rate (eGFR), and identified non-synonymous coding variants were genotyped in up to 22,546 follow-up samples. Twenty-four and 63 variants were identified in the 285 ARIC and 200 FHS participants, respectively. In both studies combined, there were 33 common and 54 rare (MAF<0.05) variants. Five non-synonymous rare variants were identified in FHS; borderline enrichment of rare variants was found in the extremes of THP (SKAT p-value?=?0.08). Only V458L was associated with THP in the FHS general-population validation sample (p?=?9*10(-3), n?=?2,522), but did not show direction-consistent and significant association with eGFR in both the ARIC (n?=?14,635) and FHS (n?=?7,520) validation samples. Pooling all non-synonymous rare variants except V458L together showed non-significant associations with THP and eGFR in the FHS validation sample. Functional studies of V458L revealed no alternations in protein trafficking.Multiple novel rare variants in the UMOD region were identified, but none were consistently associated with eGFR in two independent study samples. Only V458L had modest association with THP levels in the general population and thus could not account for the observed GWAS signal.

Dataset Information

Urinary Uromodulin Levels and UMOD Variants in Black South Africans with Hypertension-Attributed Chronic Kidney Disease.

Publications

Urinary Uromodulin Levels and <i>UMOD</i> Variants in Black South Africans with Hypertension-Attributed Chronic Kidney Disease.

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