Association of Estimated Glomerular Filtration Rate and Urinary Uromodulin Concentrations with Rare Variants Identified by UMOD Gene Region Sequencing
Year: 2012
Type: article
Study design: Observational Study
Abstract: BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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.
Source: PLoS ONE
Institutions: Johns Hopkins University, University Medical Center Freiburg, Boston University, The University of Texas Health Science Center at Houston, Dulbecco Telethon Institute, IRCCS Ospedale San Raffaele, Johns Hopkins Medicine, National Heart, Lung, and Blood Institute, Framingham Heart Study, Brigham and Women's Hospital, Harvard University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,382
Awards: G1052397333, G1394454416, G1460387277, G1490530680, G1527150935, G1605148878, G1691174148, G1732407725, G173303992, G1941623656, G2178492673, G2207378143, G250621538, G2564988809, G2741022277, G2818629771, G301743239, G3042145041, G3114902838, G3152385821, G3410686264, G3462919067, G3667269547, G4038307842, G4105274580, G4167445418, G4349057080, G457330776, G4998334444, G5074086979, G5164707915, G567847597, CHARGE consortium: omics discovery for CVD and aging phenotypes, G6033034647, G6195637971, The Framingham Heart Study, Longitudinal Study of Predictors and Consequences of Chronic Kidney Disease, G6548750934, G6552090923, G670689275, Next-Generation Medical Resequencing of Gout Disease Genes in the ARIC Cohort, G7312067039, G7406331046, G7603769780, G781162660, G7955974312, G9000124674, G9000228098
OpenAlex ID: W2096189376