جهت دسترسی به کاربرگه ی زیر، از این لینک استفاده کنید. http://192.168.1.35:80/jspui/handle/Hannan/2930
Title: Association of Estimated Glomerular Filtration Rate and Urinary Uromodulin Concentrations with Rare Variants Identified by UMOD Gene Region Sequencing
Authors: Köttgen, Anna;Yang, Qiong;Shimmin, Lawrence C.;Tin, Adrienne;Schaeffer, Céline;Coresh, Josef;Liu, Xuan;Rampoldi, Luca;Hwang, Shih-Jen;Boerwinkle, Eric;Hixson, James E.;Kao, W.H. Linda;Fox, Caroline
Keywords: Biology
Genetics
Human Genetics
Genetic Association Studies
Genome-Wide Association Studies
Genetics of Disease
Medicine
Epidemiology
Cardiovascular Disease Epidemiology
Disease Mapping
Genetic Epidemiology
Nephrology
Chronic Kidney Disease
Issue Date: 2012
Publisher: Public Library of Science
Description: 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.
URI: http://192.168.1.35:80/jspui/handle/Hannan/2930
Other Identifiers: Köttgen, Anna, Qiong Yang, Lawrence C. Shimmin, Adrienne Tin, Céline Schaeffer, Josef Coresh, Xuan Liu, et al. 2012. Association of estimated glomerular filtration rate and urinary uromodulin concentrations with rare variants identified by UMOD gene region sequencing. PLoS ONE 7(5): e38311.
1932-6203
http://nrs.harvard.edu/urn-3:HUL.InstRepos:10406348
Type Of Material: Journal Article
Appears in Collections:Harvard Medical School

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