Association of estimated glomerular filtration rate and urinary uromodulin concentrations with rare variants identified by UMOD gene region sequencing

Anna Köttgen, Qiong Yang, Lawrence C. Shimmin, Adrienne Tin, Céline Schaeffer, Josef Coresh, Xuan Liu, Luca Rampoldi, Shih Jen Hwang, Eric Boerwinkle, James E. Hixson, W. H Linda Kao, Caroline S. Fox

Research output: Contribution to journalArticle

20 Citations (Scopus)

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-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.

Original languageEnglish
Article numbere38311
JournalPLoS One
Volume7
Issue number5
DOIs
Publication statusPublished - May 31 2012

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Uromodulin
glomerular filtration rate
Glomerular Filtration Rate
Genome-Wide Association Study
Genes
heart
kidney diseases
genes
proteins
sampling
protein transport
renal function
Validation Studies
exons
Kidney Diseases
Protein Transport
haplotypes
Chronic Renal Insufficiency
DNA Sequence Analysis
urine

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Association of estimated glomerular filtration rate and urinary uromodulin concentrations with rare variants identified by UMOD gene region sequencing. / 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 S.

In: PLoS One, Vol. 7, No. 5, e38311, 31.05.2012.

Research output: Contribution to journalArticle

Köttgen, A, Yang, Q, Shimmin, LC, Tin, A, Schaeffer, C, Coresh, J, Liu, X, Rampoldi, L, Hwang, SJ, Boerwinkle, E, Hixson, JE, Kao, WHL & Fox, CS 2012, 'Association of estimated glomerular filtration rate and urinary uromodulin concentrations with rare variants identified by UMOD gene region sequencing', PLoS One, vol. 7, no. 5, e38311. https://doi.org/10.1371/journal.pone.0038311
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 S. / Association of estimated glomerular filtration rate and urinary uromodulin concentrations with rare variants identified by UMOD gene region sequencing. In: PLoS One. 2012 ; Vol. 7, No. 5.
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AU - Coresh, Josef

AU - Liu, Xuan

AU - Rampoldi, Luca

AU - Hwang, Shih Jen

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AU - Hixson, James E.

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AB - 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-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.

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