Association of estimated glomerular filtration rate and urinary uromodulin concentrations with rare variants identified by UMOD gene region sequencing.
<h4>Background</h4>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...
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Public Library of Science (PLoS)
2012-01-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Anna Köttgen |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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. |
| format | Article |
| id | doaj-art-d88b3d0d7d2b4122bbce12f872a2234e |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj-art-d88b3d0d7d2b4122bbce12f872a2234e2025-08-20T03:09:47ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0175e3831110.1371/journal.pone.0038311Association of estimated glomerular filtration rate and urinary uromodulin concentrations with rare variants identified by UMOD gene region sequencing.Anna KöttgenQiong YangLawrence C ShimminAdrienne TinCéline SchaefferJosef CoreshXuan LiuLuca RampoldiShih-Jen HwangEric BoerwinkleJames E HixsonW H Linda KaoCaroline S Fox<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0038311&type=printable |
| spellingShingle | 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 Association of estimated glomerular filtration rate and urinary uromodulin concentrations with rare variants identified by UMOD gene region sequencing. PLoS ONE |
| title | Association of estimated glomerular filtration rate and urinary uromodulin concentrations with rare variants identified by UMOD gene region sequencing. |
| title_full | Association of estimated glomerular filtration rate and urinary uromodulin concentrations with rare variants identified by UMOD gene region sequencing. |
| title_fullStr | Association of estimated glomerular filtration rate and urinary uromodulin concentrations with rare variants identified by UMOD gene region sequencing. |
| title_full_unstemmed | Association of estimated glomerular filtration rate and urinary uromodulin concentrations with rare variants identified by UMOD gene region sequencing. |
| title_short | Association of estimated glomerular filtration rate and urinary uromodulin concentrations with rare variants identified by UMOD gene region sequencing. |
| title_sort | association of estimated glomerular filtration rate and urinary uromodulin concentrations with rare variants identified by umod gene region sequencing |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0038311&type=printable |
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