Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Kottgen A

PROVIDER: S-EPMC3365030 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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

Köttgen Anna A Yang Qiong Q Shimmin Lawrence C LC Tin Adrienne A Schaeffer Céline C Coresh Josef J Liu Xuan X Rampoldi Luca L Hwang Shih-Jen SJ Boerwinkle Eric E Hixson James E JE Kao W H Linda WH Fox Caroline S CS

PloS one 20120531 5

<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 t ...[more]

PMID: 22693617

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Project description:Background and objectivesMarijuana use has become more widely accepted in the United States and has been legalized in many areas. Although it is biologically plausible that marijuana could affect kidney function, epidemiologic data are lacking.Design, setting, participants, & measurementsWe conducted a cohort study among young adults with preserved eGFR (i.e., eGFR?60 ml/min per 1.73 m2) using data from the Coronary Artery Risk Development in Young Adults (CARDIA) study. At scheduled examinations occurring every 5 years and starting at study year 10 (calendar years, 1995-1996), cystatin C was collected over a 10-year period, and urine albumin-to-creatinine ratio was collected over a 15-year period. We investigated the cross-sectional association between current and cumulative marijuana use (in marijuana-years; one marijuana-year equals 365 days of marijuana use) and eGFR by cystatin C (eGFRcys) at year 10. In longitudinal analyses, we investigated the association between cumulative marijuana use and eGFRcys change and rapid (?3%/year) eGFRcys decline over two 5-year intervals and prevalent albuminuria (urine albumin-to-creatinine ratio ?30 mg/g) over a 15-year period.ResultsPast or current marijuana use was reported by 83% (3131 of 3765) of the cohort, and the mean eGFRcys was 111 ml/min per 1.73 m2 at year 10. Over the following 10 years, 504 had rapid eGFRcys decline, and over the following 15 years, 426 had prevalent albuminuria. Compared with no use, daily current use and ?5 marijuana-years of cumulative use were associated with lower eGFRcys at year 10: -4.5% (95% confidence interval, -8.1 to -0.7%; P=0.02) and -3.0% (95% confidence interval, -5.6 to -0.4%; P=0.03), respectively. Marijuana use was not significantly associated with eGFRcys change, rapid eGFRcys decline, or prevalent albuminuria.ConclusionsAlthough we identified a modest cross-sectional association between higher marijuana exposure and lower eGFRcys among young adults with preserved eGFR, our findings were largely null and did not demonstrate a longitudinal association between marijuana use and eGFRcys change, rapid eGFRcys decline, or prevalent albuminuria.PodcastThis article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_08_24_CJASNPodcast_17_10.mp3.

Project description:BackgroundGlomerular filtration rate (GFR) is accepted as the best indicator of kidney function and is commonly estimated from serum creatinine (SCr)-based equations. Separate equations have been developed for children (Schwartz equation), younger and middle-age adults [Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation] and older adults [Berlin Initiative Study 1 (BIS1) equation], and these equations lack continuity with ageing. We developed and validated an equation for estimating the glomerular filtration rate that can be used across the full age spectrum (FAS).MethodsThe new FAS equation is based on normalized serum creatinine (SCr/Q), where Q is the median SCr from healthy populations to account for age and sex. Coefficients for the equation are mathematically obtained by requiring continuity during the paediatric-adult and adult-elderly transition. Research studies containing a total of 6870 healthy and kidney-diseased white individuals, including 735 children, <18 years of age, 4371 adults, between 18 and 70 years of age, and 1764 older adults, ?70 years of age with measured GFR (inulin, iohexol and iothalamate clearance) and isotope dilution mass spectrometry-equivalent SCr, were used for the validation. Bias, precision and accuracy (P30) were evaluated.ResultsThe FAS equation was less biased [-1.7 (95% CI -3.4, -0.2) versus 6.0 (4.5, 7.5)] and more accurate [87.5% (85.1, 89.9) versus 83.8% (81.1, 86.5)] than the Schwartz equation for children and adolescents; less biased [5.0 (4.5, 5.5) versus 6.3 (5.9, 6.8)] and as accurate [81.6% (80.4, 82.7) versus 81.9% (80.7, 83.0)] as the CKD-EPI equation for young and middle-age adults; and less biased [-1.1 (-1.6, -0.6) versus 5.6 (5.1, 6.2)] and more accurate [86.1% (84.4, 87.7) versus 81.8% (79.7, 84.0)] than CKD-EPI for older adults.ConclusionsThe FAS equation has improved validity and continuity across the full age-spectrum and overcomes the problem of implausible eGFR changes in patients which would otherwise occur when switching between more age-specific equations.

Dataset Information

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

Publications

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

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