Abstract
BackgroundRecent 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 FindingsIndividuals (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/SignificanceMultiple 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.
Highlights
Chronic kidney disease affects 5–10% of adults worldwide [1], and is associated with an increased risk of cardiovascular morbidity and mortality [2,3] as well as end-stage renal disease [4,5]
Conclusions/Significance: Multiple novel rare variants in the UMOD region were identified, but none were consistently associated with estimated glomerular filtration rate (eGFR) in two independent study samples
Using genome-wide association studies (GWAS), we and others have previously identified common variants in the UMOD gene region on chromosome 16 that are associated with measures of kidney function, including estimated glomerular filtration rate, serum creatinine, and chronic kidney disease (CKD) [6,7,8,9,10]
Summary
Chronic kidney disease affects 5–10% of adults worldwide [1], and is associated with an increased risk of cardiovascular morbidity and mortality [2,3] as well as end-stage renal disease [4,5]. The UMOD gene is exclusively transcribed in the kidney and encodes Tamm Horsfall protein, known as uromodulin, the most abundant protein in the urine of healthy individuals [13] Both rare monogenic disease-causing mutations and common variants identified by GWAS lead to altered concentrations of urinary uromodulin [10,14,15]. Whereas urinary uromodulin concentrations are typically reduced in the urine of individuals with monogenic forms of UMOD-associated disease [16], individuals carrying the CKD risk-increasing variants identified in GWAS have higher amounts of urinary uromodulin concentrations [10,14,17]. 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
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