Key result
Multiple novel rare variants in the UMOD region were identified, but none were consistently associated with eGFR, and only V458L had a modest association with urinary uromodulin levels (p=9*10^-3).
Why the study?
Do rare variants in the UMOD gene region associate with eGFR and urinary uromodulin concentrations?
Observational (n=22,546)
Yes
Do rare variants in the UMOD gene region associate with eGFR and urinary uromodulin concentrations?
p-value: p=9*10^-3
Rare variants in the UMOD region do not account for the previously observed GWAS signal for kidney function and disease in the general population.
Rare UMOD variants show no consistent eGFR link; leaves open common variants or other mechanisms for prior GWAS kidney signals.
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.
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Köttgen et al. (2012) conducted an observational in Chronic kidney disease (n=22,546). Rare variants in the UMOD gene region (e.g., V458L) vs. Non-carriers / major allele carriers was evaluated on Association with estimated glomerular filtration rate (eGFR) and urinary uromodulin concentrations (p=9*10^-3). Multiple novel rare variants in the UMOD region were identified, but none were consistently associated with eGFR, and only V458L had a modest association with urinary uromodulin levels (p=9*10^-3).
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