Common variants in UMOD associate with urinary uromodulin levels: a meta-analysis

Abstract

Uromodulin is expressed exclusively in the thick ascending limb and is the most abundant protein excreted in normal urine. Variants in UMOD, which encodes uromodulin, are associated with renal function, and urinary uromodulin levels may be a biomarker for kidney disease. However, the genetic factors regulating uromodulin excretion are unknown. We conducted a meta-analysis of urinary uromodulin levels to identify associated common genetic variants in the general population. We included 10,884 individuals of European descent from three genetic isolates and three urban cohorts. Each study measured uromodulin indexed to creatinine and conducted linear regression analysis of approximately 2.5 million single nucleotide polymorphisms using an additive model. We also tested whether variants in genes expressed in the thick ascending limb associate with uromodulin levels. rs12917707, located near UMOD and previously associated with renal function and CKD, had the strongest association with urinary uromodulin levels (P<0.001). In all cohorts, carriers of a G allele of this variant had higher uromodulin levels than noncarriers did (geometric means 10.24, 14.05, and 17.67 μg/g creatinine for zero, one, or two copies of the G allele). rs12446492 in the adjacent gene PDILT (protein disulfide isomerase-like, testis expressed) also reached genome-wide significance (P<0.001). Regarding genes expressed in the thick ascending limb, variants in KCNJ1, SORL1, and CAB39 associated with urinary uromodulin levels. These data indicate that common variants in the UMOD promoter region may influence urinary uromodulin levels. They also provide insights into uromodulin biology and the association of UMOD variants with renal function.

Copyright © 2014 by the American Society of Nephrology.

Figures

Figure 1.

The −log10(P value) plot by genomic position (Manhattan plot) for results from the meta-analysis of GWAS of uromodulin indexed to creatinine in six population-based studies. The reported locus (P<1E-72) is highlighted in orange. SNPs with minor allele frequency <5% are excluded. P values are double corrected for genomic control.

Figure 2.

Quantile-quantile plot of results from the meta-analysis of GWAS of uromodulin indexed to creatinine in six population-based studies. The inset graph shows the remaining signals after excluding SNPs in and 1 Mb around the UMOD gene. SNPs with minor allele frequency <5% are excluded from the meta-analysis. P values are double corrected for genomic control.

Figure 3.

Regional association plot of UMOD gene for the analysis indexed to urinary creatinine. The lead GWAS hit (rs12917707) and GCTA hit (rs4494548) are highlighted. The plot is modified from LocusZoom and Haploview. The small figure shows the R2 between the two SNPs highlighted in red. LD information is based on HapMap CEU.

Figure 4.

Candidate gene analysis and nephron segmentation. (A) Expression levels of UMOD, ROMK, SORL1, and CAB39 in microdissected mouse tubule segments (relative to TAL taken as 100%, white bars). Expression levels are relative to reference gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Data are means±SEM of at least three independent experiments obtained for pooled tubules from two mouse kidneys. (B) Model for the intersection of ROMK, SORL1, and CAB39 with uromodulin in cells lining the TAL.