rs77924615 — UMOD PDILT-UMOD regulatory variant

UMOD-PDILT Regulatory Variant — The Strongest Common Genetic Driver of Kidney Function Decline

Uromodulin, encoded by the UMOD gene, is the most abundant protein in normal human urine. Produced exclusively by cells lining the thick ascending limb of Henle's loop¹¹ thick ascending limb of Henle's loop
The segment of the nephron that reabsorbs sodium, chloride, and potassium without water, making urine concentrated and driving the osmotic gradient, uromodulin forms protective filaments that trap bacteria, regulate sodium transport, and modulate the immune environment of the urinary tract. How much uromodulin your kidneys produce — and the long-term consequences of that quantity — is largely set by your genome.

The rs77924615 variant sits within an intron of PDILT, a gene that flanks UMOD on chromosome 16. Despite lying outside UMOD itself, this variant functions as a cis-regulatory element²² cis-regulatory element
A DNA sequence that controls the transcription of a nearby gene through long-range chromatin interactions; it maps to an open chromatin region specifically in uromodulin-producing kidney tubular cells that governs UMOD transcription. It is the dominant genetic signal for longitudinal kidney function decline in the general population — not because it changes a protein's structure, but because it determines how much of a critical kidney protein gets made in the first place.

The Mechanism

The rs77924615 G allele occupies a chromatin region accessible specifically in the thick ascending limb and distal convoluted tubule — the exact cell types that produce uromodulin. Dual-luciferase reporter assays³³ Dual-luciferase reporter assays
A laboratory technique that measures gene activation by coupling a candidate regulatory sequence to a luminescent enzyme and comparing activity between allele versions confirmed that the G allele exhibits allele-specific enhancer⁴⁴ enhancer
A DNA sequence that increases transcription of its target gene, even when located far from the promoter or within an intron of a neighboring gene activity, driving higher UMOD transcription than the A allele. The result is more uromodulin in the kidney tubule, higher urinary and serum uromodulin concentrations, and the downstream consequences of chronic uromodulin excess: sodium reabsorption via NKCC2⁵⁵ NKCC2
The sodium-potassium-chloride cotransporter in the thick ascending limb, activated by uromodulin through SPAK/OSR1 kinase signaling overactivation, salt-sensitive blood pressure elevation, and accelerated nephron deterioration.

The Evidence

rs77924615 is one of only two independent signals at the UMOD-PDILT locus in conditional analyses. In a cross-ancestry meta-analysis of 62 longitudinal GWAS⁶⁶ cross-ancestry meta-analysis of 62 longitudinal GWAS
Gorski et al. Kidney Int 2022 — genome-wide analysis of eGFR trajectories across >100,000 individuals from diverse ancestries, rs77924615 emerged as the single strongest genetic signal for rapid kidney function decline: each copy of the G allele associated with 0.30% per year faster eGFR decline (P = 4.9 × 10⁻²⁷), rising to 0.45%/yr in individuals with diabetes. This variant was the sole variant in the credible set for rapid eGFR decline at the UMOD-PDILT locus, making it the highest-priority functional target in a region containing two independent signals.

A trans-ethnic meta-GWAS of circulating and urinary uromodulin⁷⁷ trans-ethnic meta-GWAS of circulating and urinary uromodulin
Li et al. JCI Insight 2022 — 5 studies with antibody-based uromodulin quantification across 10,735,251 genetic variants confirmed rs77924615 as the index variant for serum uromodulin with a P-value of 6.4 × 10⁻⁵⁷⁷, explaining 18% of variance in circulating uromodulin — an extraordinary proportion for a complex trait. The colocalization analyses linked this single variant to eGFR, CKD, systolic and diastolic blood pressure, and hypertension.

The largest phenome-wide study, the Million Veteran Program PheWAS⁸⁸ Million Veteran Program PheWAS
Akwo et al. Kidney Int Rep 2022 — 648,593 veterans across multiple ancestry groups found that increased uromodulin driven by UMOD-PDILT variants was associated with CKD stage 3 (OR 1.15), hypertensive CKD (OR 1.15), and higher blood pressure, but simultaneously protected against urinary tract infections (OR 0.73 for acute cystitis in White women, with a significant sex interaction P = 0.01) and kidney stones. These opposing effects reflect the dual biological roles of uromodulin — protecting the urinary tract against bacteria while driving salt-sensitive hemodynamic stress on the kidneys.

In IgA nephropathy patients, the G allele independently predicted progression to end-stage renal disease⁹⁹ progression to end-stage renal disease
Adjusted hazard ratio 2.10 (95% CI 1.14–3.88) after accounting for clinical and pathologic indices, suggesting this variant worsens outcomes on a background of existing kidney disease after multivariable adjustment, highlighting the variant's amplifying effect on kidney disease already in progress.

Practical Actions

For GG homozygotes — about 64% of people of European ancestry — the combination of two G alleles produces the highest uromodulin expression, the fastest eGFR decline trajectory, and the greatest risk of CKD and salt-sensitive hypertension. The mechanism through NKCC2 activation makes sodium restriction and loop diuretics particularly relevant. For the ~32% of Europeans with one G allele (AG), the risk is intermediate and age-dependent — largely silent before 50 but accelerating after, especially with diabetes or hypertension. The protective AA genotype (~4% of Europeans, more common in Africans) benefits from reduced CKD risk but has lower uromodulin-mediated UTI defense.

Importantly, the effect of this variant on eGFR decline is not static — it is strongly age-dependent and comorbidity-amplified. GG individuals who also develop diabetes face twice the eGFR decline rate of non-diabetic GG carriers. This interaction means metabolic risk management is especially consequential for G allele carriers.

Interactions

rs77924615 is in high linkage disequilibrium with rs4293393 (the UMOD promoter variant) in European populations, and the two variants tag largely the same biological effect. However, rs77924615 shows better separation of signal in African populations where the LD structure at this locus is more fragmented — making it the preferred tagging variant in trans-ancestry analyses. In African Americans, the rs77924615 G allele frequency is only 6%, so the absolute population burden is lower but individual risk per allele remains.

The variant interacts additively with metabolic risk factors: the eGFR decline per G allele roughly doubles in diabetic individuals (0.30% vs 0.45%/yr). Variants in APOL1 (African ancestry kidney disease risk), SHROOM3, and GATM-SPATA5L1 affect kidney function through independent mechanisms, and may compound risk when present alongside the UMOD-PDILT G allele.