rs11959928 — DAB2

Intronic regulatory variant that increases DAB2 expression in kidney tubules, amplifying TGF-β-driven fibrosis and raising chronic kidney disease risk

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Inside every kidney proximal tubule cell, a small adaptor protein called DAB2 (Disabled-2) serves as a molecular traffic controller — guiding megalin and cubilin receptors through the endocytic pathway that recovers albumin, vitamins, and hormones from filtered urine. DAB211 DAB2
Disabled-2, encoded by the DAB2 gene on chromosome 5p13.1 is essential for normal proximal tubule reabsorption. The rs11959928 variant sits in an intronic regulatory region of the DAB2 gene and alters how much DAB2 protein tubule cells produce — with downstream consequences for kidney fibrosis and chronic kidney disease (CKD).

The rs11959928 variant lies within a kidney-specific enhancer element that is active in proximal tubular cells but silent in other tissues. The A allele (risk allele) increases the transcriptional activity of this enhancer, driving higher DAB2 mRNA levels in tubules.

The clinical consequence of elevated DAB2 comes from a second, less well-known role: DAB2 is a co-activator of TGF-β22 TGF-β
transforming growth factor beta, the master driver of organ fibrosis signaling. DAB2 promotes clathrin-mediated recycling of TGF-β receptor II, protecting it from lysosomal degradation and sustaining SMAD2/SMAD3 phosphorylation. The result is a fibrotic feedback loop: more DAB2 → more TGF-β receptor at the cell surface → more SMAD signaling → more collagen and fibronectin deposition → interstitial scarring → reduced glomerular filtration rate.

This tubule-specific mechanism explains why the eQTL effect of rs11959928 on DAB2 is detectable only in kidney tubule tissue (not glomerulus or 44 other tissues in GTEx) — the enhancer is tissue-restricted33 the enhancer is tissue-restricted.

The original discovery came from the CKDGen consortium's 2010 meta-analysis of 67,093 Europeans, which identified the DAB2 locus among 13 new genome-wide significant hits for eGFR and CKD risk. Köttgen et al., Nature Genetics, 201044 Köttgen et al., Nature Genetics, 2010

Functional follow-up confirmed the biology. Tubular expression of DAB2 and its neighbor FYB both correlated strongly with eGFR in human kidney biopsy samples (DAB2 P=3.68×10⁻⁵; FYB P=3×10⁻⁸ in tubule-enriched samples), while neither showed a glomerular eQTL — pointing to a purely tubulointerstitial mechanism. Flaquer et al. / Functional Genomic Annotation study, JASN 201555 Flaquer et al. / Functional Genomic Annotation study, JASN 2015

The causal link was pinned down in a 2018 Nature Medicine study. Tubule-specific eQTL mapping across 121 human kidney samples found that the A risk allele of rs11959928 raises tubular DAB2 expression with an effect size of β=0.566 (P=3.52×10⁻⁶), and colocalization analysis gave PP_H4=0.938 — very strong evidence that the GWAS hit and the eQTL share the same causal variant. Crucially, mice with tubule-restricted Dab2 deletion were significantly protected from interstitial fibrosis after both folic-acid nephropathy and ureteral obstruction injury models, confirming the causal direction. Qiu et al., Nature Medicine, 201866 Qiu et al., Nature Medicine, 2018

Prospective data extend the finding: the DAB2 locus predicts incident CKD independently of baseline eGFR, suggesting the variant influences disease progression rather than merely reflecting starting kidney function. Grams et al., PLOS Genetics, 201377 Grams et al., PLOS Genetics, 2013

A sex-stratified analysis in a Central European CKD cohort found the A allele's association with prevalent CKD was significant in males under both additive and dominant models, with homozygous AA males showing more than a two-fold increase in CKD prevalence compared to TT homozygotes.

The A allele frequency varies substantially by ancestry: ~44% in Europeans, ~32% in Africans, and only ~17% in East Asians — so the population-attributable risk differs markedly across ethnic groups.

There is no pharmacological intervention that directly targets DAB2, but several evidence-based strategies modify TGF-β-driven renal fibrosis through upstream modulation:

  • Blood pressure control is the single most modifiable risk factor for eGFR decline. Angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) reduce TGF-β signaling in the kidney and slow CKD progression in proteinuric patients.
  • Dietary protein moderation (0.6–0.8 g/kg/day rather than high-protein diets) reduces glomerular hyperfiltration and tubular TGF-β load.
  • Sodium restriction (< 2 g/day sodium; < 5 g/day salt) reduces systemic and intraglomerular pressure, a direct upstream driver of tubular TGF-β activation.
  • eGFR and urine albumin-creatinine ratio (uACR) monitoring allows early detection of CKD progression, when RAAS-based interventions are most effective.
  • Avoiding nephrotoxic exposures — NSAIDs, contrast dye, aminoglycosides, and heavy metal exposures — is especially important for AA genotype carriers, whose tubular reserve may be more vulnerable.

The DAB2 locus operates in the same tubulointerstitial fibrosis pathway as UMOD (rs4293393) and SHROOM3 (rs17319721), two other well-replicated CKD GWAS loci. While no compound-genotype study has formally quantified the combined effect of rs11959928 with UMOD or SHROOM3 variants, carriers of multiple risk alleles across these loci are likely to experience additive acceleration of CKD progression through convergent fibrotic mechanisms.

DACH1 (rs626277) and PRKAG2 (rs7805747), two adjacent CKD GWAS hits on other chromosomes, were found to associate with CKD in the same sex-stratified cohort study as rs11959928, suggesting these loci may jointly explain CKD risk especially in male patients.

Nutrient Interactions

sodium altered_metabolism
protein increased_need

Genotype Interpretations

What each possible genotype means for this variant.

TT Typical Tubule Expression Normal

Standard DAB2 expression — typical kidney fibrosis signaling

The TT genotype represents the reference configuration at this locus. DAB2 expression in proximal tubule cells is at its basal level, and the tubule-specific enhancer controlled by this region shows standard activity. Genome-wide association studies confirm that TT individuals do not have elevated risk of CKD beyond the population baseline attributable to conventional risk factors (hypertension, diabetes, obesity, age).

Standard preventive kidney health practices apply.

AT Elevated Tubule Expression Intermediate

One risk allele — modestly elevated DAB2 in kidney tubules

The AT heterozygous state sits between baseline and maximum DAB2 upregulation. The tubule-specific enhancer at this locus shows intermediate activity, raising DAB2 transcript levels by approximately 0.28 standard deviations relative to TT (half the AA eQTL effect of β=0.566).

Mechanistically, even a partial increase in DAB2 sustains more active TGF-β receptor recycling, which increases downstream SMAD2/SMAD3 phosphorylation and promotes collagen/fibronectin production in tubular cells — the early steps of interstitial fibrosis.

Sex matters: in one cohort study, the association with CKD prevalence under dominant modeling was driven primarily by males, suggesting that sex hormones or sex-specific renal physiology may modify DAB2's fibrotic effect.

AA High Tubule Expression High Risk

Two risk alleles — significantly elevated DAB2 expression, heightened CKD risk

The AA homozygous state maximises the enhancer effect at this locus. The kidney-specific regulatory element becomes fully activated, driving DAB2 transcript levels substantially above baseline in proximal tubule cells. More DAB2 protein means more efficient recycling of TGF-β receptor II back to the cell surface (instead of lysosomal degradation), sustaining prolonged SMAD2/SMAD3 phosphorylation and downstream transcription of collagen type I and fibronectin.

In mouse models, genetic deletion of Dab2 specifically in tubular cells conferred significant protection against interstitial fibrosis after folic acid nephropathy and unilateral ureteral obstruction — two standard CKD injury models. This confirms that the excess DAB2 protein in AA carriers is not a passenger observation but a mechanistic driver of fibrotic damage.

The DAB2 locus also independently predicts CKD incidence after adjusting for baseline eGFR, suggesting the variant shapes the trajectory of kidney function decline rather than just reflecting the starting level.

Because this is an A/T SNP at an ambiguous locus, strand verification is critical: dbSNP confirms the reference allele is T and the alternate allele is A on the GRCh38 plus strand (chr5:39,397,030). The A allele is the less common allele (~39% globally) and the one confirmed by eQTL analysis to raise DAB2 expression.