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IP66-13 GENETIC INSIGHTS INTO IDIOPATHIC BULBAR URETHRAL STRICTURE: EVIDENCE FOR A TGF-Β1-MEDIATED PATHOPHYSIOLOGY
Abstract   Peer reviewed

IP66-13 GENETIC INSIGHTS INTO IDIOPATHIC BULBAR URETHRAL STRICTURE: EVIDENCE FOR A TGF-Β1-MEDIATED PATHOPHYSIOLOGY

Lola P. Lozano, Benjamin W. Darbro, Benjamin N. Breyer, Sean P. Elliott, Jeremy B. Myers, Alex J. Vanni and Bradley A. Erickson
The Journal of urology, Vol.215(5S), p.e1315
05/2026
DOI: 10.1097/01.JU.0001191672.88727.3a.13

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Abstract

INTRODUCTION AND OBJECTIVES: The most common anterior urethral stricture (aUSD) is the short, mid-bulbar urethral, idiopathic stricture – and the uniformity of its presentation and phenotype suggests a shared, though unknown, pathophysiology. Recent pathologic studies have shown high levels of chronic inflammation in these strictures – suggesting autoimmunity – and high rates of inheritance – suggesting a genetic component. Despite these strictures being relatively easy to manage surgically, identifying a genetic basis is critical because it could fundamentally change our understanding of disease mechanisms, enable earlier diagnosis, and open the door to prevention strategies and targeted therapies rather than relying solely on surgical correction. METHODS: Whole-gene sequencing (WGS) was performed on DNA obtained from whole blood sample of 28 men (age <50; BMI ≤ 30) undergoing anterior urethroplasty for short (L1/L2), bulbar strictures (S1a/S1b) of idiopathic (E2) etiology and then compared to 47 age-matched male controls without urologic history. A hypothesis-driven machine learning approach was used for the WGS data, enabling gene- and pathway-level prioritization of potentially pathologic variants relevant to fibrosis, wound repair, inflammation and sex hormone regulation, thereby increasing the likelihood that variants could be related to disease pathophysiology. RESULTS: There were a multitude of potentially pathologic genetic variants that differed between cohorts and controls that function in the pathways of interest, summarized inFigure 1A. Mutations in CGN and PKP1 may predispose to mucosal barrier injuries given the importance of these genes in cell-cell junctions; CD163L1 mutations may lead to macrophage over-activation and mucosal inflammation; mutations in PTGER3 and MMP25 are associated with fibrotic conditions. Importantly, downstream mechanistic analysis revealed that most of these genetic pathways converge on TGF-β1, a known driver of other genitourinary inflammatory and fibrotic conditions (Figure 1B). CONCLUSIONS: Multiple genetic variants were noted in a uniform cohort of men with the most common form of aUSD. As it is presumed that most aUSD is acquired, the convergence of these genetic variants on TGF-β1 suggest a shared pathophysiology through a two-hit mechanism of trauma (hit 1) coupled with impaired wound healing (hit 2).

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