Risk assessment for urolithiasis using polygenic risk score and biomarker cluster: population-based cohort study in the United Kingdom and Hong Kong

Abstract

<p><strong>Introduction and objectives</strong></p><p>Urolithiasis is a common disease with multifactorial etiology. No study has reported the risk estimates based on germline genetic risk and biomarker profiles. The study aims to examine the potential utility of polygenic risk score (PRS) and biomarker clusters for urolithiasis risk prediction.</p><p><strong>Materials and methods</strong></p><p>A population-based cohort study was performed using data from the UK Biobank. K-mean cluster analysis was conducted to distinguish individuals into different biomarker clusters. Cox proportional hazard models were employed to estimate the hazard ratios (HRs) and 95% confidence intervals (95%CIs) for genetic risk and biomarker clusters associated with urolithiasis. Validation was performed in a separate Hong Kong population.</p><p><strong>Results</strong></p><p>Among 480,098 participants with a median follow-up of 13.8 years, 6,434, 2,652 and 777 cases of incident, recurrent and multifocal urolithiasis were recorded, respectively. Individuals in the top 25% of PRS were associated with 41% increased risks of urolithiasis (HR=1.41, 95%CI: 1.34-1.48). Cluster of inflammatory and metabolic biomarker was related to 1.80-fold (1.73-1.87) higher risk of urolithiasis, followed by cluster of hematal and endocrinic biomarkers (1.78, 1.69-1.88). An additive interaction was observed between PRS and biomarker clusters, and the joint analysis showed that highest PRS (4th quartile) combined with inflammatory and metabolic profile was associated with the highest risk of incident (HR=2.66, 95%CI: 2.43-2.90), recurrent (3.56, 3.11-4.08) and multifocal urolithiasis (2.94, 2.29-3.78), compared with lowest PRS (1st quartile) plus cardiovascular and skeletal profile. Similar results were observed in site-specific calculi (kidney, ureter and bladder). Validation of biomarker cluster effects showed that I-M cluster and H-E cluster were associated with odds ratios of 1.47 (95%CI: 1.07-2.03) and 1.20 (95%CI: 0.75-1.92) on urolithiasis in Hong Kong population.</p><p><strong>Conclusion</strong></p><p>The study illustrates the potential for improving urolithiasis risk assessment by integrating genetic risk and biomarker cluster.</p>