Improving predictive accuracy in primary biliary cholangitis: A new genetic risk score
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Updated: Jun 28, 2025
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Alessio Gerussi1,2, Claudio Cappadona3,4, Davide Paolo Bernasconi5
1Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS Fondazione San Gerardo dei Tintori, Monza, Italy.
Background And Aims:
Genetic variants influence primary biliary cholangitis (PBC) risk. We established and tested an accurate polygenic risk score (PRS) using these variants.
Methods:
Data from two Italian cohorts (OldIT 444 cases, 901 controls; NewIT 255 cases, 579 controls) were analysed. The latest international genome-wide meta-analysis provided effect size estimates. The PRS, together with human leukocyte antigen (HLA) status and sex, was included in an integrated risk model.
Results:
Starting from 46 non-HLA genes, 22 variants were selected. PBC patients in the OldIT cohort showed a higher risk score than controls: -.014 (interquartile range, IQR, -.023, .005) versus -.022 (IQR -.030, -.013) (p < 2.2 × 10-16). For genetic-based prediction, the area under the curve (AUC) was .72; adding sex increased the AUC to .82. Validation in the NewIT cohort confirmed the model's accuracy (.71 without sex, .81 with sex). Individuals in the top group, representing the highest 25%, had a PBC risk approximately 14 times higher than that of the reference group (lowest 25%; p < 10-6).
Conclusion:
The combination of sex and a novel PRS accurately discriminated between PBC cases and controls. The model identified a subset of individuals at increased risk of PBC who might benefit from tailored monitoring.
