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Recent studies have provided compelling evidence that variation in GPBAR1 (HGNC:19680) is associated with primary sclerosing cholangitis (MONDO_0013433). Two independent resequencing studies in PSC cohorts (267 patients vs 274 controls) identified multiple nonsynonymous mutations in GPBAR1 and reported an overall association between a common single-nucleotide polymorphism (rs11554825) and PSC (odds ratio = 1.14, p = 0.010) (PMID:20811628, PMID:21691110).
The genetic evidence is strengthened by the identification of six nonsynonymous variants in these studies, of which five were shown in functional assays to markedly reduce or abolish receptor activity. Functional experiments employing confocal microscopy, flow cytometry, and a cAMP-sensitive luciferase assay confirmed that these variants impair GPBAR1 function, suggesting a loss-of-function mechanism that may contribute to disease susceptibility (PMID:20811628, PMID:21691110).
Although the precise inheritance pattern in PSC appears complex due to the susceptibility nature of the association, the heterozygous occurrence of these genetic variants is most consistent with an autosomal dominant risk model. No explicit familial segregation counts were provided beyond the multiple independent patient samples; however, the recurrent discovery of functionally deleterious variants across unrelated individuals reinforces the association.
Experimental evidence further supports a pathogenic role for GPBAR1 variation. Functional assessment of receptor constructs (including evaluation of receptor localization and activity) demonstrated that alterations in key domains of the GPBAR1 protein disrupt its normal signaling, providing biological plausibility for its involvement in PSC pathogenesis (PMID:20811628, PMID:21691110).
Despite a minor confounding factor of strong linkage disequilibrium in the locus, the combination of robust genetic association and consistent functional impairment suggests a strong gene-disease relationship. While additional studies may further delineate the contribution of neighboring genes, the current evidence exceeds standard ClinGen genetic scoring thresholds.
Key take‐home message: The integration of genetic and experimental data supports a strong role for GPBAR1 variation in primary sclerosing cholangitis, with clear implications for diagnostic decision‑making and therapeutic targeting.
Gene–Disease AssociationStrongResequencing studies in 267 PSC patients identified multiple deleterious nonsynonymous variants and a significant common SNP association, with functional assays confirming impairment of receptor activity (PMID:20811628, PMID:21691110). Genetic EvidenceStrongMultiple nonsynonymous variants observed in independent PSC cohorts and a modest but statistically significant association signal support a robust genetic contribution. Functional EvidenceStrongIn vitro assays including luciferase, confocal microscopy, and flow cytometry demonstrated that the identified variants result in loss of GPBAR1 function, corroborating the gene-disease link. |