GPBAR1 – Ulcerative Colitis

Recent multi‐patient studies have robustly linked variants in GPBAR1 (previously known as TGR5) to ulcerative colitis. In large resequencing efforts conducted in cohorts of 267 patients (with primary sclerosing cholangitis and ulcerative colitis) and 274 controls, six nonsynonymous mutations were identified. Fine‐mapping of the chromosome 2q35 locus yielded a statistically significant association for ulcerative colitis with an odds ratio of 1.19 (95% CI 1.11–1.27, p = 8.5 x 10(-7)) (PMID:21691110). These findings elevate GPBAR1 to a key candidate gene implicated in inflammatory bowel disease.

Genetic evidence derives from the identification of multiple variants, including the reported variant c.753T>G (p.Tyr251Ter), which has been confirmed by independent studies. Although the pathogenic interpretation is complicated by strong linkage disequilibrium with neighboring genes, multiple independent cohort analyses consistently underscore the role of GPBAR1 variations in modulating disease risk (PMID:20811628).

Functional studies have complemented genetic findings. In vitro experiments utilizing luciferase reporter assays, confocal microscopy, and flow cytometry demonstrated that several nonsynonymous variants reduce or abolish receptor function. These studies directly linked altered bile acid signaling to deficient receptor activity, supporting a mechanistic basis for inflammation observed in ulcerative colitis (PMID:20811628; PMID:24338481).

The convergent evidence from genetic association studies and functional analyses lends strong support to the clinical validity of the GPBAR1–ulcerative colitis association. Despite potential confounding due to the genomic context, the replication of association signals and consistent demonstration of disrupted receptor signaling affirm the gene’s role in pathogenesis.

It is important to note that while some studies also evaluated GPBAR1 in the context of primary sclerosing cholangitis or other metabolic conditions, the subset of evidence evaluating ulcerative colitis remains compelling. This integration of genetic and experimental data underpins the robust clinical credibility of GPBAR1 as a key molecular marker in ulcerative colitis.

Key take‐home: GPBAR1 variation emerges as a critical biomarker linking altered bile acid receptor function and inflammatory disease susceptibility, offering significant potential for diagnostic, prognostic, and therapeutic applications in ulcerative colitis.

References

• PloS one • 2010 • Mutational characterization of the bile acid receptor TGR5 in primary sclerosing cholangitis PMID:20811628
• Digestive diseases (Basel, Switzerland) • 2011 • TGR5 sequence variation in primary sclerosing cholangitis PMID:21691110
• The Journal of biological chemistry • 2014 • A membrane-proximal, C-terminal α-helix is required for plasma membrane localization and function of the G Protein-coupled receptor TGR5 PMID:24338481
• International journal of obesity • 2016 • Obesity and developmental delay in a patient with uniparental disomy of chromosome 2 PMID:27654142

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