Genome-wide association analysis in Primary sclerosing cholangitis and ulcerative colitis identifies risk loci atGPR35andTCF4

Abstract

Approximately 60%-80% of patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). Previous genome-wide association studies (GWAS) in PSC have detected a number of susceptibility loci that also show associations in UC and other immune-mediated diseases. We aimed to systematically compare genetic associations in PSC with genotype data in UC patients with the aim of detecting new susceptibility loci for PSC. We performed combined analyses of GWAS for PSC and UC comprising 392 PSC cases, 987 UC cases, and 2,977 controls and followed up top association signals in an additional 1,012 PSC cases, 4,444 UC cases, and 11,659 controls. We discovered novel genome-wide significant associations with PSC at 2q37 [rs3749171 at G-protein-coupled receptor 35 (GPR35); P 5 3.0 3 10 29 in the overall study population, combined odds ratio [OR] and 95% confidence interval [CI] of 1.39 (1.24-1.55)] and at 18q21 [rs1452787 at transcription factor 4 (TCF4); P 5 2.61 3 10 28, OR (95% CI) 5 0.75 (0.68-0.83)]. In addition, several suggestive PSC associations were detected. The GPR35 rs3749171 is a missense single nucleotide polymorphism resulting in a shift from threonine to methionine. Structural modeling showed that rs3749171 is located in the third transmembrane helix of GPR35 and could possibly alter efficiency of signaling through the GPR35 receptor. Conclusion: By refining the analysis of a PSC GWAS by parallel assessments in a UC GWAS, we were able to detect two novel risk loci at genome-wide significance levels. GPR35 shows associations in both UC and PSC, whereas TCF4 represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis. (HEPATOLOGY 2013;58:1074-1083 Abbreviations: CARD9, caspase-recruitment domain family, member 9; CI, confidence interval; CON1/2, control panel 1/2; GPR35, G-protein-coupled receptor

High-Throughput Identification and Characterization of Novel, Species-selective GPR35 Agonists

“…The poorly characterized G protein-coupled receptor (GPCR) GPR35 has been suggested as a potential target in conditions ranging from cardiovascular disease and metabolic disorders to inflammation and nociception (MacKenzie et al, 2011;Milligan, 2011,). These suggestions have arisen from studies exploring each of tissue distribution, functional studies, and genetic associations of GPR35 with disease (Leonard et al, 2005;Vander Molen et al, 2005;Wang et al, 2006;Min et al, 2010;Ellinghaus et al, 2012). However, understanding the biology of GPR35 has been restricted due to a paucity of high potency/affinity and selective ligands.…”

“…The class A orphan receptor GPR35 has been described as a potentially novel drug target (MacKenzie et al, 2011) based upon reports describing the activation of this receptor in a variety of cell types (Leonard et al, 2005;Wang et al, 2006;Ohshiro et al, 2008;Fallarini et al, 2010), the potential genetic linkage of GPR35 to disease (Shrimpton et al, 2004;Vander Molen et al, 2005;Ellinghaus et al, 2012), and the phenotypic profiling of a GPR35 knockout mouse line (Min et al, 2010). This has resulted in speculation that GPR35 may hold therapeutic potential for inflammatory disorders (Wang et al, 2006;Lattin et al, 2008;Barth et al, 2009), central nervous system function (Shrimpton et al, 2004;Lein et al, 2007;Guo et al, 2008), nociception (Ohshiro et al, 2008;Zhao et al, 2010;Cosi et al, 2011), metabolic disorders (Leonard et al, 2005;Vander Molen et al, 2005), hypertension, and cardiovascular disease (Sun et al, 2008;Min et al, 2010).…”

The Antiallergic Mast Cell Stabilizers Lodoxamide and Bufrolin as the First High and Equipotent Agonists of Human and Rat GPR35

“…However, despite rs3749171, a SNP associated in genomewide association analyses as a risk locus for ulcerative colitis (Ellinghaus et al, 2013) and inflammatory bowel disease (Jostins et al, 2012), encompassing the GPR35 locus, at least in the receptor-b-arrestin-2 interaction assays employed, neither of these variations had any detectable effect on ligand pharmacology.…”

Risk factors and outcome in patients with primary sclerosing cholangitis with persistent biliary Candidiasis

“…Unfortunately, the pathogenesis of PSC is still unresolved. Recent studies highlighted the influence of numerous genetic risk factors [11][12][13], and it is well accepted that immunological and environmental factors, such as transmission of bacterial pathogens from the gut due to increased permeability of the portal venous system, are also involved [14][15][16].…”