title: Mutational characterization of the bile acid receptor TGR5 in primary sclerosing cholangitis.
abstract: BACKGROUND
  TGR5, the G protein-coupled bile acid receptor 1 (GPBAR1), has been linked to inflammatory pathways as well as bile homeostasis, and could therefore be involved in primary sclerosing cholangitis (PSC) a chronic inflammatory bile duct disease. We aimed to extensively investigate TGR5 sequence variation in PSC, as well as functionally characterize detected variants.
  
  
  RESULTS
  Complete resequencing of TGR5 was performed in 267 PSC patients and 274 healthy controls. Six nonsynonymous mutations were identified in addition to 16 other novel single-nucleotide polymorphisms. To investigate the impact from the nonsynonymous variants on TGR5, we created a receptor model, and introduced mutated TGR5 constructs into human epithelial cell lines. By using confocal microscopy, flow cytometry and a cAMP-sensitive luciferase assay, five of the nonsynonymous mutations (W83R, V178M, A217P, S272G and Q296X) were found to reduce or abolish TGR5 function. Fine-mapping of the previously reported PSC and UC associated locus at chromosome 2q35 in large patient panels revealed an overall association between the TGR5 single-nucleotide polymorphism rs11554825 and PSC (odds ratio = 1.14, 95% confidence interval: 1.03-1.26, p = 0.010) and UC (odds ratio = 1.19, 95% confidence interval 1.11-1.27, p = 8.5 x 10(-7)), but strong linkage disequilibrium precluded demarcation of TGR5 from neighboring genes.
  
  
  CONCLUSIONS
  Resequencing of TGR5 along with functional investigations of novel variants provided unique insight into an important candidate gene for several inflammatory and metabolic conditions. While significant TGR5 associations were detected in both UC and PSC, further studies are needed to conclusively define the role of TGR5 variation in these diseases.
authors.affiliation: Norwegian PSC Research Center, Clinic for Specialized Medicine and Surgery, Oslo University Hospital Rikshospitalet, Oslo, Norway. j.e.r.hov@medisin.uio.no
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Hov
authors.forename: Verena
authors.initials: V
authors.lastname: Keitel
authors.forename: Jon K
authors.initials: JK
authors.lastname: Laerdahl
authors.forename: Lina
authors.initials: L
authors.lastname: Spomer
authors.forename: Eva
authors.initials: E
authors.lastname: Ellinghaus
authors.forename: Abdou
authors.initials: A
authors.lastname: ElSharawy
authors.forename: Espen
authors.initials: E
authors.lastname: Melum
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Boberg
authors.forename: Thomas
authors.initials: T
authors.lastname: Manke
authors.forename: Tobias
authors.initials: T
authors.lastname: Balschun
authors.forename: Christoph
authors.initials: C
authors.lastname: Schramm
authors.forename: Annika
authors.initials: A
authors.lastname: Bergquist
authors.forename: Tobias
authors.initials: T
authors.lastname: Weismüller
authors.forename: Daniel
authors.initials: D
authors.lastname: Gotthardt
authors.forename: Christian
authors.initials: C
authors.lastname: Rust
authors.forename: Liesbet
authors.initials: L
authors.lastname: Henckaerts
authors.forename: Clive M
authors.initials: CM
authors.lastname: Onnie
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
authors.forename: Martina
authors.initials: M
authors.lastname: Sterneck
authors.forename: Andreas
authors.initials: A
authors.lastname: Teufel
authors.forename: Heiko
authors.initials: H
authors.lastname: Runz
authors.forename: Adolf
authors.initials: A
authors.lastname: Stiehl
authors.forename: Cyriel Y
authors.initials: CY
authors.lastname: Ponsioen
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Morten H
authors.initials: MH
authors.lastname: Vatn
authors.forename: Pieter C F
authors.initials: PC
authors.lastname: Stokkers
authors.forename: Severine
authors.initials: S
authors.lastname: Vermeire
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mathew
authors.forename: Benedicte A
authors.initials: BA
authors.lastname: Lie
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Erik
authors.initials: E
authors.lastname: Schrumpf
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D002648:Child; D015209:Cholangitis, Sclerosing / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D003093:Colitis, Ulcerative / Q000150:complications; D004252:DNA Mutational Analysis; D004285:Dogs; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C473772:GPBAR1 protein, human; D043562:Receptors, G-Protein-Coupled
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