title: Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9.
abstract: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Both environmental and genetic factors contribute to its pathogenesis. To further clarify its genetic background, we investigated susceptibility loci recently identified for ulcerative colitis (UC) in a large cohort of 1,186 PSC patients and 1,748 controls. Single nucleotide polymorphisms (SNPs) tagging 13 UC susceptibility loci were initially genotyped in 854 PSC patients and 1,491 controls from Benelux (331 cases, 735 controls), Germany (265 cases, 368 controls), and Scandinavia (258 cases, 388 controls). Subsequently, a joint analysis was performed with an independent second Scandinavian cohort (332 cases, 257 controls). SNPs at chromosomes 2p16 (P-value 4.12 × 10(-4) ), 4q27 (P-value 4.10 × 10(-5) ), and 9q34 (P-value 8.41 × 10(-4) ) were associated with PSC in the joint analysis after correcting for multiple testing. In PSC patients without inflammatory bowel disease (IBD), SNPs at 4q27 and 9q34 were nominally associated (P < 0.05). We applied additional in silico analyses to identify likely candidate genes at PSC susceptibility loci. To identify nonrandom, evidence-based links we used GRAIL (Gene Relationships Across Implicated Loci) analysis showing interconnectivity between genes in six out of in total nine PSC-associated regions. Expression quantitative trait analysis from 1,469 Dutch and UK individuals demonstrated that five out of nine SNPs had an effect on cis-gene expression. These analyses prioritized IL2, CARD9, and REL as novel candidates.
  
  
  CONCLUSIONS
  We have identified three UC susceptibility loci to be associated with PSC, harboring the putative candidate genes REL, IL2, and CARD9. These results add to the scarce knowledge on the genetic background of PSC and imply an important role for both innate and adaptive immunological factors.
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Janse
authors.forename: Laetitia E
authors.initials: LE
authors.lastname: Lamberts
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.forename: Eva
authors.initials: E
authors.lastname: Ellinghaus
authors.forename: Kirsten
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authors.lastname: Muri Boberg
authors.forename: Espen
authors.initials: E
authors.lastname: Melum
authors.forename: Trine
authors.initials: T
authors.lastname: Folseraas
authors.forename: Erik
authors.initials: E
authors.lastname: Schrumpf
authors.forename: Annika
authors.initials: A
authors.lastname: Bergquist
authors.forename: Einar
authors.initials: E
authors.lastname: Björnsson
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Fu
authors.forename: Harm
authors.initials: H
authors.lastname: Jan Westra
authors.forename: Harry J M
authors.initials: HJ
authors.lastname: Groen
authors.forename: Rudolf S N
authors.initials: RS
authors.lastname: Fehrmann
authors.forename: Joanna
authors.initials: J
authors.lastname: Smolonska
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.forename: Roel A
authors.initials: RA
authors.lastname: Ophoff
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Porte
authors.forename: Tobias J
authors.initials: TJ
authors.lastname: Weismüller
authors.forename: Jochen
authors.initials: J
authors.lastname: Wedemeyer
authors.forename: Christoph
authors.initials: C
authors.lastname: Schramm
authors.forename: Martina
authors.initials: M
authors.lastname: Sterneck
authors.forename: Rainer
authors.initials: R
authors.lastname: Günther
authors.forename: Felix
authors.initials: F
authors.lastname: Braun
authors.forename: Severine
authors.initials: S
authors.lastname: Vermeire
authors.forename: Liesbet
authors.initials: L
authors.lastname: Henckaerts
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Cyriel Y
authors.initials: CY
authors.lastname: Ponsioen
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
mesh_terms: D000483:Alleles; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics* / Q000502:physiology; D016022:Case-Control Studies; D015209:Cholangitis, Sclerosing / Q000208:ethnology / Q000235:genetics; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000208:ethnology / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D005838:Genotype; D005858:Germany; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics* / Q000502:physiology; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics* / Q000502:physiology; D040641:Quantitative Trait Loci; D012537:Scandinavian and Nordic Countries
chemical_list: D053468:CARD Signaling Adaptor Proteins; C505855:CARD9 protein, human; D007376:Interleukin-2; D020569:Proto-Oncogene Proteins c-rel