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Title: Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9
Authors: Janse, Marcel ×
Lamberts, Laetitia E
Franke, Lude
Raychaudhuri, Soumya
Ellinghaus, Eva
Muri Boberg, Kirsten
Melum, Espen
Folseraas, Trine
Schrumpf, Erik
Bergquist, Annika
Björnsson, Einar
Fu, Jingyuan
Jan Westra, Harm
Groen, Harry J M
Fehrmann, Rudolf S N
Smolonska, Joanna
van den Berg, Leonard H
Ophoff, Roel A
Porte, Robert J
Weismüller, Tobias J
Wedemeyer, Jochen
Schramm, Christoph
Sterneck, Martina
Günther, Rainer
Braun, Felix
Vermeire, Séverine
Henckaerts, Liesbet
Wijmenga, Cisca
Ponsioen, Cyriel Y
Schreiber, Stefan
Karlsen, Tom H
Franke, Andre
Weersma, Rinse K #
Issue Date: Jun-2011
Publisher: W.B. Saunders
Series Title: Hepatology vol:53 issue:6 pages:1977-1985
Article number: 10.1002/hep.24307
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. CONCLUSION: 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.
URI: 
ISSN: 0270-9139
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Translational Research in GastroIntestinal Disorders
Department of Microbiology & Immunology - miscellaneous
Laboratory for Clinical Infectious and Inflammatory Disorders
× corresponding author
# (joint) last author

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