Three Ulcerative Colitis Susceptibility Loci Are Associated with Primary Sclerosing Cholangitis and Indicate a Role for IL2, REL, and CARD9

被引：96

作者：

Janse, Marcel ^{[1
,2
]}

Lamberts, Laetitia E. ^{[1
,2
]}

Franke, Lude ^{[2
,3
]}

Raychaudhuri, Soumya ^{[4
,5
,6
]}

Ellinghaus, Eva ^{[7
]}

Boberg, Kirsten Muri ^{[8
]}

Melum, Espen ^{[8
]}

Folseraas, Trine ^{[8
]}

Schrumpf, Erik ^{[8
]}

Bergquist, Annika ^{[9
]}

Bjornsson, Einar ^{[10
]}

Fu, Jingyuan ^{[2
,3
]}

Westra, Harm Jan ^{[2
,3
]}

Groen, Harry J. M. ^{[2
,11
]}

Fehrmann, Rudolf S. N. ^{[2
,3
]}

Smolonska, Joanna ^{[2
,3
]}

van den Berg, Leonard H. ^{[12
]}

Ophoff, Roel A. ^{[13
,14
]}

Porte, Robert J. ^{[2
,15
]}

Weismueller, Tobias J. ^{[16
,17
]}

Wedemeyer, Jochen ^{[16
,17
]}

Schramm, Christoph ^{[18
]}

Sterneck, Martina ^{[18
]}

Guenther, Rainer ^{[19
]}

Braun, Felix ^{[20
]}

Vermeire, Severine ^{[21
]}

Henckaerts, Liesbet ^{[21
]}

Wijmenga, Cisca ^{[2
,3
]}

Ponsioen, Cyriel Y. ^{[22
]}

Schreiber, Stefan ^{[7
]}

Karlsen, Tom H. ^{[8
]}

Franke, Andre ^{[7
]}

Weersma, Rinse K. ^{[1
]}

机构：

[1] Univ Med Ctr Groningen, Dept Gastroenterol & Hepatol, NL-9700 RB Groningen, Netherlands

[2] Univ Groningen, Groningen, Netherlands

[3] Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands

[4] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA

[5] Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, Boston, MA 02115 USA

[6] Broad Inst, Cambridge, MA USA

[7] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[8] Univ Oslo, Rikshosp, Oslo Univ Hosp, Norwegian PSC Res Ctr,Clin Specialized Surg & Med, N-0027 Oslo, Norway

[9] Karolinska Univ Hosp, Dept Gastroenterol & Hepatol, Stockholm, Sweden

[10] Sahlgrens Univ Hosp, Dept Internal Med, Sect Gastroenterol & Hepatol, Gothenburg, Sweden

[11] Univ Med Ctr Groningen, Dept Pulmonol, NL-9700 RB Groningen, Netherlands

[12] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Neurol, Utrecht, Netherlands

[13] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands

[14] Univ Med Ctr Utrecht, Rolf Magnus Inst, Utrecht, Netherlands

[15] Univ Med Ctr Groningen, Dept Hepatopancreaticobiliary Surg & Liver Transp, NL-9700 RB Groningen, Netherlands

[16] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, D-3000 Hannover, Germany

[17] Hannover Med Sch, Integrated Res & Treatment Ctr Transplantat IFB T, D-3000 Hannover, Germany

[18] Univ Med Ctr Hamburg Eppendorf, Dept Med 1, Hamburg, Germany

[19] Univ Med Ctr Schleswig Holstein UK SH, Dept Med 1, Campus Kiel, Germany

[20] Univ Med Ctr Schleswig Holstein UK SH, Dept Gen & Thorac Surg, Campus Kiel, Germany

[21] Univ Hosp Gasthuisberg, Dept Gastroenterol, B-3000 Louvain, Belgium

[22] Univ Amsterdam, Acad Med Ctr, Dept Gastroenterol & Hepatol, NL-1105 AZ Amsterdam, Netherlands

来源：

HEPATOLOGY | 2011年 / 53卷 / 06期

关键词：

GENOME-WIDE ASSOCIATION; INFLAMMATORY-BOWEL-DISEASE; RHEUMATOID-ARTHRITIS; CROHNS-DISEASE; INNATE IMMUNITY; RISK LOCUS; T-CELLS; GENE; VARIANTS; POPULATION;

D O I：

10.1002/hep.24307

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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 x 10(-4)), 4q27 (P-value 4.10 x 10(-5)), and 9q34 (P-value 8.41 x 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. (HEPATOLOGY 2011;53:1977-1985)

引用

页码：1977 / 1985

页数：9

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