Genome-wide association analysis in primary sclerosing cholangitis.
OBJECTIVE
We aimed to characterize the genetic susceptibility to primary sclerosing cholangitis (PSC) by means of a genome-wide association analysis of single nucleotide polymorphism (SNP) markers.


METHODS
A total of 443,816 SNPs on the Affymetrix SNP Array 5.0 (Affymetrix, Santa Clara, CA) were genotyped in 285 Norwegian PSC patients and 298 healthy controls. Associations detected in this discovery panel were re-examined in independent case-control panels from Scandinavia (137 PSC cases and 368 controls), Belgium/The Netherlands (229 PSC cases and 735 controls), and Germany (400 cases and 1832 controls).


RESULTS
The strongest associations were detected near HLA-B at chromosome 6p21 (rs3099844: odds ratio [OR], 4.8; 95% confidence interval [CI], 3.6-6.5; P = 2.6 x 10(-26); and rs2844559: OR, 4.7; 95% CI, 3.5-6.4; P = 4.2 x 10(-26) in the discovery panel). Outside the HLA complex, rs9524260 at chromosome 13q31 showed significant associations in 3 of 4 study panels. Lentiviral silencing of glypican 6, encoded at this locus, led to the up-regulation of proinflammatory markers in a cholangiocyte cell line. Of 15 established ulcerative colitis susceptibility loci, significant replication was obtained at chromosomes 2q35 and 3p21 (rs12612347: OR, 1.26; 95% CI, 1.06-1.50; and rs3197999: OR, 1.22; 95% CI, 1.02-1.47, respectively), with circumstantial evidence supporting the G-protein-coupled bile acid receptor 1 and macrophage-stimulating 1, respectively, as the likely disease genes.


CONCLUSIONS
Strong HLA associations and a subset of genes involved in bile homeostasis and other inflammatory conditions constitute key components of the genetic architecture of PSC.
Karlsen
Tom H
TH
Medical Department, Rikshospitalet University Hospital and University of Oslo, 0027 Oslo, Norway. t.h.karlsen@klinmed.uio.no
Franke
Andre
A
Melum
Espen
E
Kaser
Arthur
A
Hov
Johannes Roksund
JR
Balschun
Tobias
T
Lie
Benedicte A
BA
Bergquist
Annika
A
Schramm
Christoph
C
Weismüller
Tobias J
TJ
Gotthardt
Daniel
D
Rust
Christian
C
Philipp
Eva E R
EE
Fritz
Teresa
T
Henckaerts
Liesbet
L
Weersma
Rinse K
RK
Stokkers
Pieter
P
Ponsioen
Cyriel Y
CY
Wijmenga
Cisca
C
Sterneck
Martina
M
Nothnagel
Michael
M
Hampe
Jochen
J
Teufel
Andreas
A
Runz
Heiko
H
Rosenstiel
Philip
P
Stiehl
Adolf
A
Vermeire
Severine
S
Beuers
Ulrich
U
Manns
Michael P
MP
Schrumpf
Erik
E
Boberg
Kirsten Muri
KM
Schreiber
Stefan
S
D001646:Bile / Q000378:metabolism; D001659:Biliary Tract / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D002460:Cell Line; D016009:Chi-Square Distribution; D015209:Cholangitis, Sclerosing / Q000235:genetics* / Q000276:immunology; D003093:Colitis, Ulcerative / Q000235:genetics; D005060:Europe; D020869:Gene Expression Profiling / Q000379:methods; D005787:Gene Frequency; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D053673:Glypicans / Q000235:genetics; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016017:Odds Ratio; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors
C120300:GPC6 protein, human; D053673:Glypicans; D006680:HLA Antigens; D018836:Inflammation Mediators