title: Genetics in PSC: what do the "risk genes" teach us?
abstract: A role of genetics in primary sclerosing cholangitis (PSC) development is now firmly established. A total of 16 risk genes have been reported at highly robust ("genome-wide") significance levels, and ongoing efforts suggest that the list will ultimately be considerably longer. Importantly, this genetic risk pool so far accounts for less than 10 % of an estimated overall PSC susceptibility. The relative importance of genetic versus environmental factors (including gene-gene and gene-environment interactions) in remaining aspects of PSC pathogenesis is unknown, and other study designs than genome-wide association studies are needed to explore these aspects. For some of the loci, e.g. HLA and FUT2, distinct interacting environmental factors may exist, and working from the genetic associations may prove one valid path for determining the specific nature of environmental triggers. So far the biological implications for PSC risk genes are typically merely hypothesized based on previously published literature, and there is therefore a strong need for dedicated translational studies to determine their roles within the specific disease context of PSC. Apparently, most risk loci seem to involve in a subset of biological pathways for which genetic associations exist in a multitude of immune-mediated diseases, accounting for both inflammatory bowel disease as well as prototypical autoimmunity. In the present article, we will survey the current knowledge on PSC genetics with a particular emphasis on the pathophysiological insight potentially gained from genetic risk loci involving in this profound immunogenetic pleiotropy.
authors.affiliation: Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, 4950 Nydalen, 0424, Oslo, Norway.
authors.forename: Trine
authors.initials: T
authors.lastname: Folseraas
authors.forename: Evaggelia
authors.initials: E
authors.lastname: Liaskou
authors.forename: Carl A
authors.initials: CA
authors.lastname: Anderson
authors.forename: Tom H
authors.initials: TH
authors.lastname: Karlsen
mesh_terms: D000818:Animals; D015209:Cholangitis, Sclerosing / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans
references.citation: Lancet. 2013 Nov 9;382(9904):1587-99
references.pmid: 23810223
references.citation: Immunity. 1995 Oct;3(4):521-30
references.pmid: 7584142
references.citation: Hum Mol Genet. 2003 Mar 15;12(6):647-56
references.pmid: 12620970
references.citation: Gastroenterology. 2010 Mar;138(3):1102-11
references.pmid: 19944697
references.citation: J Biol Chem. 2013 Apr 26;288(17):11761-70
references.pmid: 23460643
references.citation: PLoS One. 2010 Nov 08;5(11):e15376
references.pmid: 21079743
references.citation: Nat Genet. 2009 Sep;41(9):1011-5
references.pmid: 19701192
references.citation: Nature. 2012 Nov 1;491(7422):119-24
references.pmid: 23128233
references.citation: J Hepatol. 2010 May;52(5):712-7
references.pmid: 20347497
references.citation: J Immunol. 1999 Dec 15;163(12):6606-13
references.pmid: 10586055
references.citation: Nat Rev Microbiol. 2011 Apr;9(4):279-90
references.pmid: 21407244
references.citation: Semin Liver Dis. 2011 May;31(2):188-207
references.pmid: 21538284
references.citation: Annu Rev Immunol. 2008;26:453-79
references.pmid: 18062768
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 16;109(42):16986-91
references.pmid: 23033494
references.citation: J Biol Chem. 2005 Apr 8;280(14):13762-70
references.pmid: 15623513
references.citation: Nat Immunol. 2011 Jul 03;12(8):778-85
references.pmid: 21725321
references.citation: J Hepatol. 2007 May;46(5):899-906
references.pmid: 17383044
references.citation: J Immunol. 2011 Apr 15;186(8):4782-93
references.pmid: 21398603
references.citation: J Autoimmun. 2013 Oct;46:41-54
references.pmid: 23931959
references.citation: Gut. 2001 Jul;49(1):131-41
references.pmid: 11413121
references.citation: Nat Genet. 2013 Sep;45(9):984-94
references.pmid: 23933821
references.citation: Am J Hum Genet. 2010 Jun 11;86(6):970-7
references.pmid: 20560212
references.citation: Diabetes. 2006 May;55(5):1265-9
references.pmid: 16644681
references.citation: Nat Genet. 2009 Dec;41(12):1335-40
references.pmid: 19915574
references.citation: Scand J Gastroenterol. 1998 Jan;33(1):99-103
references.pmid: 9489916
references.citation: J Biomol Screen. 2013 Jun;18(5):599-609
references.pmid: 23396314
references.citation: Nat Rev Genet. 2009 Jan;10(1):43-55
references.pmid: 19092835
references.citation: J Hepatol. 2012 Aug;57(2):366-75
references.pmid: 22521342
references.citation: FEBS Lett. 2006 Sep 18;580(21):5003-8
references.pmid: 16934253
references.citation: Genes Immun. 2012 Jun;13(4):321-7
references.pmid: 22237417
references.citation: Circ Res. 2012 Feb 3;110(3):416-27
references.pmid: 22194622
references.citation: Semin Liver Dis. 1991 Feb;11(1):31-9
references.pmid: 2047887
references.citation: Immunol Rev. 2008 Dec;226:19-28
references.pmid: 19161413
references.citation: Eur J Immunol. 2000 Oct;30(10):2857-63
references.pmid: 11069067
references.citation: J Hepatol. 2005 Feb;42(2):252-6
references.pmid: 15664252
references.citation: Nat Immunol. 2011 Apr;12(4):352-61
references.pmid: 21399638
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18680-5
references.pmid: 19846760
references.citation: J Hepatol. 2013 Sep;59(3):571-82
references.pmid: 23603668
references.citation: Inflamm Bowel Dis. 2013 Mar-Apr;19(4):E58-9
references.pmid: 22593026
references.citation: Nat Rev Genet. 2013 Sep;14(9):661-73
references.pmid: 23917628
references.citation: Hepatology. 2013 Sep;58(3):1074-83
references.pmid: 22821403
references.citation: Curr Opin Gastroenterol. 2014 May;30(3):310-9
references.pmid: 24565892
references.citation: Science. 2013 Mar 1;339(6123):1084-8
references.pmid: 23328391
references.citation: Am J Gastroenterol. 2006 Sep;101(9):2070-5
references.pmid: 16879434
references.citation: Nat Genet. 2011 Oct 16;43(11):1131-8
references.pmid: 22001757
references.citation: Mol Cell Biol. 1996 Jun;16(6):2898-905
references.pmid: 8649400
references.citation: Hepatology. 2009 Jan;49(1):133-40
references.pmid: 19065673
references.citation: Best Pract Res Clin Gastroenterol. 2001 Aug;15(4):611-27
references.pmid: 11492971
references.citation: Mucosal Immunol. 2008 Mar;1(2):131-8
references.pmid: 19079170
references.citation: Dig Dis. 2012;30 Suppl 1:32-8
references.pmid: 23075866
references.citation: Hepatology. 2011 Jun;53(6):1967-76
references.pmid: 21413052
references.citation: Nat Genet. 2013 Jun;45(6):670-5
references.pmid: 23603763
references.citation: J Hepatol. 2014 May;60(5):1010-6
references.pmid: 24412607
references.citation: Scand J Immunol. 2004 Jul-Aug;60(1-2):199-208
references.pmid: 15238090
references.citation: Int J Immunogenet. 2008 Jun;35(3):179-92
references.pmid: 18397301
references.citation: Biochem J. 2010 Nov 15;432(1):153-63
references.pmid: 20819079
references.citation: Scand J Gastroenterol. 2012 Jul;47(7):820-6
references.pmid: 22554193
references.citation: Immunology. 2013 May;139(1):19-29
references.pmid: 23566200
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14747-52
references.pmid: 17804789
references.citation: Gut. 2005 Jan;54(1):91-6
references.pmid: 15591511
references.citation: EMBO J. 2010 Dec 1;29(23):4048-61
references.pmid: 20953163
references.citation: Immunol Rev. 2009 May;229(1):322-36
references.pmid: 19426231
references.citation: PLoS Genet. 2011 Aug;7(8):e1002254
references.pmid: 21852963
references.citation: J Biol Chem. 2006 Aug 4;281(31):22021-22028
references.pmid: 16754668
references.citation: Biochem Biophys Res Commun. 2008 Jan 18;365(3):426-32
references.pmid: 17991429
references.citation: Cell. 2008 Oct 3;135(1):37-48
references.pmid: 18854153
references.citation: BMC Immunol. 2012 Mar 14;13:12
references.pmid: 22413885
references.citation: Clin Gastroenterol Hepatol. 2008 Aug;6(8):939-43
references.pmid: 18674735
references.citation: Inflamm Bowel Dis. 2012 Mar;18(3):536-45
references.pmid: 21456044
references.citation: Nat Rev Genet. 2004 Dec;5(12):889-99
references.pmid: 15573121
references.citation: Hepatology. 2006 Nov;44(5):1063-74
references.pmid: 17058222
references.citation: J Biol Chem. 1993 Jul 25;268(21):15461-8
references.pmid: 8393443
references.citation: Dig Liver Dis. 2010 Jun;42(6):390-400
references.pmid: 20172772
references.citation: Nat Rev Genet. 2014 Jan;15(1):34-48
references.pmid: 24296534
references.citation: Biochem Biophys Res Commun. 2010 Jul 30;398(3):420-5
references.pmid: 20599711
references.citation: Am J Hum Genet. 2008 Oct;83(4):520-8
references.pmid: 18940312
references.citation: Nat Immunol. 2005 Jan;6(1):90-8
references.pmid: 15568026
references.citation: Hum Immunol. 1992 Aug;34(4):242-52
references.pmid: 1464552
references.citation: Biochem J. 2012 Mar 15;442(3):649-59
references.pmid: 22233340
references.citation: Hepatology. 2010 May;51(5):1833-42
references.pmid: 20232293
references.citation: Biochem Biophys Res Commun. 2010 Apr 30;395(2):232-7
references.pmid: 20361937
references.citation: Immunity. 2003 May;18(5):687-98
references.pmid: 12753745
references.citation: Hepatology. 2008 Oct;48(4):1157-66
references.pmid: 18781607
references.citation: Semin Immunopathol. 2009 Jul;31(2):207-21
references.pmid: 19495760
references.citation: J Exp Med. 2005 Mar 7;201(5):793-804
references.pmid: 15738054
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4571-6
references.pmid: 17360565
references.citation: Am J Gastroenterol. 2000 Nov;95(11):3195-9
references.pmid: 11095341
references.citation: J Clin Invest. 2001 Oct;108(8):1185-94
references.pmid: 11602626
references.citation: Nat Genet. 2011 Jan;43(1):17-9
references.pmid: 21151127