1. PSC and genetics Tom Hemming Karlsen
Research Institute of Internal Medicine &
Department of Transplantation Medicine
University of Oslo & Oslo University Hospital, Norway
New Haven – June 25th 2016

2. ous-research.no/nopsc www.ipscsg.org

3. Liver transplantation in Norway
(Fosby et al., 2015)

4. Primary sclerosing cholangitis

5. Primary sclerosing cholangitis

6. IBD prevalence in PSC - geography

7. IBD prevalence in PSC - geography
(Tanaka et al., 2014)

8. «Unknown» PSC patients ♀ 71%
PSC prevalence in IBD
Known PSC prevalence 2.2%
True PSC prevalence 8.1%
UC 6.8%, CD 9.1%
«Unknown» PSC patients ♀ 71%
(Lunder et al., Gastroenterology early online)

9. (Gou et al., in submission)
PSC-IBD
(Gou et al., in submission)

10. GWAS examples - drug-induced liver injury
Flucloxacillin
Lumiracoxib
Amoxicillin-clavulunate
(For references to studies, see

11. GWAS examples – AIH, PBC and PSC
Autoimmune hepatitis
Primary biliary cirrhosis
Primary sclerosing cholangitis
(For references to studies, see

12. «GWAS genetics»
Additional impact from unexplained (or “missing”) heritability
Additional impact from environmental factors
(Bach, 2002)

13. The HLA associations in PSC

14. A fundamental biological problem

15. HLA associations and the antigen

16. (Ellinghaus et al., Nature Genetics 2016)
Genetics and the gut
(Ellinghaus et al., Nature Genetics 2016)

17. The gut microbiome FUT2 PCA (Wacklin et al. 2011)
(Kummen et al, Gut 2016)

18. The gut-liver relationship in PSC

19. The magnitude of non-genetic factors
(Wang et al., in revisions)

20. The magnitude of genetic factors
(Wang et al., in revisions)

21. The gut microbiota in PSC
(Karlsen, in press Gut)

22. Other non-HLA genes

23. Genome-wide significant risk genes
Locus
Chr.
lead SNP
Gene
Study (year) 1 rs
MMEL1, TNFRSF14
Folseraas et al. 2012 2 rs
BCL2L11
Melum et al. 2011 3 rs
CD28, CTLA4
Liu et al. 2013 4 rs
CCL20
Ellinghaus et al. 2016 5 rs
GPR35
Ellinghaus et al. 2013 6 rs
MST1 7 rs
NFKB1 8 rs
IL2, IL21 9 rs
BACH2 10 rs
IL2RA
Srivastava et al. 2012 11 rs
SIK2 12 rs
HDAC7 13 rs
RFX4, RIC8B 14 rs
SH2B3, ATXN2 15 16 rs
CLEC16A, SOCS1 18 rs
TCF4 17 rs
CD226 19 rs
PRKD2, STRN4 21 rs
PSMG1

24. Independently reported risk genes
Locus
Chr.
lead SNP
Gene
Study (year) 1 rs
MMEL1, TNFRSF14
Folseraas et al. 2012 2 rs
BCL2L11
Melum et al. 2011 3 rs
CD28, CTLA4
Liu et al. 2013 4 rs
CCL20
Ellinghaus et al. 2016 5 rs
GPR35
Ellinghaus et al. 2013 6 rs
MST1 7 rs
NFKB1 8 rs
IL2, IL21 9 rs
BACH2 10 rs
IL2RA
Srivastava et al. 2012 11 rs
SIK2 12 rs
HDAC7 13 rs
RFX4, RIC8B 14 rs
SH2B3, ATXN2 15 16 rs
CLEC16A, SOCS1 18 rs
TCF4 17 rs
CD226 19 rs
PRKD2, STRN4 21 rs
PSMG1

25. Hypothesis-free → hypothesis-driven

26. Familial PSC variants

27. (Yiang et al., in preparation)
Familial PSC
(Yiang et al., in preparation)

28. Modifier genes

29. Modifier genes
(Alberts et al, EASL 2016)

30. Cholangiocarcinoma genetics

31. Cholangiocarcinoma genetics
Chromosome
Frequency (%)
Potential therapeutics for further study
KRAS
ch12
38%
Refametinib (phase II in HCC)
CDKN2A
chr9
20%
Ilorasertib (phase II in solid tumors)
SMAD4
chr18
18%
TGFβ receptor inhibitor (phase I, i.e. LY (Galunisertib))
ERBB2
chr17 8%
Trastuzumab, Pertuzumab
BRAF V600
chr7 6%
Vemurafenib, Encorafenib
EGFR
Gefitinib, Erlotinib, Afatinib, (Cetuximab)
TGFBR2
chr3 2%
TGFβ receptor inhibitor
FGF23
chr12
FGFR4 inhibitor (phase I, i.e. BLU-554, FGF401)
FGFR2
chr10
BGJ398 (phase II study),
PIK3CA 4%
Everolimus (RAD001)
Total
66%
(patients with one or more „druggable“ targets)
(Goeppert et al, EASL 2016)

32. Concluding statements
~30 risk genes, specific interactions with environment
Familial PSC is rare, consider if ≥3 affected and no IBD
Genetics in risk stratification currently being explored
Encouraging first findings in CCA sequencing project