PSC genetic research

[Guest guest]

Dear All;

I find this recent article to be very interesting:

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Gastroenterology. 2006 Sep;131(3):781-7.

Polymorphisms in the steroid and xenobiotic receptor gene influence

survival in primary sclerosing cholangitis.

Karlsen TH, Lie BA, Frey Froslie K, Thorsby E, Broome U, Schrumpf E,

Boberg KM

Medical Department, Rikshospitalet University Hospital, Oslo,

Norway; Institute of Immunology, Rikshospitalet University Hospital,

Oslo, Norway.

Background & Aims: The steroid and xenobiotic receptor (SXR) is a

ligand-dependent transcription factor that mediates protection

against bile acid-induced liver injury in cholestatic animal models.

Ursodeoxycholic acid and rifampicin are known ligands. We

investigated whether functional polymorphisms of the SXR gene

influence disease susceptibility or disease progression in patients

with primary sclerosing cholangitis (PSC). Methods: Polymorphisms at

8 loci across the SXR gene were genotyped in 327 Scandinavian PSC

patients and 275 healthy controls. Kaplan-Meier survival analyses

and regressions were performed to estimate effects from

genotypes on patient survival, defined as time from diagnostic

cholangiography to death or liver transplantation. Results:

Susceptibility to PSC was not associated with any of the SXR

polymorphisms studied. Median survival was significantly reduced in

patients homozygous for the minor allele as compared with patients

carrying at least 1 major allele of the neighboring polymorphisms

rs6785049 (10.8 vs 14.0 years, respectively, P = .01), rs1054190

(3.6 vs 13.6 years, respectively, P = .004), and rs3814058 (3.5 vs

13.3 years, respectively, P = .01). The increased risk of death or

liver transplantation was confirmed in univariate regressions

(relative risk [RR](rs6785049) = 1.7, 95% CI: 1.1-2.6; RR(rs1054190)

= 3.1, 95% CI: 1.4-7.1; and RR(rs3814058) = 2.2, 95% CI: 1.2-4.2 for

the 3 polymorphisms, respectively). In multiple regressions

including age at PSC onset, rs1054190 remained an independent risk

factor. Conclusions: Functional SXR gene variants appear to modify

disease course in PSC. Further investigations of polymorphisms in

the SXR gene may provide insight into the prognostic importance of

SXR-regulated pathways in this disease, perhaps even in a

therapeutic perspective. PMID: 16952547.

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As I understand it, the steroid and xenobiotic receptor gene (SXR)

is the same as the pregnane X receptor (PXR):

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603065

PXR/SXR is the target for the anti-itching agent, rifampin

(rifampicin). You may recall that PXR was also recently shown to

determine susceptibility to inflammatory bowel disease, particularly

ulcerative colitis:

Dring MM, Goulding CA, Trimble VI, Keegan D, AW, Brophy KM,

Smyth CM, Keeling PWN, O'Donoghue D, O'Sullivan M, O'Morain C,

Mahmud N, Wikstrom AC, Kelleher D, McManus R 2006 The pregnane X

receptor locus is associated with susceptibility to inflammatory

bowel disease. Gastroenterology 130: 341-348.

So the PXR/SXR gene seems to affect both susceptibility to

ulcerative colitis and survival in PSC, at least in these

preliminary genetic studies. Therefore, it is likely to become a

major target of interest for PSC researchers.

Best regards.

Dave

(father of (21); PSC 07/03; UC 08/03)