Re: PSC and CFTR

[Guest guest]

Hi

Are they saying that Inflammatory Bowel disease is also in the PSC

CFTR genetic sequence they are studying? - (I hope that makes sense)

Thanks

>

> While the link between PSC and CFTR is not particularly new,

perhaps

> what's more significant about this article is that it's from

> respected IBD genetic researchers ( Rutgeerts and Séverine

> Vermeire), suggesting that they may be turning their attention to

> PSC, which would be good news for us.

>

> Best regards,

>

> Dave

> (father of (23); PSC 07/03; UC 08/03)

[Guest guest]

Hi ;

I think what they are saying is that certain variants (alleles) of

the CFTR gene seem to be associated with protection against the type

of PSC that comes without any IBD. I havn't seen the full paper yet,

but it could be that this association is a result of the fact that

the CFTR gene (on chromosome 7) is surrounded by inflammatory bowel

disease susceptibility genes.

If you look at chromosome 7, you'll see that the MDR3 gene (which is

the cause of progressive familial intrahepatic 3, and which has also

been implicated in PSC, and gallbladder disease), is at position

7.21. Right next to this is an ulcerative colitis susceptibility

gene, MDR1 at 7q.21, then another ulcerative colitis susceptibility

gene, MUC3A (encoding an intestinal mucin) at 7.q22. CFTR is at

7q.31, and then right next to this is another inflammatory bowel

disease susceptibility gene, interferon regulatory factor 5 (IRF5),

at 7.q32.

http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim

7q21.1 ABCB4, PGY3, MDR3 ATP-binding cassette, subfamily B, member 4

(P-glycoprotein-3/multiple drug resistance-3) 171060 Cholestasis,

progressive familial intrahepatic 3, 602347 (3);Cholestasis, familial

intrahepatic, of pregnancy, 147480 (3); Gallbladder disease 1, 600803

(3) within 500kb of MDR1 RE

7q21.1 ABCB1, PGY1, MDR1, IBD13 ATP-binding cassette, subfamily B,

member 1 (P-glycoprotein-1/multiple drug resistance-1) 171050

Colchicine resistance (3); {Inflammatory bowel disease 13,

susceptibility to}, 612244 (3) REa, A, REb 5(Pgy1)

7q22 MUC3A Mucin 3A, intestinal 158371 {Ulcerative colitis,

susceptibility to}, 191390 (1) REa, A

7q31.2 CFTR, ABCC7, CF, MRP7 Cystic fibrosis transmembrane

conductance regulator (ATP-binding cassette, subfamily C, member 7)

602421 Cystic fibrosis, 219700 (3); Congenital bilateral absence of

vasdeferens, 277180 (3); Sweat chloride elevation without CF (3);

{Pancreatitis, idiopathic} (3); {Hypertrypsinemia, neonatal} (3)

distal and 5' to MET F, Fd 6(Cftr

7q32 IRF5, IBD14, Interferon regulatory factor 5 607218

{Inflammatory bowel disease 14, susceptibility to}, 612245 (3)

The last gene, closely linked to CFTR, was discovered by the Belgium

group:

_______________________

Hum Mol Genet. 2007 Dec 15;16(24):3008-16.

An insertion-deletion polymorphism in the interferon regulatory

Factor 5 (IRF5) gene confers risk of inflammatory bowel diseases.

Dideberg V, Kristjansdottir G, Milani L, Libioulle C, Sigurdsson S,

Louis E, Wiman AC, Vermeire S, Rutgeerts P, Belaiche J, Franchimont

D, Van Gossum A, Bours V, Syvänen AC.

Department of Human Genetics, CHU de Liège, Belgium.

The interferon regulatory factor 5 (IRF5) gene encodes a

transcription factor that plays an important role in the innate as

well as in the cell-mediated immune responses. The IRF5 gene has been

shown to be associated with systemic lupus erythematosus and

rheumatoid arthritis. We studied whether the IRF5 gene is also

associated with inflammatory bowel diseases (IBD), Crohn disease (CD)

and ulcerative colitis (UC). Twelve polymorphisms in the IRF5 gene

were genotyped in a cohort of 1007 IBD patients (748 CD and 254 UC)

and 241 controls from Wallonia, Belgium. The same polymorphisms were

genotyped in a confirmatory cohort of 311 controls and 687 IBD

patients (488 CD and 192 UC) from Leuven, Belgium. A strong signal of

association [P = 1.9 x 10(-5), odds ratio (OR) 1.81 (1.37-2.39)] with

IBD was observed for a 5 bp indel (CGGGG) polymorphism in the

promoter region of the IRF5 gene. The association was detectable also

in CD patients (P = 6.8 x 10(-4)) and was particularly strong among

the UC patients [P = 5.3 x 10(-8), OR = 2.42 (1.76-3.34)]. The

association of the CGGGG indel was confirmed in the second cohort [P

= 3.2 x 10(-5), OR = 1.59 (1.28-1.98)]. The insertion of one CGGGG

unit is predicted to create an additional binding site for the

transcription factor SP1. Using an electrophoretic mobility shift

assay, we show allele-specific differences in protein binding to this

repetitive DNA-stretch, which suggest a potential function role for

the CGGGG indel. PMID: 17881657.

_______________________

I am guessing that this group stumbled upon the CFTR association with

PSC (without IBD) as a result of their studies with IRF5?

Best regards,

Dave

(father of (23); PSC 07/03; UC 08/03)

>

> Hi

> Are they saying that Inflammatory Bowel disease is also in the PSC

> CFTR genetic sequence they are studying? - (I hope that makes sense)

> Thanks

>