More on IL23R

January 25, 2007

As was mentioned a couple of months ago, a new inflammatory bowel

disease gene was recently identified, IL23R.

Duerr RH, KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ,

Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T,

Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee AT,

Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH. A genome-

wide association study identifies IL23R as an inflammatory bowel

disease gene. Science. 2006 314(5804): 1461-1463. PMID: 17068223.

and this suggests that targeting IL-23 would be a rational strategy

for treatment of inflammatory bowel disease.

This discovery has stirred a lot of interest, and has been the

subject of a several commentaries/editorials recently:

Neurath MF. IL-23: a master regulator in Crohn disease.

Nat Med. 2007 13: 26-28. PMID: 17206128.

Marx J. Biomedicine. Puzzling out the pains in the gut.

Science. 2007 315(5808): 33-35. PMID: 17204619.

Lang L. Study identifies a gene for inflammatory bowel disease.

Gastroenterology. 2007 132(1): 5. PMID: 17241850.

and was also the subject of a press release by CCFA:

http://www.ccfa.org/about/press/il23

Interestingly, this same gene has now been found to be associated

with psoriasis susceptibility:

Am J Hum Genet. 2007 80(2):273-390.

A Large-Scale Genetic Association Study Confirms IL12B and Leads to

the Identification of IL23R as Psoriasis-Risk Genes.

Cargill M, Schrodi SJ, Chang M, VE, R, Callis KP,

Matsunami N, Ardlie KG, Civello D, Catanese JJ, Leong DU, Panko JM,

McAllister LB, Hansen CB, Papenfuss J, Prescott SM, White TJ, Leppert

MF, Krueger GG, Begovich AB

Celera, Alameda, CA, USA.

We performed a multitiered, case-control association study of

psoriasis in three independent sample sets of white North American

individuals (1,446 cases and 1,432 controls) with 25,215 genecentric

single-nucleotide polymorphisms (SNPs) and found a highly significant

association with an IL12B 3'-untranslated-region SNP (rs3212227),

confirming the results of a small Japanese study. This SNP was

significant in all three sample sets (odds ratio [OR](common) 0.64,

combined P [Pcomb]=7.85x10-10). A Monte Carlo simulation to address

multiple testing suggests that this association is not a type I

error. The coding regions of IL12B were resequenced in 96 individuals

with psoriasis, and 30 additional IL12B-region SNPs were genotyped.

Haplotypes were estimated, and genotype-conditioned analyses

identified a second risk allele (rs6887695) located ~60 kb upstream

of the IL12B coding region that exhibited association with psoriasis

after adjustment for rs3212227. Together, these two SNPs mark a

common IL12B risk haplotype (OR(common) 1.40, Pcomb=8.11x10-9) and a

less frequent protective haplotype (OR(common) 0.58, Pcomb=5.65x10-

12), which were statistically significant in all three studies. Since

IL12B encodes the common IL-12p40 subunit of IL-12 and IL-23, we

individually genotyped 17 SNPs in the genes encoding the other chains

of these cytokines (IL12A and IL23A) and their receptors (IL12RB1,

IL12RB2, and IL23R). Haplotype analyses identified two IL23R missense

SNPs that together mark a common psoriasis-associated haplotype in

all three studies (OR(common) 1.44, Pcomb=3.13x10-6). Individuals

homozygous for both the IL12B and the IL23R predisposing haplotypes

have an increased risk of disease (OR(common) 1.66, Pcomb=1.33x10-8).

These data, and the previous observation that administration of an

antibody specific for the IL-12p40 subunit to patients with psoriasis

is highly efficacious, suggest that these genes play a fundamental

role in psoriasis pathogenesis. PMID: 17236132.

This study was the subject of a press release by Celera:

http://www.celera.com/celera/pr_1166043623

This finding helps explain why antibodies that target the IL-12p40

subunit common to both IL-12 and IL-23 are effective in controlling

psoriasis.

Toichi E, G, McCormick TS, Chang T, Mascelli MA, Kauffman CL,

Aria N, Gottlieb AB, Everitt DE, Frederick B, Pendley CE, KD.

An anti-IL-12p40 antibody down-regulates type 1 cytokines,

chemokines, and IL-12/IL-23 in psoriasis. J Immunol. 2006 177(7):4917-

26. PMID: 16982934.

Such antibodies are also being tested in IBD; see for example:

Burakoff R, Barish CF, Riff D, Pruitt R, Chey WY, Farraye FA, Shafran

I, Katz S, Krone CL, Vander Vliet M, s C, Sherman ML, son

E, Bleday R. A phase 1/2A trial of STA 5326, an oral interleukin-

12/23 inhibitor, in patients with active moderate to severe Crohn's

disease. Inflamm Bowel Dis. 2006 12(7):558-565. PMID: 16804392.

It's interesting that both psoriasis and IBD are converging, with

common therepeutic targets (both also seem to respond to tumor

necrosis factor inhibitors, like infliximab (Remicade))!

I'll try to expand on these findings in the next newsletter.

Best regards,

Dave

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

January 26, 2007

THis is interesting Dave.

It fits my family genetics as well. My mom has psoriasis and I did

include this in the medical history for Mayo.

It will be interesting you see how this all connects.

Lee

January 26, 2007

THis is interesting Dave.

It fits my family genetics as well. My mom has psoriasis and I did

include this in the medical history for Mayo.

It will be interesting you see how this all connects.

Lee

January 27, 2007

Hi Lee;

That's very intriguing that your Mom has psoriasis, and it does seem

consistent with a common genetic component of psoriasis and IBD.

What I have found interesting is that the eicosapentaenoic acid (EPA)

in fish oils seems to be doing a somewhat similar job to these newer

antibodies that target the common subunit of IL-12 and IL-23 (IL-

12p40). The anti-inflammatory compound " Resolvin E1 " derived from EPA

seems to be down-regulating this same inflammatory pathway:

Proc Natl Acad Sci U S A. 2005 May 24;102(21):7671-6.

Resolvin E1, an endogenous lipid mediator derived from omega-3

eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene

sulfonic acid-induced colitis.

Arita M, Yoshida M, Hong S, Tjonahen E, Glickman JN, Petasis NA,

Blumberg RS, Serhan CN

Center for Experimental Therapeutics and Reperfusion Injury, Brigham

and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Resolvin E1 (RvE1; 5S,12R,18R-trihydroxyeicosapentaenoic acid) is an

antiinflammatory lipid mediator derived from omega-3 fatty acid

eicosapentaenoic acid (EPA). At the local site of inflammation,

aspirin treatment enhances EPA conversion to 18R-oxygenated products,

including RvE1, which carry potent antiinflammatory signals. Here, we

obtained evidence for reduced leukocyte infiltration in a mouse

peritonitis model, where the administration of EPA and aspirin

initiated the generation of RvE1 in the exudates. Similar results

were obtained with the administration of synthetic RvE1, which

blocked leukocyte infiltration. RvE1 also protected against the

development of 2,4,6-trinitrobenzene sulfonic acid-induced colitis.

The beneficial effect was reflected by increased survival rates,

sustained body weight, improvement of histologic scores, reduced

serum anti-2,4,6-trinitrobenzene sulfonic acid IgG, decreased

leukocyte infiltration, and proinflammatory gene expression,

including IL-12 p40, TNF-alpha, and inducible nitric oxide synthase.

Thus, the endogenous lipid mediator RvE1 counter-regulates leukocyte-

mediated tissue injury and proinflammatory gene expression. These

findings show an endogenous mechanism that may underlie the

beneficial actions of omega-3 EPA and provide targeted approaches for

the treatment of intestinal inflammation. PMID: 15890784.

In response to your question about the " Trauner M " on the paper about

PSC being the atherosclerosis of the bile-duct, yes this is the same

Trauner who is working on nor-urso and that we met in

Bethesda in Sept. 2005.

Best regards,

Dave

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

January 27, 2007