IL-2Ralpha/CD25 gene and autoimmune diseases

[Guest guest]

Clin Endocrinol (Oxf). 2007 Apr;66(4):508-12.

Association of the interleukin-2 receptor alpha (IL-2Ralpha)/CD25

gene region with Graves' disease using a multilocus test and tag SNPs.

Brand OJ, Lowe CE, Heward JM, lyn JA, JD, Todd JA, Gough

SC

Department of Medicine, Division of Medical Sciences, Institute of

Biomedical Research, University of Birmingham, Edgbaston, Birmingham,

B15 2TT, UK.

Objective A small number of immune response genes have been

consistently associated with the common autoimmune conditions.

Recently, a linkage disequilibrium (LD) mapping approach, using tag

single nucleotide polymorphisms (SNPs), identified genetic

association between type 1 diabetes (T1D) and the interleukin-2

receptor alpha (IL-2Ralpha)/CD25 gene region on chromosome 10p15.

Because certain autoimmune diseases, such as autoimmune thyroid

disease (AITD) and T1D cluster together in certain families, we

sought to determine if the TID-associated CD25 region was also

associated with Graves' disease (GD). Design We performed a case-

control association study of 20 tag SNPs. Patients 1896 GD patients

were collected from seven major centres in the UK and 1822

geographically matched controls from the 1958 British Birth Cohort.

Measurements The 20 tag SNPs were analysed using a multilocus test to

identify an association between GD and the CD25 region. Odds ratios

(ORs) were calculated for the tag SNPs, allowing a comparison with

previous results for T1D. Results The multilocus test provided

statistical evidence of an association between GD and the CD25 region

(P = 4.5 x 10(-4)), with the pattern of association of the 20 tag

SNPs similar to that found in T1D. Conclusions Association with GD,

as well as that previously reported with T1D, suggests that the CD25

region is acting as a general susceptibility locus for autoimmune

disease, and is consistent with a major role for the IL-2-receptor

pathway in the development and function of T cells in the control of

autoimmunity. PMID: 17371467.

This paper is interesting for a couple of reasons. First, PSC and PBC

are often associated with other autoimmune diseases (such as diabetes

and thyroid disease), and this paper reports the identification of a

gene associated not only with type 1 diabetes but also autoimmune

thyroid disease. CD25 is an important receptor on regulatory T cells

(Tregs)! Second, this is the same gene, IL-2Ralpha (CD25), that has

recently been implicated as a possible gene involved in PBC:

Wakabayashi K, Lian ZX, Moritoki Y, Lan RY, Tsuneyama K, Chuang YH,

Yang GX, Ridgway W, Ueno Y, Ansari AA, Coppel RL, Mackay IR, Gershwin

ME. IL-2 receptor alpha(-/-) mice and the development of primary

biliary cirrhosis. Hepatology. 2006 Nov;44(5):1240-9. PMID: 17058261.

Aoki CA, Roifman CM, Lian ZX, Bowlus CL, Norman GL, Shoenfeld Y,

Mackay IR, Gershwin ME. IL-2 receptor alpha deficiency and features

of primary biliary cirrhosis. J Autoimmun. 2006 Aug;27(1):50-3. Epub

2006 Aug 10. PMID: 16904870.

The more genes that are found like this that are involved in multiple

autoimmune diseases, the more chance there will be of working out the

exact mechanisms of the diseases, and the higher the likelihood of

developing effective therapies in the future.

There is obvious similarity between the above series of reports and

the recent discovery that IL-23R is involved in both Crohn's disease

and psoriasis:

Dubinsky MC, Wang D, Picornell Y, Wrobel I, Katzir L, Quiros A,

Dutridge D, Wahbeh G, Silber G, Bahar R, Mengesha E, Targan SR,

KD, Rotter JI. IL-23 receptor (IL-23R) gene protects against

pediatric Crohn's disease. Inflamm Bowel Dis. 2007 Feb 16; [Epub

ahead of print] PMID: 17309073.

Peyrin-Biroulet L, Parmentier-Decrucq E, Branche J, Desreumaux P. IL-

23R, a novel susceptibility gene for inflammatory bowel disease.

Med Sci (Paris). 2007 Mar;23(3):250-252. PMID: 17349281.

Van Limbergen JE, RK, Nimmo ER, Drummond HE, L,

NH, Davies G, Gillett PM, McGrogan P, Hassan K, Weaver LT,

Bisset MW, Mahdi G, DC, Satsangi J. IL23R Arg381Gln is

associated with childhood onset inflammatory bowel disease in

Scotland. Gut. 2007 Mar 2; [Epub ahead of print] PMID: 17337463.

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. A large-scale genetic association study

confirms IL12B and leads to the identification of IL23R as psoriasis-

risk genes. Am J Hum Genet. 2007 Feb;80(2):273-90. PMID: 17236132.

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 Dec 1;314(5804):1461-3. PMID: 17068223.

Things are moving very rapidly in the autoimmune/autoinflammatory

disease genetics field, and I hope this progress is soon extended to

PSC.

Best regards,

Dave

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