Sequence Variants in the Genes for the Interleukin-23 Receptor (IL23R) and Its Ligand (IL12B) Confer Protection Against Psoriasis

Overview

Journal Hum Genet

Specialty Genetics

Date 2007 Jun 26

PMID 17587057

Citations 150

Authors

Francesca Capon

Paola Di Meglio

Joanna Szaub

Natalie J Prescott

Christina Dunster

Laura Baumber

Kirsten Timms

Alexander Gutin

Victor Abkevic

A David Burden

Jerry Lanchbury

Jonathan N Barker

Richard C Trembath

Frank O Nestle

Affiliations

Soon will be listed here.

Abstract

Psoriasis is an inflammatory skin disorder that is inherited as a multifactorial trait. Genetic analyses have repeatedly identified a primary disease susceptibility locus lying within the major histocompatibility complex (MHC), on chromosome 6p21. A small number of non-MHC susceptibility loci have also been identified. These regions tend to overlap with susceptibility intervals for Crohn's disease and atopic dermatitis, suggesting the possibility that genetic variants affecting inflammatory pathways may contribute to the pathogenesis of multiple disorders. Here, we report a genetic analysis of the interleukin 23 receptor gene (IL23R), which was recently identified as a susceptibility determinant for Crohn's disease. We initially examined the results of a whole-genome association scan, carried out on 318 cases and 288 controls. We observed a significant increase of a non-synonymous substitution (p.Arg381Gln) among controls (P = 0.00036). We validated this finding by extending our cohort to include a further 519 cases and 528 controls. In the overall sample, the frequency of the 381Gln allele was 3.6% in cases and 7% in controls, yielding a P value of 0.00014. Next, we examined genetic variation at the IL12RB1, IL23A and IL12B genes, respectively, encoding the second subunit of the IL23R receptor and the two subunits of its ligand. This analysis identified independent associations for IL12B SNPs rs10045431 (P value for the extended dataset = 0.0001) and rs3212227 (P = 0.036). Altogether, these findings indicate that genes participating in IL23 signalling play a significant role in the pathogenesis of chronic epithelial inflammation.

Citing Articles

Psoriasis and inflammatory bowel disease: concomitant IMID or paradoxical therapeutic effect? A scoping review on anti-IL-12/23 and anti-IL-23 antibodies.

Bezzio C, Cavalli C, Franchellucci G, Dal Buono A, Gabbiadini R, Scalvini D Therap Adv Gastroenterol. 2024; 17:17562848241299564.

PMID: 39575159 PMC: 11580083. DOI: 10.1177/17562848241299564.

Shared Pathophysiology of Inflammatory Bowel Disease and Psoriasis: Unraveling the Connection.

Jauregui W, Abarca Y, Ahmadi Y, Menon V, Zumarraga D, Rojas Gomez M Cureus. 2024; 16(9):e68569.

PMID: 39364475 PMC: 11449469. DOI: 10.7759/cureus.68569.

Exploring shared mechanisms between ulcerative colitis and psoriasis and predicting therapeutic natural compounds through bioinformatics and molecular docking.

Yang Y, Gong Z, Yang J, Cai Y, Hong S, Mao W Heliyon. 2024; 10(18):e37624.

PMID: 39309918 PMC: 11416260. DOI: 10.1016/j.heliyon.2024.e37624.

An Insight on the Possible Association between Inflammatory Bowel Disease and Biologic Therapy with IL-17 Inhibitors in Psoriasis Patients.

Orzan O, Tieranu C, Olteanu A, Dorobantu A, Cojocaru A, Mihai M Pharmaceutics. 2023; 15(8).

PMID: 37631384 PMC: 10458821. DOI: 10.3390/pharmaceutics15082171.

Human NCF1 Variant Promotes IL-23/IL-17-Dependent Mannan-Induced Psoriasis and Psoriatic Arthritis.

Li Y, Li Z, Nandakumar K, Holmdahl R Antioxidants (Basel). 2023; 12(7).

PMID: 37507888 PMC: 10376330. DOI: 10.3390/antiox12071348.

References

Nickoloff B, Nestle F . Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities. J Clin Invest. 2004; 113(12):1664-75. PMC: 420513. DOI: 10.1172/JCI22147. View

Steer S, Abkevich V, Gutin A, Cordell H, Gendall K, Merriman M . Genomic DNA pooling for whole-genome association scans in complex disease: empirical demonstration of efficacy in rheumatoid arthritis. Genes Immun. 2006; 8(1):57-68. DOI: 10.1038/sj.gene.6364359. View

Duerr R, Taylor K, Brant S, Rioux J, Silverberg M, Daly M . A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006; 314(5804):1461-3. PMC: 4410764. DOI: 10.1126/science.1135245. View

Trembath R, Clough R, Rosbotham J, Jones A, Camp R, Frodsham A . Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis. Hum Mol Genet. 1997; 6(5):813-20. DOI: 10.1093/hmg/6.5.813. View

Stuart P, Nair R, Abecasis G, Nistor I, Hiremagalore R, Chia N . Analysis of RUNX1 binding site and RAPTOR polymorphisms in psoriasis: no evidence for association despite adequate power and evidence for linkage. J Med Genet. 2005; 43(1):12-7. PMC: 2564497. DOI: 10.1136/jmg.2005.032193. View

Dudbridge F . Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol. 2003; 25(2):115-21. DOI: 10.1002/gepi.10252. View

Cookson W, Ubhi B, Lawrence R, Abecasis G, Walley A, Cox H . Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci. Nat Genet. 2001; 27(4):372-3. DOI: 10.1038/86867. View

Ueda H, Howson J, Esposito L, Heward J, Snook H, Chamberlain G . Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature. 2003; 423(6939):506-11. DOI: 10.1038/nature01621. View

Weedon M, McCarthy M, Hitman G, Walker M, Groves C, Zeggini E . Combining information from common type 2 diabetes risk polymorphisms improves disease prediction. PLoS Med. 2006; 3(10):e374. PMC: 1584415. DOI: 10.1371/journal.pmed.0030374. View

10.

Cargill M, Schrodi S, Chang M, Garcia V, Brandon R, Callis K . A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet. 2007; 80(2):273-90. PMC: 1785338. DOI: 10.1086/511051. View

11.

Huffmeier U, Traupe H, Burkhardt H, Schurmeier-Horst F, Lascorz J, Bohm B . Lack of evidence for genetic association to RUNX1 binding site at PSORS2 in different German psoriasis cohorts. J Invest Dermatol. 2005; 124(1):107-10. DOI: 10.1111/j.0022-202X.2004.23571.x. View

12.

Capon F, Trembath R, Barker J . An update on the genetics of psoriasis. Dermatol Clin. 2004; 22(4):339-47, vii. DOI: 10.1016/S0733-8635(03)00125-6. View

13.

Lee Y, Ruschendorf F, Windemuth C, Schmitt-Egenolf M, Stadelmann A, Nurnberg G . Genomewide scan in german families reveals evidence for a novel psoriasis-susceptibility locus on chromosome 19p13. Am J Hum Genet. 2000; 67(4):1020-4. PMC: 1287873. DOI: 10.1086/303075. View

14.

Helms C, Cao L, Krueger J, Wijsman E, Chamian F, Gordon D . A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis. Nat Genet. 2003; 35(4):349-56. DOI: 10.1038/ng1268. View

15.

Kastelein R, Hunter C, Cua D . Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol. 2007; 25:221-42. DOI: 10.1146/annurev.immunol.22.012703.104758. View

16.

Kikly K, Liu L, Na S, Sedgwick J . The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation. Curr Opin Immunol. 2006; 18(6):670-5. DOI: 10.1016/j.coi.2006.09.008. View

17.

Power C, Elliott J . Cohort profile: 1958 British birth cohort (National Child Development Study). Int J Epidemiol. 2005; 35(1):34-41. DOI: 10.1093/ije/dyi183. View

18.

Bottini N, Vang T, Cucca F, Mustelin T . Role of PTPN22 in type 1 diabetes and other autoimmune diseases. Semin Immunol. 2006; 18(4):207-13. DOI: 10.1016/j.smim.2006.03.008. View

19.

Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J . A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol. 2002; 168(11):5699-708. DOI: 10.4049/jimmunol.168.11.5699. View

20.

Capon F, Helms C, Veal C, Tillman D, Burden A, Barker J . Genetic analysis of PSORS2 markers in a UK dataset supports the association between RAPTOR SNPs and familial psoriasis. J Med Genet. 2004; 41(6):459-60. PMC: 1735814. DOI: 10.1136/jmg.2004.018226. View