To study the association of single nucleotide polymorphisms (SNPs) of the TNF-α promoter and IL12B/IL23R genes with the response to anti-TNF-α in patients with psoriasis.
This meta-analysis showed that the IL-23 R (rs11209026 and rs7530511) polymorphisms are associated with psoriasis risk in Europeans and that the IL-12B (rs6887695 and rs3212227) polymorphisms are associated with susceptibility to psoriasis in Europeans.
We identified seven susceptibility loci outside the human leukocyte antigen region (9p24 near JAK2, 10q22 at ZMIZ1, 11q13 near PRDX5, 16p13 near SOCS1, 17q21 at STAT3, 19p13 near FUT2, and 22q11 at YDJC) shared between PS and CD with genome-wide significance (p < 5 × 10(-8)) and confirmed four already established PS and CD risk loci (IL23R, IL12B, REL, and TYK2).
The risk increased some 26-fold in individuals with risk alleles in both MHC and LCE as compared with those without risk alleles, and individual carrying risk alleles of MHC and IL12B has around 36-fold higher risk of psoriasis than those with protective alleles.
Recently, the results of multiple well-powered genome-wide association studies have identified several additional loci outside the major histocompatibility complex region associated with psoriasis risk, including three genes involved in interleukin (IL)-23 signaling (IL-23R, IL-23A, IL-12B), two genes that regulate nuclear factor-kappaB signaling (TNIP1, TNFAIP3), and two genes involved in the modulation of T-helper type 2 immune responses (IL-4, IL-13).
These results showed that IL12B is an important genetic factor in psoriasis pathogenesis in the Thai population, with an association strong enough to yield significant confirmatory evidence using a modest sample size.
Our study confirms the effects of IL-12B and IL-23R variants on psoriasis in East Asian populations, and provides a reference point for further investigation of the role of the IL-12/IL-23 pathway in chronic epithelial inflammation in Asian and other ethnic populations.
Variants in or near genes that encode subunits of cytokines (IL12B, IL23A) or cytokine receptors (IL23R) are interesting given that the gene product of IL12B, p40, is the target of a recently approved monoclonal antibody therapy for psoriasis (ustekinumab).
Four variants of the IL12B and IL23R genes were analyzed in 1,114 PV patients, 748 patients with psoriatic arthritis (PA) and 937 healthy controls before and after stratification for the major psoriasis risk allele at psoriasis susceptibility locus 1 (PSORS1).
Predisposition to psoriasis is known to be affected by genetic variation in HLA-C, IL12B, and IL23R, and although other psoriasis-associated variants have been identified, incontrovertible statistical evidence for these markers has not yet been obtained.
Using a multi-tiered, case-control association design, scanning 25 215 gene-centric SNPs, we previously identified two psoriasis susceptibility genes: IL12B and IL23R.
Our results confirm associations between IL12B and IL23R and psoriasis in Caucasians, and provide a genetic basis for the clinical association between psoriasis and Crohn's disease.