Psoriasis 11, Susceptibility To

For a phenotypic description and a discussion of genetic heterogeneity of psoriasis, see PSORS1 (177900).

Mapping

Cargill et al. (2007) performed a case-control association study of psoriasis in 3 independent sample sets of white North American individuals using 25,215 gene-centric single-nucleotide polymorphisms (SNPs). They found a highly significant association with a SNP in the 3-prime untranslated region of the IL12B gene (161561) on chromosome 5q31-33, confirming the results of a small Japanese study (Tsunemi et al., 2002). Since IL12B encodes the common IL12 p40 subunit of IL12 and IL23, Cargill et al. (2007) individually genotyped 17 SNPs in the genes encoding the other chains of these cytokines, IL12A (161560) and IL23A (605580), and their receptors: IL12RB1 (601604), IL12RB2 (601642), and IL23R (607562). Haplotype analyses identified 2 IL23R missense SNPs that together marked a common psoriasis-associated haplotype in all 3 studies. Individuals homozygous for both the IL12B and the IL23R predisposing haplotypes had increased risk of disease. IL23R maps to chromosome 1p31 (see PSORS7; 605606). These data, and the observation that administration of an antibody specific for the IL12 p40 subunit to patients with psoriasis is highly efficacious (Kauffman et al., 2004), suggested that these genes play a fundamental role in psoriasis pathogenesis.

In 2 samples of psoriasis patients, Capon et al. (2007) observed an association between the disease and 2 SNPs upstream of the IL12B coding region. One (rs7709212) offered protection against the disease (odds ratio of 0.76; p = 0.006) and the other (rs10045431) conferred increased risk (odds ratio of 1.41; p = 0.0001).

In a genomewide association study of 1,139 patients with psoriasis and 1,132 controls of Chinese Han ancestry, Zhang et al. (2009) confirmed an association between psoriasis and the IL12B SNP rs7709212 (p = 2.03 x 10(-6)). The findings were replicated in 2 independent samples of 5,182 cases and 6,516 controls of Chinese Han ancestry, and 539 cases and 824 controls of Chinese Uygur ancestry, respectively, yielding a combined p value of 1.12 x 10(-20). A second IL12B SNP, rs3213094, also showed significant associations (p = 3.39 x 10(-6); combined p = 2.58 x 10(-26)). Zhang et al. (2009) noted that signals at the 2 SNPs are not independent as they are in linkage disequilibrium.

In a genomewide association study of 1,359 patients with psoriasis and 1,400 controls, Nair et al. (2009) found a significant association between psoriasis and the IL12B SNP rs2082412 (p = 5 x 10(-10)). The findings were replicated in an additional 5,048 cases and 5,051 controls, yielding a combined p value of 2 x 10(-28). The G allele conferred an odds ratio of 1.44. Two other SNPs in the chromosome 5q31-q33 region also showed significant associations with psoriasis in this study: rs17728338 upstream of the TNIP1 gene (607714) and rs20541 in the IL13 gene (147683), yielding combined p values of 1 x 10(-20) and 5 x 10(-15), respectively. Nair et al. (2009) noted that all 3 genes play a role in inflammatory processes.

Huffmeier et al. (2009) analyzed 4 variants in the IL12B and IL23R gene in 748 patients with psoriatic arthritis (see 607507), 1,114 patients with psoriasis, and 937 controls. The strongest associations in both disease groups were found with IL12B variants rs3212227 and rs6887695 (p values ranging between 2.10 x 10(-5) and 9.67 x 10(-7) with corresponding odds ratios of 1.43 to 1.50). The IL12B risk haplotype also showed an association in both groups (p value on the order of 10(-6)). The effect for rs11209026 in the IL23R gene was slightly weaker for psoriasis (p = 2.42 x 10(-6)) and psoriatic arthritis (p = 0.002). The findings confirmed previous studies that variants in the IL12B and IL23R genes are susceptibility factors for psoriasis, and extended the findings to psoriatic arthritis.