A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes

Abstract

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 approximately 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.

Figure  1.

Results from the Monte Carlo simulation, showing the distribution of the 1,000 most significant combined P values under two null models. The arrow indicates the P value for rs3212227 (3.39×10^-9).

Figure  2.

The physical map of the 360 kb around IL12B on human chromosome 5. Four known genes map to the area: EBF, FLJ31951, UBLCP1, and IL12B. AK097548 is a gene model with one mRNA as supporting evidence. Thirty-one markers spanning this region were genotyped in two independent case-control psoriasis sample sets. These markers included 27 tag SNPs, 1 putative promoter SNP (rs17860508), 2 missense SNPs (rs3213119 and rs3213096), and the original hit, rs3212227. On the basis of a visual examination of the CEU HapMap genotypes, 26 of the markers genotyped in the study map to a loosely defined block of LD. Blocks on either side of this central region were queried using five additional markers.

Figure  3.

Pairwise LD between the 31 IL12B-region SNPs, as measured by r² in the cases and controls of both the discovery and replication 1 sample sets. The indexes of the SNPs (table 4) were arranged vertically from SNP 2 to SNP 31 and horizontally from SNP 1 to SNP 30.

Figure  4.

3-SNP sliding-window analyses of the IL12B-region SNPs