We performed a multi-tiered, case-control association study of psoriasis in three independent, white North American sample sets (1446 cases/1432 controls) with 25,215 gene-centric SNPs and found a highly significant association with an IL12B 3’UTR SNP (rs3212227) confirming the results of a small Japanese study. This SNP was significant in all three sample sets (ORcommon = 0.64, Pcomb = 7.85E-10). A Monte Carlo simulation to address multiple testing suggests 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 genotyped. Haplotypes were estimated and genotype-conditioned analyses identified a second risk allele (rs6887695) located approximately 60kb upstream of the IL12B-coding region that exhibited association with psoriasis after adjusting for rs3212227. Together these two SNPs mark a common IL12B-risk haplotype (ORcommon = 1.40, Pcomb = 8.11E-09) and a less frequent protective haplotype (ORcommon = 0.58, Pcomb = 5.65E-12) that 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, IL23R). Haplotype analyses identified two IL23R missense SNPs that together mark a common psoriasis-associated haplotype in all three studies (ORcommon = 1.44, Pcomb = 3.13E-06). Individuals homozygous for both the IL12B and IL23R predisposing haplotypes are at increased risk for disease (ORcommon = 1.66, Pcomb = 1.33E-08). These data, and the previous observation that administration of an antibody specific for the IL-12p40 subunit to psoriasis patients is highly efficacious, suggest that these genes play a fundamental role in psoriasis pathogenesis.
- Association study,
- Linkage Disequilibrium,
- Psoriasis genetics,
Available at: http://works.bepress.com/steve_schrodi/3/