Using a multi-tiered, case-control association design, scanning over 25,000 gene-centric SNPs, we recently identified two psoriasis susceptibility genes: IL12B and IL23R (Cargill et al, 2007). One of the IL23R missense SNPs implicated in psoriasis has also been strongly associated with predisposition to inflammatory bowel disease (Duerr et al, 2006; Van Limbergen et al, 2007; Rioux et al, 2007; Libioulle et al, 2007; Dubinsky et al, 2007). To refine our initial association results and further investigate the region involved in psoriasis risk, we extended our genetic analysis by resequencing this gene in 96 psoriatic individuals. Twelve novel IL23R SNPs were discovered including one missense, two synonymous and three 3’ UTR SNPs. Using a series of selection criteria, we identified 58 additional IL23R–linked SNPs which were genotyped in our three independent, white North American sample sets (>2800 individuals in toto). Single marker and preliminary haplotype analyses have been performed on the full set of interrogated SNPs. A sliding window of haplotype association demonstrates co-localization of psoriasis susceptibility within the boundaries of IL23R across all sample sets, thereby decreasing the likelihood that neighboring genes, particularly IL12RB2 which lies directly adjacent to IL23R, are driving the association of this region with psoriasis. The refinement of disease association patterns within IL23R to specific predisposing and protective genetic variants will play an important role in the elucidation of the causes of psoriasis and possibly additional autoimmune phenotypes as well as the role of IL23R genetic variants in response to therapy and dosage.
Available at: http://works.bepress.com/steve_schrodi/24/