1. ¹Celera, 1401 Harbor Bay Parkway, Alameda, CA, USA
2. ²Department of Human Genetics, University of Utah, Salt Lake City, UT, USA
3. ³LineaGen Research Corporation, Salt Lake City, UT, USA
4. ⁴Department of Dermatology University of Utah, Salt Lake City, UT, USA

Correspondence: Dr SJ Schrodi, Celera, 1401 Harbor Bay Parkway, Alameda 94502, USA. E-mail: steven.schrodi@celera.com

Received 9 April 2008; Revised 14 May 2008; Accepted 18 June 2008; Published online 24 July 2008.

Abstract

Using a multi-tiered, case–control association design, scanning 25 215 gene-centric SNPs, we previously identified two psoriasis susceptibility genes: IL12B and IL23R. These results have recently been confirmed. To better characterize the IL23R psoriasis-association, we used a fine mapping strategy to identify 59 additional IL23R-linked SNPs, which were genotyped in our three independent, white North American sample sets (>2800 individuals in toto). A sliding window of haplotype association demonstrates colocalization of psoriasis susceptibility effects within the boundaries of IL23R across all sample sets, thereby decreasing the likelihood that neighboring genes, particularly IL12RB2, are driving the association at this region. Additional haplotype work identified two 5-SNP haplotypes with strong protective effects, consistent across our three sample sets (OR_common=0.67; P_comb=4.32E-07). Importantly, heterogeneity of effect was extremely low between sample sets for these haplotypes (P_Het=0.961). Together, these protective haplotypes attain a frequency of 16% in controls, declining to 11% in cases. The characterization of association patterns within IL23R to specific predisposing/protective variants will play an important role in the elucidation of psoriasis etiology and other related phenotypes. Further, this work is essential to lay the foundation for the role of IL23R genetics in response to pharmaceutical therapy and dosage.