1. ¹School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, UK
2. ²Public Health Genetics Unit, Wort's Causeway, Cambridge, UK

Correspondence: Dr R Tazi-Ahnini, School of Medicine and Biomedical Sciences, University of Sheffield, Beach Hill Road, Sheffield S10 2RX, UK. Tel: +44 1142 713 785; Fax: +44 1142 711 711; E-mail: r.taziahnini@sheffield.ac.uk

³Current address: Institute of Immunology, Biomedical Sciences Research Center 'Al. Fleming', Vari, Greece

⁴These authors have contributed equally to this work.

Received 9 July 2007; Revised 22 January 2008; Accepted 5 February 2008; Published online 26 March 2008.

Abstract

Family-based analysis has revealed several loci for psoriasis and the locus, PSORS5, on chromosome 3q21 has been found in two independent studies. In this region, cystatin A (CSTA) encodes a skin barrier cystein protease inhibitor found in human sweat and it is over-expressed in psoriatic skin. Three CSTA markers at positions –190 (g.-190T>C), +162 (c.162T>C) and +344 (c.344C>T) were analysed in 107 unrelated patients and 216 matched controls. There was a significant trend for association with CSTA c.162T>C and psoriasis (odds ratio (OR)=3.45, P<0.001). Analysis of constructed haplotypes showed a highly significant association between disease and CSTA –190T/+162C/+344C (CSTA TCC) (P=10^-6). In independent study, a TDT analysis in 126 nuclear families confirmed the over-transmission of CSTA TCC (P=0.0001). The presence of statistical interaction between CSTA TCC haplotype and HLA-Cw6 at PSORS1 locus was detected by performing TDT analysis on CSTA haplotypes stratified by the presence or absence of the risk allele at HLA-Cw6 locus. To estimate the disease risk we employed conditional logistic regression on the family data. The CSTA TCC haplotype is only associated with psoriasis in those individuals carrying the risk allele at the HLA-Cw6 locus (OR=2.22, P=0.0004, 95% CI= 1.42, 3.49). These results represent a major step towards the dissection of genetic factors involved in the pathogenesis of psoriasis.