Association analysis of the skin barrier gene cystatin A at the PSORS5 locus in psoriatic patients: evidence for interaction between PSORS1 and PSORS5

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.À190T4C), þ 162 (c.162T4C) and þ 344 (c.344C4T) were analysed in 107 unrelated patients and 216 matched controls. There was a significant trend for association with CSTA c.162T4C and psoriasis (odds ratio (OR) ¼ 3.45, Po0.001). Analysis of constructed haplotypes showed a highly significant association between disease and CSTA -190T/ þ 162C/ þ 344C (CSTA TCC) (P ¼ 10 À6 ). In independent study, a TDT analysis in 126 nuclear families confirmed the over-transmission of CSTA TCC (P ¼ 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 ¼ 2.22, P ¼ 0.0004, 95% CI ¼ 1.42, 3.49). These results represent a major step towards the dissection of genetic factors involved in the pathogenesis of psoriasis.

Enhanced StefinA and Sprr2 expression during papilloma formation in HPV8 transgenic mice

“…In the human skin, StefinA expression is known to be upregulated in psoriatic lesions, characterized by epidermal hyperproliferation, abnormal keratinocyte differentiation and premature desquamation of the stratum corneum [21]. Recently, Takahashi et al [22] could also demonstrate an antiapoptotic effect of StefinA in cultured normal human keratinocytes.…”

HLA-C, CSTA and DS12346 susceptibility alleles confer over 100-fold increased risk of developing psoriasis: evidence of gene interaction

“…In selecting markers for genotyping, we chose the well-known HLACw6 allele for the PSORS1 locus and CSTA c162T4C for PSORS5, a locus on chromosome 3q21, previously shown to be associated with psoriasis. 9,14 In addition, refinement work for the PSORS4 locus has narrowed down the region to the proximity of the D1S2346 microsatellite marker. 15 We have therefore genotyped seven microsatellite markers on chromosome 1q21, four of which (D1S498, D1S1664, D1S305 and D1S2346) have been previously reported to show linkage to psoriasis.…”

“…For the restriction fragment length polymorphism genotyping of the PSORS1 (HLA-Cw6) locus, genomic DNA was amplified by PCR using the conditions and primers as described previously. 9 PCRs were conducted using fluorescently labelled primers (HEX and FAM dyes) for the microsatellite marker genotyping at PSORS4. Conditions, primers and details for the individual microsatellite markers are listed in Table 1.…”

Toxicology of the Skin

“…The disease tends to follow periods of relapses and remissions that can vary in duration over the course of a lifetime (377). One of the psoriasis gene complexes, on chromosome 6p21.3 is linked to the major histocompatibility complex, but other loci have been associated with genes involved in barrier function (425)(426)(427)(428)(429)(430)(431)(432)(433)(434)(435)(436)458). The risk of developing psoriasis is 4% if no parents are affected, 28% if one parent is affected, and 65% if both the parents have the disease.…”

“…Loci associated with barrier function include the involucrin gene in PSORS4 in Singaporean Chinese with early-onset disease, and cystatin A at the PSORS5 locus (430)(431)(432). These include loci associated with cutaneous barrier function as well as those associated with altered immune function.…”