Haplotype analysis of distantly related populations implicates corneodesmosin in psoriasis susceptibility.

Psoriasis (MIM *177900) is a hyperproliferative skin disorder, characterised by inflammatory cell dermal infiltration, disruption of keratinocyte terminal differentiation, and premature desquamation of the stratum corneum.1 Although the disease pathogenesis is poorly understood, it is well recognised that genetic factors underlie psoriasis susceptibility, as documented by family clustering of the disease and increased concordance rates in monozygotic twin pairs.2,3 To date, genome wide scans have identified seven distinct psoriasis susceptibility regions ( PSORS 1-7 4) and have provided compelling evidence for a major role of the PSORS1 locus on chromosome 6p21.5–9 Linkage disequilibrium (LD) based studies of microsatellite maps have refined the PSORS1 boundaries to a 150 kb interval10–12 harbouring three sets of coding polymorphisms that have repeatedly shown association with psoriasis: HLA-Cw*0602, HCR*269, and CDSN*TTC.13–18 In a recent analysis of a UK family cohort, we have shown that the most common psoriasis susceptibility chromosomes (cluster E) carry HCR*269, CDSN*TTC, and two SNPs (defined as n7 and n9) lying proximal to HLA-C and showing extremely significant disease association. We also observed a rare haplotype (cluster D), marginally over-transmitted to affected patients and likely to have originated from cluster E by a double recombination event, replacing HCR*269 while preserving SNPs 7/9 and CDSN*TTC.19 This observation suggested that CDSN SNPs might be required to confer psoriasis susceptibility, in conjunction with determinants lying in the HLA-C genomic region. CDSN is also a very attractive biological candidate, since corneodesmosin is a desmosomal protein involved in keratinocyte cohesion/desquamation.20–22 With this study, we have sought to validate the hypothesis of CDSN involvement in psoriasis by: (1) confirming that cluster D is a risk haplotype, through the analysis of an independent population, originating from the Gujurat region of northern India; and (2) defining CDSN genetic variation …