Cytogenetic analysis of 477 psoriatics revealed an increased frequency of aberrations involving chromosome region 11q.

Psoriasis is an inflammatory skin disorder affecting approximately 3% of the population. Genetic studies published so far have shown a complex genetic inheritance with heterogeneity and a putative major susceptibility locus in the HLA region on chromosome 6. We have collected a large amount of material consisting mostly of small nuclear families in order to perform a genome-wide scan for psoriasis-associated genes. In order to focus the scan properly on possible candidate regions, we performed a cytogenetic analysis of 477 unrelated psoriatics. We divided our findings into sporadic, affecting a minor fraction of the cells, and constitutional, i.e. they were present in all cells examined. We found three cases of balanced translocation, all of which involved chromosome 11q. Two of these had a breakpoint in q12-13, whilst one involved the telomeric part of chromosome 11q. In order to characterise further the breakpoint on 11q12-13, we used bacterial artificial chromosomes (BACs) analysed by fluorescent in situ hybridisation (FISH). We were able to show that the persons had a close, but not identical breakpoints; they were separated by at least 5 cM. The major atopy locus is located in this region, as well as a locus for insulin-dependent diabetes mellitus, both being conditions with a pathogenetic mechanism involving antigen presentation.

Psoriasis susceptibility locus in chromosome region 3q21 identified in patients from southwest Sweden.

We have performed a pair-wise linkage study in the search for psoriasis susceptibility regions. A preliminary scan was performed on 20 families. In this set we obtained indications of linkage on chromosome 3q21. This region was further investigated using material from a total of 104 families (set 1B) resulting in a non-parametric linkage (NPL) of 1.77. The material was stratified in families whose parental origin is in southwest Sweden (set 1C). A maximum NPL value of 2.77 was obtained in this group. A transmission disequilibrium test (TDT) was performed on the stratified material (set 1C) and a significant P value of 0.005 was obtained, at marker D3S1269. The locus was confirmed with TDT in replicate material consisting of 148 families in which a single member was affected (P value 0.0007) at marker D3S1551. Thus, we have observed a significant P value using TDT in the vicinity of markers D3S1269/D3S1551, suggesting a novel psoriasis susceptibility region.

A genome-wide search for genes predisposing to familial psoriasis by using a stratification approach.

We have performed a genome scan, using markers spaced by 10 cM, in the search for psoriasis-susceptibility loci. The family material of 134 affected sibling pairs was ascertained on the basis of a population genetic study in which 65% of the probands had two healthy parents. Genotyping results were analyzed for non-random excessive allele-sharing between sib pairs by using GENEHUNTER ver 1.1. A stratification approach was applied to increase the homogeneity of the material by means of an operational definition of joint complaints among affected individuals. Significant linkage to the human leukocyte antigen region on chromosome 6p in a cohort including 42 families without joint complaints (nonparametric linkage score of 2.83, P=0.002) strongly supported the validity of this operational definition as it replicated results from an earlier linkage report with similar stratification criteria. New candidate regions on chromosomes 3 and 15 were identified. The highest non-parametric linkage values in this study, 2.96 (P=0.0017) and 2.89 (P=0.0020), were reached on chromosome 15 in a subgroup with joint complaints and on chromosome 3 in a subgroup without joint complaints. In addition, confirmation of previously reported loci was established on chromosomes 4q, 6p, and 17q. This study indicates that distinct disease loci might be involved in psoriasis etiology for various phenotypes.

Analysis of three suggested psoriasis susceptibility loci in a large Swedish set of families: confirmation of linkage to chromosome 6p (HLA region), and to 17q, but not to 4q.

Psoriasis is known to be a heterogeneous disease with so far three reported major psoriasis susceptibility loci on chromosome 4q, 6p and 17q. In this study we investigated three reported gene locations by nonparametric and parametric linkage analysis in a large family set consisting of 104 families (153 sib pairs) from Sweden. We could confirm linkage to chromosome 6p. A maximum heterogeneous lod score of 2.78 was reached at locus D6S276 (alpha = 0.60). Allelic association studies within the HLA region indicated linkage disequilibrium at locus TNFbeta with a significant p value of 0.0009. Furthermore, we obtained weak evidence of linkage to the locus on chromosome 17q while no evidence of linkage could be found to the chromosome 4q region.