Psoriasis is a common chronic inflammatory disorder of the skin. To further understand the pathogenesis of psoriasis we have chosen to investigate the molecular genetic basis of the disorder. We have used a two-stage approach to search the human genome for the location of genes conferring susceptibility to psoriasis, using a total of 106 affected sibling pairs identified from 68 independent families. As over a third of the extended kindreds included affected relatives besides siblings, in addition to an analysis of allele sharing between affected sibling pairs, a novel linkage strategy was applied that extracts full non-parametric information. Four principal regions of possible linkage were identified on chromosomes 2, 8, 20 (p <0.005) and markers from the MHC region at 6p21 (p <0.0000006) for which significant evidence of linkage disequilibrium was also observed (p <0.00002). Whilst data from limited case control associations exist to implicate the MHC, the results of this genome wide analysis demonstrate that, at least in the population studied, a gene or genes located within the MHC and close to the class 1 HLA loci, represent the major determinant of the genetic basis of psoriasis.
Mutation rates at two expanded simple tandem repeat loci were studied in the germ line of first-and second-generation offspring of inbred male CBA͞H, C57BL͞6, and BALB͞c mice exposed to either high linear energy transfer fission neutrons or low linear energy transfer x-rays. Paternal CBA͞H exposure to either x-rays or fission neutrons resulted in increased mutation rates in the germ line of two subsequent generations. Comparable transgenerational effects were observed also in neutron-irradiated C57BL͞6 and xirradiated BALB͞c mice. The levels of spontaneous mutation rates and radiation-induced transgenerational instability varied between strains (BALB͞c>CBA͞H>C57BL͞6). Pre-and postmeiotic paternal exposure resulted in similar increases in mutation rate in the germ line of both generations of CBA͞H mice, which together with our previous results suggests that radiation-induced expanded simple tandem repeat instability is manifested in diploid cells after fertilization. The remarkable finding that radiationinduced germ-line instability persists for at least two generations raises important issues of risk evaluation in humans.
The pathogenesis of all forms of psoriasis remains obscure. Segregation analysis and twin studies together with ethnic diVerences in disease frequency all point to an underlying genetic susceptibility to psoriasis, which is both complex and likely to reflect the action of a number of genes. We performed a genome wide analysis using a total of 271 polymorphic autosomal markers on 284 sib relative pairs identified within 158 independent families. We detected evidence for linkage at 6p21 (PSORS1) with a non-parametric linkage score (NPL)=4.7, p=2 × 10 -6 and at chromosome 1p (NPL=3.6, p=1.9 × 10 -4 ) in all families studied. Significant excess (p=0.004) paternal allele sharing was detected for markers spanning the PSORS1 locus. A further three regions reached NPL scores of 2 or greater, including a region at chromosome 7 (NPL 2.1), for which linkage for a number of autoimmune disorders has been reported. Partitioning of the data set according to allele sharing at 6p21 (PSORS1) favoured linkage to chromosomes 2p (NPL 2.09) and 14q (NPL 2.0), both regions implicated in previous independent genome scans, and suggests evidence for epistasis between PSORS1 and genes at other genomic locations. This study has provided linkage evidence in favour of a novel susceptibility locus for psoriasis and provides evidence of the complex mechanisms underlying the genetic predisposition to this common skin disease. (J Med Genet 2001;38:7-13) Keywords: psoriasis; PSORS1; epistasis Psoriasis is a chronic disfiguring skin disorder characterised by the triad of keratinocyte hyperproliferation, inflammatory infiltration, and vascular dilatation and proliferation.
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