Identifying a gene for psoriasis on chromosome 6 (<i>Psors1</i>)
Authors: A.D. Burden
Journal: British Journal of Dermatology (2000)

The genetic nature of psoriasis has been apparent to generations of clinical dermatologists, who have noticed that it clusters in some families, but that the mode of inheritance does not follow Mendelian patterns. The heritability of psoriasis (i.e. the amount of phenotypic variability due to genetic factors) has been estimated to be about 80% based on twin studies.1 Over the past 6 years, at least eight independent genome wide scans have been performed to identify the chromosomal location of the genes that determine susceptibility to psoriasis. Using linkage techniques in psoriasis families, statistical evidence has been obtained for chromosomes 6p,2-4 17q,3, 5 4q,6 1q,7 and 3q.8 These loci are now designated Psors1, Psors2, Psors3, Psors4 and Psors5, respectively. Lesser degrees of statistical support have been produced for loci on chromosomes 1p, 2q, 8q, 16q, 19p and 20p.2, 3 It is now clear that Psors1 on chromosome 6p21.3 is a major locus for psoriasis susceptibility in many populations. Much activity is now being directed at identifying the psoriasis gene(s) at this site. The region over which genetic linkage extends is large, covering much of the major histocompatability complex (MHC). Classical linkage analysis (in which families are studied for cosegregation of a trait and a genetic marker) is a relatively blunt tool to refine the exact position of the gene within the MHC, as linkage can extend over several megabases of DNA on each side of the gene. Genetic association between a marker and a trait in a population is generally only detectable over shorter distances and can therefore been used to fine map a locus.9 Association between chronic plaque psoriasis and HLA antigens was first described in 197210, 11 and since then, many phenotypes at HLA-A, -B, -C, DRB1, -DQA1 and -DQB1 loci have been associated with psoriasis. Haplotype analysis places the psoriasis locus nearer the class I end of the MHC telomeric to HLA-B12 and, when the region is fine mapped by association analysis, the peak of the association is telomeric to HLA-C (Fig. 1).13 There is evidence, also from analysis of haplotypes, that classical HLA loci are not themselves psoriasis genes but, by virtue of their position, are in strong linkage disequilibrium with a non-HLA susceptibility locus.12 Other genes in this region are therefore under study. Within the last 6 months, the first complete sequence and gene map of a human MHC has been described.14 Two hundred and twenty-four gene loci are coded, many of unknown function, and it is estimated that about 40% of the expressed genes are involved in the immune system. Many of these genes are therefore potential candidates as psoriasis susceptibility genes both on the basis of their chromosomal position and their function. One such gene is MICA, which has previously been found to be associated with psoriasis15 and psoriatic arthritis16 in caucasian populations. In this issue of the journal, Cheng et al. report a population association between chronic plaque psoriasis and a polymorphism in the MICA gene in a Chinese population.17 Two hundred and four of 300 (68%) subjects with plaque psoriasis carried an A5·1 allele of the MICA gene, compared with 76 of a control population of 200 (38%), giving an odds ratio of 3·47. MICA (MHC Class I Chain-related gene A) is a member of a new family of distant relatives of the class I HLA genes first described in 1994.18 It is located 46 kb towards the centromere from HLA-B and encodes a 383 amino acid cell surface protein. In contrast with classical class I genes, MICA is not induced by interferon γ but it is expressed on virus infected cells and tumour cells.19 Recently NKG2D has been identified as a receptor for MICA present on γδ T lymphocytes, CD8+ve αβ T cells and NK cells.20 The biological function of MICA is not yet established but it is speculated that it is a marker of cellular distress, targeting a cell for destruction by NK cells or cytotoxic T cells. This may be relevant to some of the models of the immunopathogenesis of psoriasis that have recently been proposed.21 It is equally plausible that the HLA-associated psoriasis gene is not involved in immunoregulation. For instance, two groups have reported an association in caucasian populations between psoriasis and polymorphisms in the S gene. This gene, located 140 kilobases telomeric of HLA-C, encodes corneodesmosin, an epidermal adhesion protein.22, 23 An example of another HLA-associated disease for which the HLA-associated gene proved not be concerned in immunoregulation is hereditary haemochromatosis. The gene (HFE) is involved in iron transport.24 It is also a cautionary tale for those trying to locate Psors1 – when HFE was identified, it was found to lie more than three megabases telomeric of the initially linked loci and completely outside the HLA region. If MICA were a susceptibility locus for psoriasis, the genetic association would be expected to exist in every population. However, because of extensive linkage disequilibrium in this region of the genome, it has been demonstrated that there are five ‘frozen blocks’ in which recombination rarely occurs, resulting in stable ancestral haplotypes.25 One of these blocks spans the region from centromeric of MICA to telomeric of the S gene. This makes it difficult to determine the contribution of any one particular gene within the region to the aetiology of psoriasis. The study of diverse ethnic groups in which ancestral recombination events have generated different disease-associated ancestral haplotypes may shed some light upon the role of MICA. There are data that suggest that the HLA associations with psoriasis may differ between Chinese and caucasian populations.26 It is now important to determine the haplotypes across the HLA region of which the MICA alleles reported by Cheng et al. form a part in this Chinese population. The molecular genetic basis of psoriasis is expected to be complex. Multiple loci are likely to be involved and data have already been published suggesting an interaction (epistasis) between Psors1 and loci on chromosome 1 and 20.27, 28 Nevertheless, it has been estimated that the proportion of genetic susceptibility to psoriasis attributable to Psors1 in a British population is about 30%2, 4 and the identification of this gene will be a major and long-awaited advance in our understanding of the pathogenesis of psoriasis.