Psoriasis is a member of a class of common, HLA associated diseases of presumed immunopathogenesis. Disease susceptibility appears to be heritable in many of these conditions, including psoriasis, insulin- dependent diabetes mellitus, rheumatoid arthritic, the spondyloarthropathies, lupus erythematosus, multiple sclerosis, pemphigus vulgaris, and celiac disease/dermatitis herpetiformis. However, the mode of inheritance in psoriasis and these other diseases has been difficult to define in simple Mendelian terms, and it has been in general difficult to demonstrate that these associations are due to tight monogenic linkage to the implicated HLA susceptibility alleles on chromosome 6p21.3. Although the role of environmental factors in this class of diseases cannot be defined, the participation of additional genes, not necessarily linked to HLA, has long been suspected. The recent development of highly polymorphic, PCR-based microsatellite markers and their systematic mapping to the human genome how allows a systematic search for these additional genetic determinants of disease to be undertaken. As one of the most common, most heritable, and most highly HLA-associated examples of this class of diseases, psoriasis represents an ideal target for the application of this emerging genetic technology. Moreover, answers gained from the study of psoriasis by these methods may prove applicable to this entire class of diseases. On the basis of epidemiologic data and the pattern of inheritance in psoriatic kindreds, we hypothesize that in addition to an HLA or tightly linked gene, only one additional major gene determines psoriasis susceptibility. To test this hypothesis, we propose the following specific aims: (1) To complete the identification of extended kindreds in which psoriasis is segregating, with probands selected on the basis of juvenile onset of disease, to clinically evaluate these probands and their family members for the presence of psoriasis, and to collect blood for EBV immortalization and DNA isolation. (2) To genotype these kindreds for approximately 400 PCR-based microsatellite markers, scanning the genome at an interval of approximately 7.5 cM, and to type these individuals for HLA Class I and Class II antigens by serological and DNA-based methods, respectively. (3) To test the marker data obtained in Specific Aim 2 for evidence of linkage to psoriasis by lod score, sib pair and affected pedigree member (APM) methods, including the investigation of the effects of assumed mode of inheritance, sporadic cases, imprinting, and variable age of onset. (4) To further test candidate loci identified in Specific Aim 3 for evidence of two-locus involvement, utilizing i) a two-trait-locus epistasis linkage model, and/or (ii) a two-trait-locus lod score method for multilocus involvement.
Showing the most recent 10 out of 65 publications
