Genetics of psoriasis and psoriatic arthritis

Rajan Nair, PhD, and James T. Elder, MD PhD

Susceptibility to psoriasis is multifactorial, meaning that multiple genes and environmental factors are responsible for its development. Most Caucasian psoriatics carry a major gene (PSORS1) residing in the MHC Class I region. In order to identify the PSORS1 disease allele, Dr. Elder's laboratory has been making use of recombinant ancestral haplotype mapping and comparative DNA sequencing of risk- and non-risk haplotypes. Over the past four years, his laboratory has cloned and sequenced a 300,000 bp critical stretch of the MHC Class I region, extending from HLA-B to corneodesmosin and containing ten genes, in a panel of 2 disease-allele-bearing chromosomes and five normal chromosomes. Their analysis indicates that only two of these genes manifest coding sequence differences that are unique to the disease chromosomes. These genes are currently undergoing extensive genotyping in a panel of over 2,500 subjects.

Importantly, only about 10% of individuals who inherit the PSORS1 disease allele actually get psoriasis. This implies that other genes must also be important for the development of psoriasis. Two regions, on chromosomes 16 and 17, have attracted particular interest because they have been linked to psoriasis and/or psoriatic arthritis by more than one laboratory independently. Dr. Elder's team has initiated a comprehensive strategy for screening every gene in each of these two intervals for association with psoriasis in 2,000 cases and 1,000 controls to be collected over the next 3 years, as well as in 561 families already in hand (Familial Psoriasis Study).

Psoriatic arthritis is a potentially-crippling joint disease found in 10 to 40% of psoriasis patients. Its severity and exact clinical manifestations vary from patient to patient, suggesting again that multiple genes are involved leading to variations in severity and clinical presentation. Dr. Elder's team has also begun a large genetic study of psoriatic arthritis, which will rely on cases and controls rather than families. This is possible because advances in technology are allowing the identification and screening of common variants in each of our 30,000 genes. (These projects are funded by the National Institutes of Health.)

Future plans for the psoriasis genetics laboratory include a whole genome association analysis of psoriasis and a genome-wide association analysis of gene expression in psoriasis. Initiation of these projects awaits NIH approval of funding.

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