U-M scientists ID major psoriasis susceptibility gene
U-M scientists have found a common genetic variation in an immune system gene that makes people much more likely to develop psoriasisa disfiguring inflammatory skin disease.
Named PSORS1 (SORE-ESS-1), for psoriasis susceptibility 1, the gene is the first genetic determinant of psoriasis to be definitively identified in a large clinical study. Its discovery could lead to new, more effective treatments for psoriasis without the risks and side effects of current therapies.
The gene's causative role in psoriasis was demonstrated in a study of 2,723 people from 678 families in which at least one family member had the disease. Results of the studythe most comprehensive analysis of a psoriasis gene to datewill be published in the May 2006 issue of the American Journal of Human Genetics.
Psoriasis is a chronic disease that affects about 2 percent of the U.S. population. People with psoriasis develop thick, flaky white patches on their skin and scalp. The disease is disfiguring and can have a negative effect on quality of life. About 25 percent of people with psoriasis eventually develop psoriatic arthritis, which can be severe.
Unlike diseases caused by a mutation in just one gene, psoriasis is what scientists call a multi-factorial disease. This means that people must inherit several disease-related genes, plus be exposed to one or more environmental triggers, in order to get psoriasis.
"For every individual with psoriasis who carries the PSORS1 gene, there are 10 other people with the gene who don't get psoriasis," says study director Dr. James Elder, professor of dermatology and of radiation oncology in the Medical School and the Ann Arbor VA Healthcare System.
"It's as if you are pushing a shopping cart down the aisle at the grocery store and putting genes in your cart," Elder adds. "There are several different brands of each gene on the shelf and one of them is bad for you. If you pull down enough bad ones, then you can get sick.
"But even if you get all the bad genes, you still need a trigger from the environment to develop the disease," Elder explains.
The PSORS1 gene is actually one of over 20 different varieties (scientists call them alleles) of a gene called HLA-C. "In terms of our grocery store analogy, think of PSORS1 as one of 20 'brands' of HLA-C on the shelf," Elder says.
Located on human chromosome 6, HLA-C is one of several genes in the major histocompatibility complex (MHC) that regulate how the immune system fights off infection. MHC genes carry DNA-coded instructions for proteins whose job it is to distinguish between what belongs in the body and what doesn't.
Scientists have been searching for genes associated with psoriasis for more than 30 years, but until now studies have been inconclusive, according to Rajan Nair, the study's first author and assistant research professor in dermatology.
To determine which of the 11 genes was linked to psoriasis, U-M scientists used a technique called haplotype mapping. Haplotypes are clusters of alleles that tend to be inherited together as a group, because they are located close to each other on the same chromosome.
Now that U-M scientists have identified HLA-Cw6 as being the PSORS1 gene, Elder says scientists can concentrate on finding ways to block its ability to bind to cell surface antigens, which could lead to the development of safer treatments for psoriasis.
The study has been a collaborative effort involving physicians, scientists and patients from dermatology departments at U-M, the University of Kiel in Germany, Detroit's Henry Ford Hospital, and the Ann Arbor VA Healthcare System.
Additional U-M collaborators in the study include Philip Stuart, senior research associate; research fellows Dr. Ioana Nistor, Dr. Ravi Hiremagalore and Dr. Nicholas Chia; Goncalo Abecasis, associate professor of biostatistics, and Dr. John Voorhees, the Duncan O. and Ella M. Poth Distinguished Professor of Dermatology.