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Ann Arbor, Mich. - Researchers at the University of Michiganhave identified the PSORS1 gene, a prime determinant ofsusceptibility for psoriasis. The culprit is HLA-Cw6, an allele ofthe HLA-C gene, part of the major histocompatibility complexlocated on chromosome 6.
Ann Arbor, Mich. - Researchers at the University of Michigan have identified the PSORS1 gene, a prime determinant of susceptibility for psoriasis. The culprit is HLA-Cw6, an allele of the HLA-C gene, part of the major histocompatibility complex located on chromosome 6.
"We think PSORS1 contributes one-third of a person's genetic liability for psoriasis," James Elder, M.D., Ph.D., says. "However, it's not a predictive factor. Only 60 percent of psoriasis patients carry this allele. And only one out of 10 who inherit it get sick. So a positive test doesn't mean a patient will get sick and a negative test doesn't mean he or she won't."
In the mid-1980s, scientists discovered that psoriasis involved a malfunctioning of one or more immune system genes, after cyclosporine (by attacking T-cells) incidentally cleared the skin of patients undergoing therapy for psoriatic arthritis.
Today doctors know the disease is a function of multiple genetic events plus at least one environmental trigger, such as strep throat. To further sharpen the focus, researchers are trying to locate allele combinations that are highly predictive of susceptibility.
A previous University of Michigan study narrowed the search to a segment of chromosome 6 that included 11 genes. By comparing DNA sequences in haplotypes from five people with the disease to sequences in healthy people, the Michigan team was able to target one gene (HLA-C) and one allele (HLA-Cw6).
Dr. Elder tells Dermatology Times, "While this allele has been associated with psoriasis for many years, a much larger study was needed to definitively confirm the finding and demonstrate that this gene, not nearby genes, is the actual determinant of psoriasis susceptibility."
Studying the study parameters
The University of Michigan launched a two-center study in partnership with the University of Kiel in Germany. Funding came from the National Institute of Arthritis, Musculoskeletal, and Skin Diseases, the Dudley and Dawn Holmes Fund, the National Psoriasis Foundation and the National Center for Research Resources.
To participate, patients needed at least two typical lesions (neither could be located on the scalp where psoriasis can be difficult to differentiate from dandruff). Alternatively, the patient could have one lesion covering at least one percent of the body surface. All degrees of severity were acceptable.
Patients completed a questionnaire, detailing the amount of psoriasis, family members with the disease, medications taken, body weight and smoking status. Off-center patients received an enrollment kit and were sent to nearby phlebotomists.
The Michigan team isolated white blood cells and DNA from the blood samples, first using the DNA to differentiate disease chromosomes from non-disease chromosomes. Next they narrowed the search by performing linkage and association tests. By sequencing chromosomes, two candidate genes emerged: HLA-C and CDSN (corneodesmosin).
Further studies, using the large patient sample to identify rare recombinants, clearly implicated the HLA-Cw6 allele.
"Doctors have known for a long time that there was probably an association between psoriasis and HLA-Cw6," Dr. Elder says. "But there are many genes around it, each with multiple alleles. We weeded out those genes and determined the prime cause really is HLA-Cw6."
Future research direction
The next step is to definitively locate other key alleles and combinations thereof that lead to psoriasis.
Up to now, genetic research has relied on linkage tests that correlate disease transmission with an arbitrary marker allele at a given locus within families. Future research will deploy association tests, using a specific marker allele at a given locus across families.