Alopecia areata: Study reveals genetic clues

October 1, 2010

Recent published findings of a Genome Wide Association Study (GWAS) for alopecia areata (AA) have pinpointed at least eight genes linked to the disease.

National report - Recent published findings of a Genome Wide Association Study (GWAS) for alopecia areata (AA) have pinpointed at least eight genes linked to the disease.

This information provides new insights into the basis of this autoimmune disease, according to Angela M. Christiano, Ph.D., professor of dermatology and genetics and development and vice chairman for basic science, department of dermatology, Columbia University Medical Center, New York.

The disease
Alopecia areata (AA) is among the most highly prevalent human autoimmune diseases, affecting more than 5 million people in the United States alone. Hair loss in a circular pattern usually occurs mainly on the scalp, and sometimes on the beard or the body, and it can progress to cover the entire scalp (alopecia totalis).

Hair loss can continue further and cover the whole body (alopecia universalis), and at that point it attacks all hairs including the eyelashes and nose hairs.

“Not everyone recognizes how common alopecia areata is,” says Dr. Christiano, who has the disease herself. “It is very frequent, and 1 percent to 2 percent of all dermatology visits are for AA.

“It is also thought to be underreported, because affected individuals don’t always tend to seek treatment for it, particularly in the early stages.”

Evidence suggests alopecia areata is a genetically determined autoimmune disease.

“Alopecia areata fits the profile a polygenic disease, one that is caused by alterations in more than one gene, usually acting with some environmental or epigenetic component, although we are not sure what those factors will be,” Dr. Christiano says.

Genome-wide Association studies
Dr. Christiano’s group has been working to unlock the cause of the genetics of alopecia areata for about 12 years. Traditionally, genetic linkage studies look at families with several people who are affected by a particular disease. The segregation of the different genes through the family is analyzed to pinpoint candidate disease genes.

In the past five years, the GWAS method, which enables researchers to conduct case-control studies with thousands of individuals, has been introduced as an additional method for gene discovery. GWAS studies require large numbers of individuals who have been carefully phenotyped for the disease. This is made possible by the National Alopecia Areata Registry.

The recent GWAS in AA included 1,054 cases and 3,278 controls and identified 139 single nucleotide polymorphisms (SNPs) that are significantly associated with AA.

“We tested approximately 600,000 markers across the whole genome, and we looked for places where the patients had a different frequency of given alleles than the controls. … We found eight different regions that gave an indication that they were associated with alopecia areata,” Dr. Christiano says.

One region encompassed the HLA complex, which confirms the involvement of the MHC genes, which were implicated in AA 20 years ago. This locus is also implicated in most other autoimmune diseases.

“We know that certain MHC haplotypes, or a group of markers that segregate together, go along with certain autoimmune diseases,” she says. Researchers also found seven other genomic loci that harbor interesting candidate genes for AA.

“Five are expressed in the immune system, and two of them are expressed in the hair follicle itself. It is exciting to find a combination of genes that were expressed both in the target organ as well as the immune cells,” Dr. Christiano says.

The study looked at the nature of those immune system genes and found similarities with other autoimmune diseases. The expectation for many years was that AA would be closely related to psoriasis and vitiligo, two other common skin autoimmune diseases. However, the GWAS preliminary findings showed that AA has only one gene in common with each of those diseases, in addition to the HLA locus.

Instead, AA candidate regions line up very closely with Type 1 diabetes, multiple sclerosis, rheumatoid arthritis and celiac disease.

“That was a big shock, because we really hadn’t been thinking of those disease as ones that might share common mechanisms with AA,” Dr. Christiano says.

She notes that in genetic studies, the “common cause hypothesis” suggests that defects in a core set of genes predispose the patient to autoimmunity, but in different diseases, the end organ is different.

“When we looked at these diseases compared to AA, we found that there is at least one unifying mechanism in all of those diseases, and that is upregulation of a ‘danger signal’ on the end organ itself,” Dr. Christiano says.

“For example, in diabetes, the MICA gene is upregulated in the pancreas, which starts a particular type of immune response mediated by the NKG2D receptor. Previous studies in AA had shown expression of MICA in affected hair follicles, and in the GWAS study, we found evidence for a different class of danger signals, called ULBPs, that we believe are functioning the same way in the hair follicle,” she says.

These danger signals serve as homing beacons for cytotoxic immune cells to infilitrate the organ and start to destroy it. The signals are generally turned off in normal tissues, but for unknown reasons in certain autoimmune diseases, they are upregulated in the end organ, she says.

In this context, the researchers found that AA fit into this disease paradigm, since ULBP3 is found to be upregulated in AA hair follicles. Dr. Christiano notes that research for these other diseases, such as diabetes and rheumatoid arthritis, has focused on this pathway for many years, and therefore might provide clues for research and future treatments for AA.

The GWAS study also confirmed the validity of the C3H-HeJ mouse model of AA, an inbred mouse strain that has been available for about 20 years. This model also may help accelerate pre-clinical research to test some of these new therapeutic targets.

“It is a very exciting time for the field to have identified the first set of genes,” Dr. Christiano says. “Now we and others must replicate those findings in another several thousand individuals, as well as AA patients from different backgrounds.

“We hope to do that in the coming year, and then the fun really starts - that is, trying to figure out how it all works together to generate an autoimmune attack on the hair follicle, and how to stop the disease using the newly identified genetic pathways as a starting point.”

National Alopecia Areata Registry
The National Institutes of Health’s national registry for alopecia areata patients is accepting new patient enrollment. The registry will help researchers continue their GWAS studies in alopecia areata. Patients with AA can register online. See: http://clinicaltrials.gov/ct/show/NCT00069589

For more information: Petukhova L, et al. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature. 2010;466:113-117.