Frontal Fibrosing Alopecia : The First Four Genes
Frontal fibrosing alopecia (FFA) is a scarring alopecia that affects women to a much greater extent than men. It is increasing in frequency around the world - for reasons that are not clear.
The cause of FFA has been quite a mystery since it was first reported in 1994. Now for the first ever, researchers from the UK and Spain have uncovered 4 new genes that appear to be relevant to FFA. The group studied 844 FFA cases and 3,760 unaffected controls from the UK, identifying three genetic regions (FFA-associated loci) that were subsequently validated using data from Spain in 172 women with FFA and 385 without. A fourth genetic was uncovered in a meta-analysis of data from both cohorts. Taken together these data suggested that significant FFA contributors fall at chromosomes 2, 6, 8, and 15. These four regions are believed to be strongly associated with the onset of Frontal fibrosing alopecia (FFA).
HLA-B*07:02 on chromosome 6
Of the 4 genetic areas, a location within the HLA-B gene was found to be the most strongly associated with the occurrence of FFA. More specifically, the researchers’ fine-mapping analyses led to the human leukocyte antigen locus HLA-B*07:02 on chromosome 6, which is part of the major histocompatibility complex (MHC).
This appears to be highly relevant because the HLA-B is an important so called “immune recognition gene.” A variation in these genetic coding in these immune recognition genes is thought to contribute to autoimmunity - which in the case of FFA would lead to autoimmune destruction of the hair follicle. What was remarkable in this study was the observation that specific mutations in the HLA B gene carried a 4.73 fold increased risk of developing FFA. When I look at the data, this points to a really significant association. It is this gene that might influence how autoantigens get presented to the immune system.
Other genes potentially relevant to FFA
The other genes were less directly associated with FFA (increased risk of about 1.5 fold) but nevertheless thought to also have a role. The group found a second genetic location of importance, CYP1B1 which is a gene that codes for a metabolic enzyme that is involved in xenobiotic and sex hormone degradation. The gene on chromosome 2 is known by several names including Cytochrome
P450 1B1 microsomal enzyme as well as by the second name “xenobiotic mono-oxygenase and aryl hydrocarbon hydroxylase.” This gene is responsible for how estrogen gets metabolized in the body. FFA is thought to be influenced to some degree by hormonal and environmental factors. I have no doubt that these findings will continue to fuel interest in better understanding the role of environmental factors. ST3GAL1 on chromosome 8 encodes a membrane bound sialotransferase. It is now understood that changes in glycans on the surface of T cells can influence the activity of these T cells.
Additional data from FFA-affected scalp tissue indicated a very significant rise in innate and adaptive immune response genes. Individuals with FFA had an increase in transcripts in genes encoding the interferon pathway - a pathway that is also involved in diseases like alopecia areata. This information may be relevant to how treatments are designed in the future. The involvement of the interferon pathway also calls in question the possibility that drugs blocking interferon (ie jak inhibitors) could have an important role in treatment.
Taken together, this is an important study. This is the first study to point to potential genes that could be relevant to frontal fibrosing alopecia. It reminds us that continued focus on inflammatory and hormonal factors is likely going to lead us to improved understanding of this complex disease.
Christos Tziotzios et al. Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02. Nature 2019. Online March 8, 2019
Dr. Jeff Donovan is a Canadian and US board certified dermatologist specializing exclusively in hair loss. To schedule a consultation, please call the Whistler office at 604.283.1887