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Frontal Fibrosing Alopecia GWAS Implicates Risk Loci with Links to Immune System

NEW YORK (GenomeWeb) – New research in European women suggests that susceptibility to frontal fibrosing alopecia (FFA), a scarring, inflammatory hair loss condition that primarily affects women, likely involves innate and adaptive immune factors. 

As they reported today in Nature Communications, the researchers, led by a team at King's College London, began with a genome-wide association study involving 844 FFA cases and almost 3,800 unaffected controls from the UK, identifying three FFA-associated loci that were subsequently validated in another 172 Spanish women with the hair loss condition and 385 without. A meta-analysis of data from both cohorts highlighted a fourth locus, suggesting that significant FFA contributors fall at chromosomes 2, 6, 8, and 15.

The team's 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) and showed particularly strong ties to FFA. Meanwhile, transcriptomic data from FFA-affected scalp tissue pointed to a dramatic rise in innate and adaptive immune response genes, providing clues to potential treatment targets for FFA.

"The insight into the pathobiology of FFA from the genetic susceptibility loci combined with the observation that there is an increase in transcripts encoding components of the [interferon gamma] pathway in affected scalp tissue suggest that drugs such as JAK inhibitors, some of which have already proved effective in alopecia areata and trialed in lichen planopilaris, may prove to be efficacious for FFA," senior and co-corresponding author John McGrath, a dermatology researcher at King's College London, and his colleagues wrote.

In a paper appearing in the New England Journal of Medicine last month, a Tel Aviv University-led team used exome sequencing and saw an overrepresentation of variants in and around hair shaft formation-related genes in women with central centrifugal cicatricial alopecia, a scarring alopecia that is especially common in African American women and other women of African ancestry.

Less is known about the genetics behind other forms of alopecia, the UK team explained, including FFA — a subtype of another form of scarring alopecia called alopecia lichen planopilaris. Past studies suggest that the immune-related condition has genetic components­ and can segregate within families, though environmental factors are suspected as well.

"To date there have been no systematic investigations into the molecular genetic basis of FFA or any other lichenoid inflammatory disorder," the authors wrote, prompting the current GWAS search for common variants involved in FFA susceptibility.

The researchers used Illumina Infinium arrays to genotype more than 8.4 million variants in the British women with or without FFA who were profiled for the discovery stage of the analysis. From there, they validated suspicious SNPs and performed a meta-analysis GWAS, using data from almost 8 million variants for members of the Spanish cohort to land on the four loci with significant FFA associations.

The team dug into the FFA associations with fine-mapping, blood plasma metabolomics, and RNA sequencing on FFA-affected scalp tissues from seven post-menopausal women with the condition and on healthy scalp samples from seven matched, unaffected control individuals. In the process, the investigators pinpointed the FFA-associated HLA-B allele HLA-B*07:02, which seems to boost FFA susceptibility several times in women of European descent. 

"Through imputation of classical HLA alleles, we implicate the Class I allele HLA-B*07:02 as conferring a fivefold increase in risk of FFA," the authors wrote, noting that "highly polymorphic HLA genes and their encoded proteins play a key role in self and non-self immune recognition and are known to determine susceptibility to numerous infections and autoimmune disorders."