New Understanding of Genetics of Male FFA

HLA-B (HLA-B*07:02 allele)  and CYP1B1 Confer Increased Risk for Males to Develop FFA

Frontal fibrosing alopecia (FFA) is a scarring alopecia that affects women to a much greater extent than men. About 95 % of cases occur in females and 5 % occur in males. FFA is felt to be increasing in frequency around the world - for reasons that are not clear.

In 2019, researchers from the UK and Spain created quite the excitement in the world with the publication of four genes that seem to convey an increased risk for women to develop FFA. This study was publsiehd in Nature.

The group studied 844 FFA cases and 3,760 unaffected controls from the UK, and 172 women with FFA in Spain and 385 unaffected controls.

A review of the important 2019 paper is shown here:

The authors found 4 genes that come with an increased risk. These were:

1. HLA -B*07:02 or simply “HLA-B” on chromosome 6

This was found to have the strongest association. The pinpointing of HLA-B was important because it confirmed an immune basis to the disease. HLA-B is part of the major histocompatibility complex and is one of the so called “immune recognition genes.” This gene appears to influence how antigens get presented to our immune system.  HLA -B*07:02 appears to  help with the presentation of follicular autoantigens and the destruction of stem cells that reside in the hair follicle bulge. Women with a certain variation in the genetic coding for this gene had a five fold increased risk of developing FFA.

2. CYP1B1

This 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.  It  also plays an important role in the  hydroxylation of testosterone and progesterone

 3. ST3GAL1 on chromosome 8

This 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.

4. SEMA4B

This is a membrane protein involved in the nervous system.

Rayinda et al 2023: A New Study of Male FFA

In a new study authors set out to investigate the genetics of FFA in males. The found that HLA B and CYP 1B1 have a role in male FFA similar to females. However, they did not find a role for ST3GAL1 and SEMA4B

Conclusion

This is a much needed study as we continue to understand how FFA develops. The authors concluded that there is a substantial effect of the HLA-B*07:02 allele on FFA risk in males. There is also evidence to support the contribution of the p.Asn453Ser missense variant in CYP1B1.

The authors point out that their study had limited power to detect effects of a magnitude similar to that observed in female FFA (power < 80%) so it is possible -albeit unlikely that  these genes have some role too.

REFERENCE

Tziotzios C et al. Genome-wide association study in frontal fibrosing alopecia identifies four susceptibility loci including HLA-B*07:02. Nature 2019 Mar 8;10(1):1150. doi: 10.1038/s41467-019-09117-w.

Rayinda T et al. Shared Genetic Risk Variants in Both Male and Female Frontal Fibrosing Alopecia. J Invest Dermatol. 2023 May 19;S0022-202X(23)02068-7.