Dr Tuntas Rayinda and colleagues recently published their findings from the AUK-funded work they have been doing on frontal fibrosing alopecia (FFA). FFA involves inflammation and scarring hair loss of the eyebrows, frontal scalp, and often back of the scalp, and may also include hair loss in other body regions. They previously did a ‘genome wide association study’ (GWAS), where they scanned the entire genetic code in 844 women with FFA and 3760 control subjects, to identify differences in genes. This work has brought us closer to understanding what is causing the disease. They have now followed this up with a study investigating the genetic basis for FFA in males.

A gene is a set of instructions for building amino acids, which are then assembled very carefully into proteins, each with their own unique function. In the female FFA study, they found differences in genes coding for proteins involved in handling foreign substances (xenobiotic metabolism), maintenance of a type of white blood cell (T cell homeostasis), and presentation of markers on the surface of cells, recognised by immune cells (antigen presentation). The areas of the genetic material (genome) these differences were found in are described as 'susceptibility loci', as they are believed to partially explain the risk of developing the disease.  

In this new study, they looked at men with FFA, of which there are estimated to be far fewer (only 3-5% of cases are male). They then compared this data with the data from females with FFA they had studied previously. In clinics, they had observed that the pattern of scarring and hair loss is consistent in males and females, although in males FFA typically presents earlier and facial hair loss is more evident. As such, they hypothesised that the genetic basis for male FFA would also be similar, and they investigated the same genetic regions that were found to be different in females with FFA. In total, they studied 92 men with FFA from the UK, USA, Germany, Spain and Greece, and compared them to 330 control subjects without FFA. They looked at the 4 genes that were found to be different in females:  

CYP1B1 – codes for an enzyme that is involved in metabolism (structural alterations) of drugs, fats, hormones and vitamins;  

HLA-B – codes for part of the ‘human leukocyte antigen’ complex, which helps the immune system tell the difference between the body’s own and foreign substances.  

ST3GAL1 – codes for an enzyme involved in ‘sialylation’, which is to add sialic acid to another substance. This step can regulate the function of antibodies (proteins that recognise and bind to foreign substances such as viruses, which leads to their elimination).  

SEMA4B – codes for a protein that spans the plasma membrane, the outer barrier of the cell. It is believed to regulate the activity of basophils, white blood cells involved in allergic reactions.  

In addition, they looked at 28 other ‘loci’ (regions of the genome) which had suggested associations with FFA in females.  

Each person has two versions of the same gene, called alleles, inherited from each parent (they could be the same two or different ones). Of all the genes studied, the HLA-B*07:02 allele, a specific version of the HLA-B gene, was found to represent the highest risk for FFA. That is, those with this version had a 4 times higher risk of FFA than those with a different version. The researchers think having this version of the gene may involve hair follicles presenting signals to the immune system (auto-antigens or ‘self-antigens’) that are recognised by immune cells as a sign to attack, which then results in the destruction of stem cells in the hair follicle. This prevents hair follicles from regenerating and continuing hair growth.  

In this new study of males, evidence of an association with FFA was found for rs2523616, a region within the HLA-B gene. The strength of this effect was slightly different between the groups of males from different countries, but overall this was similar to what was found in females. In males, like in the female group, the HLA-B*07:02 allele also had the strongest association with FFA.  

As genes contain a sequence that codes for amino acids, a change in even the smallest unit of this code can change what amino acid is produced, resulting in a faulty protein. Such a variation in a gene is called a single nucleotide polymorphism (SNP). Within the CYP1B1 gene, such a variation was found to be associated with increased risk for FFA in females. This study now shows evidence that this is also the case in males.  

The other two genes of interest, ST3GL1 and SEMA4B did not show evidence of an association with FFA in males. This could mean differences in the genetic basis for FFA in males and females. However, it could also mean the study did not have enough power to detect a difference, as it had fewer participants than the female study. They note that the direction of the effect, that is, a higher risk with the identified variation, was the same for these genes in males and females, although it was not as strong in males. Similarly, the direction of the effect was consistent between females and males for 17 of the other 28 genes studied.  

Moreover, they investigated whether genetic susceptibility in female FFA can also be used to predict disease in males by calculating "genetic risk scores" based on genetic risk loci of female FFA. The results showed that the genetic risk scores of male FFA are higher compared to male controls in all three different populations/cohorts. 

The findings support the theory that FFA is an immune-mediated inflammatory and scarring type of hair loss driven by a strong genetic background. The study also provides further evidence that the abnormality in hormones and metabolism of foreign substances (xenobiotics) may play a role in the mechanism of FFA. Further genetic studies involving larger numbers of individuals, for both males and females with FFA, can aid in the better understanding of FFA, as well as the discovery of potential targets for treatment in the future. In addition, identifying environmental triggers that interact with genes identified as carrying higher risk for developing FFA could help prevent the disease in the future. That is, in the future it may be possible to make recommendations for environmental triggers to avoid, for people who are at higher genetic risk for developing FFA.  

You can read the full study text here.