May 2020

Environmental, endocrine and genetic factors in hair follicle pathobiology: frontal fibrosing alopecia as a model disease (BSF Young Investigator Award)

About Dr Tziotzios

Dr Tziotzios graduated from the University of Cambridge. He undertook Integrated Academic Training as NIHR Academic Clinical Fellow in Dermatology at St. John’s where he developed an interest in molecular genetic research and hair disorders. He secured substantial research grant funding to undertake doctoral research into dissecting the molecular pathogenesis of frontal fibrosing alopecia (FFA), a highly distressing type of scarring hair loss affecting almost exclusively women. His PhD research at St. John’s has culminated in high-impact publications, including an original article in Nature Communications, and several distinctions such as the BAD Whimster Prize, the RSM Research Prize and the NIHR/BAD Award.

Dr Christos Tziotzios is currently Consultant Dermatologist & Honorary Clinical Senior Lecturer at St. John’s Institute of Dermatology, Guy’s and St. Thomas’ Hospitals NHS Foundation Trust & King’s College London. He is Specialist Consultant in the St John’s NHS Hair & Nail Clinic and he is affiliated to Prof John McGrath’s Genetic Skin Disease Group in the Faculty of Medicine of King’s College London. He has worked closely with Prof Michael Simpson and Dr Nick Dand, with whom he continues to collaborate.

The impact of hair loss and frontal fibrosing alopecia (FFA)

The impact of hair loss, especially in women, can be profound. Hair loss can be non-scarring (such as androgenetic alopecia or alopecia areata) or scarring, with the former being potentially reversible whilst the latter is irreversible.

FFA is a T cell-driven alopecia, which is considered to be a clinical variant of follicular lichen planus, also known as lichen planopilaris (LPP). LPP is regarded as the prototypic primary lymphocytic scarring alopecia and is the scalp counterpart of the commoner lichen planus, which affects other body parts. FFA is one of many scarring alopecias, which are known to be irreversible. This is because the cells (which are known as stem cells) responsible for regenerating the hair follicle are destructed by the inflammation. It is therefore important to stop the inflammation as early as possible to prevent permanent scarring hair loss.

Since FFA was first identified by Kossard in 1994, there has been a rapid increase in the incidence of the condition and this has led to intense clinical and public interest in the condition. FFA is often referred to as a dermatological epidemic with possible environmental trigger(s) implicated in addition to a genetic basis.

A better understanding of the molecular basis of FFA and its interplay with environmental risk factors could thus provide insight into lichenoid inflammation, scarring and mechanisms of stem cell destruction. Furthermore, the identification of environmental triggers that interact with genes underpinning FFA could ultimately contribute to disease prevention by avoidance of exposures in genetically predisposed individuals.

Background work

Our recently published large-scale study of the molecular genetic basis of FFA was the first systematic investigation into the molecular basis of FFA or any other lichenoid inflammatory disorder. We hypothesised that common genetic variation contributes to FFA and undertook a genome-wide association study (GWAS) in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and performed statistical meta-analysis. We observed and reported highly robust and significant association with a number of genes related to immune response, T-cells and also hormonal drug metabolism. We also looked at gene expression in affected scalp skin tissue biopsies and discovered that certain pathways (such as the Janus kinase and interferon-gamma pathways) are very relevant to the disease and therefore targeting these may help in the discovery of new treatments.

Our findings suggested that FFA has a strong genetic basis and is of autoimmune nature with involvement of hormonal drug exposure and their metabolism. Additional lines of evidence implicating exposure to hormonal contraception as a potential risk factor is also emerging from an ongoing study of discordant monozygotic twins. Taken together, alongside the temporal relationship between the introduction of oral contraceptives (a female-specific CYP1B1 substrate) in the 1960s and the appearance of FFA in the published literature in the 1990s, prompted us to pursue the notion further: a preliminary case-only gene-environment interaction analysis of the CYP1B1 variant in 736 cases showed support for an interaction between CYP1B1 and exposure to hormonal contraception (P=0.016).

Ongoing work:

The Young Investigator Award from the British Skin Foundation will enable me to explore how exposure to hormonal drugs might interact with the metabolic enzyme-encoding gene CYP1B1 in causing FFA. This will be accomplished by undertaking a case-control gene-environment interaction analysis.

In addition, we will continue to expand our European female FFA cohort via strengthening our collaborative links with academic centres in Germany, Spain, Italy and Greece with a view to undertake a larger-scale meta-GWAS. We anticipate that this will help us understand any of the 28 loci, which we identified as loci of suggestive genome-wide significance, are truly associated with FFA.

Finally, we are hoping to build a bio-resource of human hair follicular units to help us accomplish a study linking gene expression with genetic variation. Such an open-access resource will help future functional genomic work in the field of hair follicle and stem cell research.

How this research may help patients

Increasing our understanding of the genetic basis of the condition may enable us to devise genetic risk scoring tools, which may allow us to predict who might be at risk of developing the condition. Concurrently, identifying environmental factors associated with FFA may well help prevent people from developing the disease, depending on the actual contribution of such factors. Finally, our research may also provide guidance into novel and better treatments: our previous work provided molecular evidence for the use of a new class of drugs (targeting the Janus kinase pathway), a treatment approach which has already been found to be beneficial in a preliminary study.

Dr Christos Tziotzios

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