In the 1990’s I remember reading a paper by Zaias et al., (1) which discussed the idea that onychomycosis was, in part, genetic. Rather strange I thought for an infectious disease. The argument made was through the observation in families where a member of the household was infected with fungal foot infection but not all other family members succumbed to the infection. They proposed an inheritability which was autosomal dominant – typically one parent and the offspring would exhibit recurrent tinea pedis and nail infection. There is no doubt the condition is infectious with around a third of the European population suffering with fungal foot infection (2) but could the susceptibility be inherited? Alternatively, could other factors be at play for example - increase international travel, higher rates of immune-suppression, increased virulence, drug resistance or increased life expectancy?
Technically, as with any infection, susceptibility to the disease is down to three main factors - environment, characteristics of the dermatophyte and the host. Environmental aspects include geography, humidity, temperature and climate whilst the characteristics of the dermatophyte include its virulence and susceptibility to drugs for example. Host factors are quite broad but include lifestyle, medial status, occupation, social habits and gender. Known risk factors for fungal foot infection include increasing age, concomitant diseases (vascular and dermatological), gender and smoking (3, 4) amongst others identified so far. Untangling the influence and the effects of the three aspects is not an easy task but recent work has tried to uncover the genes potentially responsible for dermatophyte susceptibility.
The idea that fungal skin infection have a genetic susceptibility dates back to 1921 (5) with many papers since (6) but technologically it is complex to study with additional environmental and host factors that may interplay. With advances in genomics, the task has been made easier, but possibly, more complex as genetic susceptibility may be due to a combination of specific genes (polygenic) rather than the result of a single gene (monogenic). Inherited primary immunodeficiencies (known as PID’s) are inherited defects within the immune response. Depending on the affected pathways, PID’s can have different severity, onset and risks of infections (7).
Recent studies have highlighted potential monogenic candidates which may confer susceptibility. Attention has been focussed in the CARD9 human protein which has been shown to have a critical role in recognition of early dermatophyte skin infection (8). CARD9 protein is a key molecule linking with surface cell receptors that sense infection to create an immune response through signalling and inflammatory pathways. Patients with CARD9 genetic deficiencies have been shown to be extremely vulnerable to fungal infection but have normal responses to bacterial and viral infections. Human Dectin-1 is another potential candidate as it has been shown to lead to recurrent fungal infections in 4 women from the same family. Genetic analysis uncovered a mutation in the gene coding for the receptor which meant normal signalling pathways did not occur in response to fungal infection, resulting in a lack of cytokine production and clearance of the infection (9).
One study of 446 children looked at chronic fungal scalp infection and compared their genomes with unaffected children and discovered a number of potential gene candidates which affect different aspects of immune function which may explain chronic carriage of the dermatophyte (10). Most recently, a 2022 study (11) looked at the genomes stored on the UK biobank (which holds health and genetic information on half a million UK participants). They cross referenced these with known cases of dermatophytosis within the dataset. They analysed data from 487 000 patients of which 561 had dermatophytosis. They identified one susceptibility locus known as the Tubulointerstitial Nephritis Antigen (TINAG), with genome-wide significance for dermatophytosis.
TINAG encodes a glycoprotein in the epithelium of the Bowman's capsule of the kidney but what is its relevance to dermatophyte infections? Firstly, TINAG is highly expressed in the testes. Reduced testosterone levels contribute to increase risk of fungal skin infection – this possibly explaining why men, particularly older men, succumb to fungal skin infection, as their testosterone levels reduce with age. In addition, TINAG receptors are expressed within T cells – important for clearing fungal infections. T cells are the final part in a chain of events which lead to elimination of fungal infection so any deficiency within that process can lead to chronic fungal infection (11).
As we are now able to comb the human genome, it is likely that the full profile of the genetic basis of disease susceptibility has started a journey which may take some time before it is fully understood. However, small pieces of the puzzle are being uncovered with new research which can help contribute to a bigger picture. Ultimately, as more is uncovered it will allow preventative and therapeutic measure to be more accurately targeted and lead to more effective management of many diseases including dermatoses.
References
1. Zaias N, Tosti A, Rebell G. Autosomal dominant pattern of distal sub-ungual onychomycosis caused by T Rubrum. J Am Acad Dermatol. 1996;34:302-4.
2. Burzykowski G, Molenberghs D, Abeck E, Haneke E, Hay RJ, Katsambas D, et al. High prevalence of foot diseases in Europe: results of the Achilles project. Mycoses. 2003;46:496-505.
3. Sigurgeirsson B, Steingrimsson O. Risk factors associated with onychomycosis. J Eur Acad Dermatol Venereol. 2004;18:48-51.
4. Gupta AK, Gupta MA, Summerbell RC. The epidemiology of onychomycosis:Possible role of smoking and peripheral arterial disease. J Eur Acad Dermatol Venereol. 2000;14:466-9.
5. Hodges RS. Ringworm of the nails: a preliminary report of sixteen cases of onychomycosis with a cultural study of twelve of these cases due to trichophytons. Archives of Dermatology and Syphilology. 1921;4(1):1-26.
6. Gnat S, Łagowski D, Nowakiewicz A. Genetic Predisposition and its Heredity in the Context of Increased Prevalence of Dermatophytoses. Mycopathologia. 2021;186(2):163-76.
7. Marianna S, Xin L, Alessia V, Maxim B F, Chiara S, Simone R, et al. Looking for Sunshine: Genetic Predisposition to Sun-Seeking in 265,000 Individuals of European Ancestry. J Invest Dermatol. 2020.
8. Drummond RA, Franco LM, Lionakis MS. Human CARD9: A Critical Molecule of Fungal Immune Surveillance. Frontiers in Immunology. 2018;9(1836).
9. Ferwerda B, Ferwerda G, Plantinga TS, Willment JA, van Spriel AB, Venselaar H, et al. Human dectin-1 deficiency and mucocutaneous fungal infections. N Engl J Med. 2009;361(18):1760-7.
10. Abdel-Rahman SM, Simon S, Wright KJ, Ndjountche L, Gaedigk A. Tracking Trichophyton tonsurans Through a Large Urban Child Care Center: Defining Infection Prevalence and Transmission Patterns by Molecular Strain Typing. Pediatrics. 2006;118(6):2365-73.
11. Lehrer S, Rheinstein PH. Genome-wide association study of dermatophytosis in the UK Biobank cohort. J Eur Acad Dermatol Venereol. 2022;n/a(n/a).