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Clinical and Genetic Aspects of Alopecia Areata: A Cutting Edge Review

Department of Dermatology, College of Medicine and Post Baccalaureat Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 801, Taiwan
Department of Cosmetic Science, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Genes 2023, 14(7), 1362;
Submission received: 10 May 2023 / Revised: 21 June 2023 / Accepted: 23 June 2023 / Published: 28 June 2023
(This article belongs to the Special Issue Genetics of Complex Cutaneous Disorders)


Alopecia areata (AA) is a chronic, non-scarring, immune-mediated skin disease that affects approximately 0.5–2% of the global population. The etiology of AA is complex and involves genetic and environmental factors, with significant advancements in genetic research occurring in recent years. In addition to well-known genes such as PTPN22, CTLA4, and IL2, which have been widely supported as being associated with AA, an increasing number of specific gene-related loci have been discovered through advances in genetic research. For instance, gene analysis of microRNAs can reveal the critical role of miRNAs in regulating gene expression, aiding in the understanding of cellular and organismal functional regulatory mechanisms. Furthermore, numerous studies have confirmed the existence of correlations between AA and other immune-related diseases. Examples include hyperthyroidism and rheumatoid arthritis. By understanding the interrelationships between AA and other immune diseases, we can further comprehend potential shared genetic foundations or pathogenic mechanisms among different diseases. Genetic research plays a crucial role in unraveling the pathogenesis of AA, as the identification of genetic variations associated with AA can assist in formulating more effective and targeted treatment strategies.

1. Introduction

Alopecia areata (AA) is an autoimmune disease that leads to hair loss on the scalp and other hairy parts of the body as a result of hair follicles being attacked by the immune system. This disease typically presents as circular or patchy bald spots without scarring. In some cases, it can also affect the nails, making them brittle or pitted [1]. AA is relatively common and can affect people of any age, with a slightly higher prevalence in adult females [2]. The exact cause of AA is unknown, but it is believed to involve genetics, environmental factors, and immune system dysfunction. AA could have a significant negative impact on patients’ quality of life, affecting their psychological health, social life, and overall satisfaction. Patients may experience anxiety, depression, low self-esteem, and social difficulties, all of which can damage their quality of life [3]. In addition, due to the lack of hair protection, the affected areas are more vulnerable to exposure to ultraviolet radiation, leading to sunburn or sunspots on the scalp. Overall, AA can have negative impacts on the appearance, emotions, and social status of the affected individuals, highlighting the importance of early diagnosis and treatment.
Genetic research is crucial for understanding the etiology and treatment of AA. Many studies have shown that AA may result from the abnormal expression and interaction of multiple genes [4,5] which are involved in biological processes such as the immune system and hair follicle growth and development. Thus, genetic testing can help assess patients’ susceptibility and predict and diagnose the disease. For instance, central centrifugal cicatricial alopecia (CCCA) is a prevalent alopecia disorder that predominantly affects women of African and African descent. It has been established that mutations in PADI3 are implicated in CCCA. If patients exhibit these mutations during genetic testing, they may have an increased predisposition to CCCA or be at risk of developing the condition [6]. Furthermore, AA-based genetic research can facilitate the development of new treatments. Indeed, recent breakthroughs in genetic research have led to the application of JAK inhibitors in the treatment of AA. This review article conducted a literature search on PubMed utilizing key terms including alopecia areata, alopecia totalis, alopecia universalis, genetic, and GWAS, among others and provides an overview of the epidemiology and pathology of and treatment options for AA, as well as a comprehensive review of the genetic research conducted in the field.

2. Epidemiology

Currently, the global prevalence of AA is approximately 0.1%, with a lifetime incidence of around 2% [2,7]. Most literature suggests that there is no significant difference in incidence rates between males and females. Some studies have suggested a higher incidence in females, but this may be due to greater awareness and attention to hair loss and subsequent treatment in females, while the incidence also varies across different countries [8]. AA can occur at any age, but the most common age range is between 30 and 40 years old, with some differences in diagnosis age between males and females. Males are more likely to be diagnosed in childhood, while females are more likely to present during puberty [9]. Recent research on AA in children has indicated that it is the third most common skin disease manifestation in children. Between 2010 and 2017, over 140,000 children in the United States were diagnosed with AA, with a prevalence rate of approximately 0.23% and the highest incidence in the 11–12-year age group. In addition, it was found that the number of new cases of AA in children is increasing each year [10]. Here we summarize the incidence and prevalence rates of AA in different countries in Table 1, the prevalence rates by age in Table 2, and the age of diagnosis/onset in Table 3.

3. Etiology and Pathogenesis

AA is a complex autoimmune disease with multiple etiological factors. The disease is associated with genetic, environmental, infectious, and immune system abnormalities [5]. Immune system dysfunction is one of the main causes of AA pathogenesis, with abnormal T and B lymphocytes in AA patients secreting cytokines and autoantibodies that attack hair follicle cells, leading to hair loss. These immune cells release cytokines, such as interferon-γ and tumor necrosis factor, when they enter the hair follicle and then induce apoptosis of hair follicle cells [5]. Furthermore, AA is an autoimmune disorder characterized by immune-mediated hair loss, and the currently acknowledged pathogenesis primarily revolves around the disruption of immune privilege. Immune privilege refers to the phenomenon where specific tissues or regions exert inhibitory effects on the immune system to protect themselves from immune attacks. This privileged state is observed in certain tissues or organs, such as the eyes, testes, and placenta. Mechanisms underlying immune privilege include reduced antigen presentation, immune cell death, or the release of immunosuppressive molecules. Disruption of immune privilege can result in immune system attacks on these tissues, leading to diseases or autoimmune reactions [29,30]. Under normal circumstances, hair follicles are recognized as immune-privileged sites by the body’s immune system, remaining unaffected. However, in individuals with AA, the immune system erroneously perceives the hair follicles as exogenous entities, instigating an immune response that results in hair loss. In addition, autoantibodies bind to antigens on the surface of hair follicle cells, forming immune complexes that further damage hair follicle cells. Immune system abnormalities in AA patients may also be related to other autoimmune diseases. For example, a study in 2021 found a higher incidence of thyroid dysfunction in AA patients compared to the general population, and when AA patients have thyroid dysfunction, the disease severity may be increased [31]. Thyroid disease is an autoimmune disease caused by immune system abnormalities, suggesting that AA may share similar pathogenesis with other autoimmune diseases. Another important factor is genetics. Studies have shown that the risk of AA in families of AA patients is several times higher than that in the general population, and about 10% of family members are diagnosed with AA [32]. Several genetic factors associated with AA have been identified, including the HLA gene cluster on chromosome 6. Specific HLA gene variants, such as HLA-DQB1 and HLA-DRB1, are closely related to AA, whereas other non-HLA gene variants, such as TLR7, IL-2/IL-21, and IL-23R, are also associated with AA [33]. These studies indicate that genetic factors play an important role in the occurrence and development of AA. The pathogenesis of AA is complex, involving multiple cells, molecules, and pathological processes. Despite many related studies on the genetic level, unfortunately, the disease mechanism of AA is not fully understood.

4. Genetics of Alopecia Areata

4.1. Genetic Susceptibility

Although the pathogenesis of AA is multifactorial, numerous studies have confirmed that genetics plays an important role. A study on familial clustering of AA [32], conducted in Germany and Belgium, found that approximately 20% of patients had at least one family member with AA, indicating a genetic risk for AA. Moreover, AA tends to occur multiple times within the same family with a history of the disease, further underscoring its genetic basis. Other family and twin studies have confirmed the genetic risk for AA, which causes AA to occur more frequently among siblings than among parents and offspring [34]. Additionally, twin studies have provided valuable information on the genetic basis of AA, suggesting that the probability of both monozygotic twins being affected by AA is much higher than that of dizygotic twins both being affected if one of the twins is affected [35].

4.2. GWAS and Other Gene-Related Studies in Alopecia Areata

Petukhova et al. conducted the first genome-wide association study (GWAS) on AA, which identified 139 genotypes and 175 predicted single-nucleotide polymorphisms (SNPs) significantly associated with AA by comparing allele frequencies of 1054 unrelated AA patients and 3278 controls. These SNPs were mainly clustered in eight regions of the genome, covering immune-related and hair follicle-specific genes [36]. Lee et al. used exome sequencing to screen for candidate variants in six individuals with extensive alopecia universalis (AU) and identified 25 SNPs and 1 insertion/deletion. Subsequently, genotyping analysis of 14 additional AU patients revealed that six of these candidate variants were associated with AA or AU susceptibility [37]. Another GWAS study using pooling-based DNA genotyping found that variants in the HLA region showed the strongest association with AA, and the authors also identified the SPATA5 gene locus as a novel susceptibility locus for AA [38].
In 2016, Petukhova et al. used three techniques, namely the identification of enriched pathways, biological processes, and protein–protein interactions (PPIs), to analyze the pathways associated with AA-related genes identified through GWAS. They found that the functions of these genes were associated with specific immune pathways, with the emphasis on the importance of the JAK-STAT signaling pathway, building the basis for future precision medicine development [39]. In addition, microRNAs have been implicated in AA. Aylar et al. [40] analyzed 617 microRNAs and found that 78 of them were significantly associated with AA, with miR-1237, miR-30b/d, and miR-548h-2 still being significantly associated with AA after correction. Among these, miR-30b/d was the most important microRNA in subsequent analyses due to its miRNA-specific signal in the regional association plot, significant expression in AA-related tissues, and predicted target genes that include several AA-associated loci. Thus, microRNA intervention may be a potential treatment strategy for AA in the future. Furthermore, another study in 2023 reported that the KRT82 gene was significantly associated with AA. Among 849 AA patients, 19 patients (2.24%) had KRT82 gene variants, while among 15,640 controls, only 88 people (0.56%) had KRT82 gene variants. In addition, the study also identified two other genes, KRTCAP3 and DECR2, that were associated with AA, but more studies are needed to confirm these findings [41]. In addition to GWAS, many studies, such as whole-exome sequencing and genome-wide microRNA analysis, have been conducted to evaluate the association between specific genes and AA in greater depth. We have reviewed the current genetic research related to AA and summarized the results in Table 4 and Table 5. Through GWAS analysis, whole-genome sequencing, and other analytical methods, genes associated with alopecia areata (AA) have been identified, mainly focusing on immune regulation genes, HLA genes, and inflammation-related pathway genes. Immune regulation genes such as FASLG, PTPN22, and NOTCH4 are involved in T cell regulation and differentiation. Inflammation-related pathway genes such as IL36A, IL-6, and IL-18 participate in cytokine release regulation, NF-κB and MAPK pathways, and coordination of immune function. Variations in HLA genes can affect immune cell recognition and attack hair follicles, leading to the development of AA. Genes such as HLA-DRA, HLA-DRB, and HLA-DQA1 have been confirmed to be involved in the pathogenesis of AA. Other genes, such as CLCNKA, involved in regulating chloride ion transport across cell membranes, and CPT2, which encodes the carnitine palmitoyltransferase 2 protein involved in cellular fatty acid metabolism, have also been found to be associated with AA. Owing to the findings of genetic research, alopecia areata (AA) has been found to be associated with other diseases such as type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus (SLE), and atopic dermatitis. Table 5 summarizes the shared contributory genes between AA and other diseases. Therefore, during routine clinical evaluation of AA, physicians should also conduct comprehensive assessments for other diseases, including clinical inspection (atopic dermatitis), blood glucose levels (for type 1 DM), hormone levels (for Grave’s disease), immune-related markers (for SLE and multiple sclerosis), and gastrointestinal evaluations (for inflammatory bowel diseases, such as celiac disease and ulcerative colitis). These assessments aim to screen for potential comorbidities in AA patients. Since AA is visually apparent and easily detectable compared to the aforementioned autoimmune diseases, if an AA patient is found to have any of the autoimmune diseases listed in Table 5, the manifestation of AA can be considered an aiding biomarker for diagnosing the underlying immune disease.

4.3. Relationship between Human Leukocyte Antigen (HLA) System and Alopecia Areata

The HLA (human leukocyte antigen) system is a critical component of the human immune system that is controlled by genes located on chromosome 6. Its primary function is to recognize and distinguish self cells from foreign cells and elicit an appropriate immune response to protect the body from invasion and harm by pathogens and foreign substances. Studies have shown that HLA-DRB1*04 and HLA-DRB1*16 polymorphisms are associated with increased AA risk, while HLA-DRB1*0301, HLA-DRB1*09, and HLA-DRB1*13 polymorphisms are associated with reduced AA risk [57]. Furthermore, a recent case-control study found an increased frequency of HLA-B*39 and HLA-DRB1*15 alleles in AA patients, while the frequency of HLA-A*11 and HLA-B*35 was lower [58]. Since AA is an autoimmune disease associated with an overactive immune system, studying the relationship between the HLA system and AA can advance our understanding of the disease mechanism, identify relevant pathogenic genes, and develop more effective treatment strategies.

4.4. Single Nucleotide Polymorphism (SNP) Studies

Genome-wide studies of genetic variants have led to the finding that single-nucleotide polymorphisms (SNPs) are involved in AA pathogenesis. A pilot study in 2022 showed that while MTHFR gene expression is significantly elevated in AA patients, variations in MCP-1 rs1024611 and MTHFR rs1801133 may affect the pathogenesis of AA by impacting MCP-1 activity [70]. A study of Iranians analyzed the SNP genotypes of FAS (rs1800682) and FASLG (rs5030772) and found that the frequency of the G allele of FASLG gene is significantly higher in AA patients and there is an association between the FASLG rs5030772 variation and AA [42]. A study of Egyptians found a significant correlation between MIR17HG rs4284505 (A > G) and AA [63]. A case-control study of Jordanians analyzed some SNPs in five genes, TAP1, CXCL1, CXCL2, HSPA1B, and TNFα, and found a significant association between TNFα rs1800629 and AA [71]. Although SNP research in AA is increasing, the studies are still limited to specific populations. More extensive SNP research can help reveal the mechanism of AA occurrence, discover potential treatments, and provide new biomarkers for the prevention and diagnosis of AA. We summarize the SNP studies on AA in Table 6.

4.5. Studies of Gene Functions in Hair Follicles

Since it is well known that the pathogenesis of AA involves immune system attacks on hair follicles, gene functions in hair follicles may thus deserve further investigation. For example, Minjuan et al. found that the 3′ untranslated region (3′ UTR) of the junctional adhesion molecule A (JAM-A) gene functions as an important competitive endogenous RNA to maintain the function of hDPC, a specialized cell crucial for hair growth, and promote hair follicle regeneration in AA. JAM-A’s 3′ UTR forms a feedback loop with versican (VCAN) and miR-221-3p to regulate hDPC maintenance, proliferation, and differentiation [81]. Shymaa et al. [49] identified the involvement of hsa-miR-34a-5p in various hair follicle-related biological processes and vascular pathways by exploring the microRNA database. Their study revealed that MIR34A rs2666433 polymorphism and miR-34a may play a role in hair loss susceptibility. Furthermore, Syntaxin 17 (STX17) and Peroxiredoxin 5 (PRDX5) are genes related to the cellular and physiological functions of hair follicles. Mutations in STX17 have been found to be associated with gray coat color in horses, and since dark-colored hair is more common in patients with AA, STX17, the gene involved in melanin synthesis, may thus be potentially associated with AA. In addition, PRDX5 is thought to ameliorate cellular oxidative stress, the process often deregulated in the scalp of AA patients [50], and in AA patients’ hair follicle bulbs, the mRNA expression of Toll-like receptors 7 (TLR7) and interferon γ genes was significantly increased [53]. Together, understanding gene functions in hair follicles should lead to breakthrough discoveries in the treatment of AA and provide new directions for precision medicine.

5. Disease Associations with AA

Through the analysis in Table 4, we found that many of the genes associated with AA are also related to other diseases. As early as 2011, a nationwide population-based study revealed significant correlations between AA and vitiligo, systemic lupus erythematosus, psoriasis, atopic dermatitis, autoimmune thyroid disease, and allergic rhinitis [26]. In 2022, Sule Goksin et al. reported that AA patients not only tend to have autoimmune diseases but also develop multiple systemic diseases, autoimmune diseases, and psychiatric disorders [82]. Moreover, a study conducted in Saudi Arabia found that 62.7% of the 177 AA patients they recruited had insufficient serum vitamin D levels [83], which can also be observed in pediatric alopecia areata. A cross-sectional study found that pediatric alopecia areata patients tend to have comorbidities including atopic dermatitis, anemia, obesity, psoriasis, and depression. In summary, dermatologists treating AA patients need to have the ability to identify potential comorbidities and adopt a multidisciplinary approach to evaluate and manage these patients, thereby achieving better clinical outcomes.

6. Therapies for Alopecia Areata

6.1. Standard Management

Approximately 30–50% of patients diagnosed with patchy AA exhibit spontaneous remission within the initial six months to one year following disease onset, while approximately 60% of patients experience complete hair regrowth within a five-year timeframe [84]. Previous studies have indicated that patients with mild AA (scalp involvement area <25%) have demonstrated a spontaneous remission rate of approximately 68%. Furthermore, among patients with lesional involvement >50%, there is an observed spontaneous remission rate of 8% [85].
Although previous literature has indicated that certain cases of localized AA may undergo spontaneous resolution even without intervention, proactive management remains essential for patients with more severe presentations [86,87,88]. The current standard treatments for AA are commonly used worldwide, including in countries such as the United States, the United Kingdom, and Italy. We have compiled a consensus on AA treatment from various countries [87,89,90,91,92,93].
Intralesional corticosteroids (ICs) are the first-line treatment for small- to medium-sized areas of alopecia areata (AA) in adults, with Triamcinolone acetonide injection at concentrations of 2.5–10 mg/mL is commonly used. The main side effects of ICs are pitting atrophy and injection pain, which typically improve within a few months [33]. Topical corticosteroids (TCs) are the most common treatment for AA in patients who cannot receive ICs, with potent steroids such as betamethasone dipropionate 0.05% cream, lotion, or ointment being used in both adults and children [94]. Although occlusion may enhance treatment efficacy, there is insufficient evidence to prove its safety. Possible side effects include temporary folliculitis and skin atrophy. Systemic corticosteroids are also a common treatment, typically using an initial dose of oral prednisolone 0.5 mg/kg for a six-week course. However, long-term treatment may carry systemic side effects such as weight gain and risk of osteoporosis and a higher risk of relapse after discontinuation [94]. Minoxidil, a vasodilator, has been found to be a safe and effective treatment for AA when used locally in combination with other therapies. Studies have shown that low-dose minoxidil (0.25 to 5 mg daily to twice daily) is a safe and successful treatment for androgenetic alopecia and AA [95]. Methotrexate (MTX) is often used as monotherapy or adjuvant therapy for AA. A 2018 study found that combination therapy had a higher complete remission rate compared to monotherapy, but some patients experienced relapse after dose reduction [96]. Cyclosporine is also a commonly used treatment, and like MTX, it is often used in combination with other therapies. A systematic review by Joanna et al. [97] suggested that using cyclosporine in combination with systemic corticosteroids was more effective than using cyclosporine alone. In addition, diphenylcyclopropenone (DPCP) is the preferred drug for treating severe AA and regulates the autoimmune system by modulating the CD4+/CD8+ T lymphocyte ratio. A randomized clinical trial compared the efficacy of using DPCP alone versus combining DPCP with anthralin for treating AA. The study found that the combination of DPCP and anthralin had an effectiveness equal to that of DPCP alone, while the addition of anthralin did not enhance the therapeutic effect of DPCP in treating AA. [98]. Squaric acid dibutylester (SADBE) is another option for contact immunotherapy. A retrospective cohort study of 49 AA patients treated with SADBE in Japan confirmed that SADBE local immunotherapy is an effective and safe approach for treating AA [99]. Table 7 summarizes the standard treatments currently used in clinical practice for AA.

6.2. Novel Drugs for Alopecia Areata

In recent years, there has been a growing interest in emerging therapies for alopecia areata (AA), among which JAK inhibitors have received considerable attention. While further research is needed to establish the long-term safety of JAK inhibitors, several studies have already demonstrated their efficacy in treating AA [101]. Baricitinib, an orally administered Janus kinase 1 (JAK1) and JAK2 inhibitor, has been shown in phase 3 trials to effectively treat severe AA in adults without causing significant adverse effects [102]. In a phase 2 clinical trial involving 654 patients, they were randomly assigned to receive either 2 mg baricitinib, 4 mg baricitinib, or a placebo, administered once daily for 36 weeks. Compared to the placebo group, the group that received baricitinib had a significantly higher proportion of patients achieving the desired treatment goal (SALT ≤ 20) [103]. In a phase 3 trial involving 546 patients, similar treatment outcomes were observed, confirming the efficacy of baricitinib in improving the condition of AA patients [102]. Baricitinib was previously approved by the FDA in 2018 for the treatment of rheumatoid arthritis and is currently approved for the treatment of severe AA. Reported side effects of baricitinib include upper respiratory tract infections, headaches, acne, and others, but the severity is generally mild to moderate.
Ritlecitinib and brepocitinib have also shown positive results in two phase 2 trials for the treatment of AA [104]. A meta-analysis of JAK inhibitors [105] suggests that oral JAK inhibitors are effective for treating AA, but topical or sublingual administration may be less effective. Additionally, the efficacy of baricitinib, ritlecitinib, and brepocitinib appear to be similar in this study. Maddison et al. have provided a comprehensive review of JAK inhibitors for the treatment of AA, including other drugs such as tofacitinib, ruxolitinib, delgocitinib, and CTP-543 [106]. Although the efficacy of JAK inhibitors is supported by most studies, the high rate of relapse after discontinuation and the high cost of treatment still requires further investigation for long-term maintenance and drug performance. We compile the newer treatments for AA in Table 8.
In a 2019 randomized control trial study on patients with moderate to severe AA, Apremilast, a PDE-4 inhibitor, did not show significant improvement in the group receiving 30mg of oral Apremilast (n = 12) compared to placebo (n = 8) after 24 weeks of treatment [107]. Although this study yielded negative results, it suggests that the PDE-4 pathway may not be a therapeutic target for patients with moderate to severe AA. Further large-scale studies are needed to confirm the use of PDE-4 inhibitors in AA. Biologics such as Dupilumab, Aldesleukin, and Secukinumab have been studied for their use in AA treatment [108], but most studies have not shown significant therapeutic effects or have yielded conflicting results. Although biologics are a potential treatment option, there is currently no clear evidence to support their role in AA treatment.
In addition to above managements, Youyu et al. [109] analyzed 36 miRNAs with significantly different expressions in the blood of severe AA patients and found that miR-185-5p, miR-125b-5p, and miR-186-5p play important roles in active AA patients. These results suggest a correlation between miRNA expression in the blood and AA and may be used to predict disease progression or develop new treatment modalities in the future. In 2020, a study investigated the effects of long non-coding RNAs (lncRNAs) and competing endogenous RNAs (ceRNAs) on AA patients and found that specific ceRNAs may play a key role in the pathogenesis of AA by regulating the interaction between cytokines and cytokine receptors [110]. This finding suggests that ceRNAs may be a new target for future treatments. The use of plant-based preparations in hair loss has also been a topic of interest. Erkin et al. [111] used a topical mixture composed of six different herbal extracts (HE) for cell experiments and found that IL-1α gene expression was significantly decreased (p < 0.0001) in cells treated with HE. While IL-1α is a follicle growth inhibitor, this study thus provides a new idea for the treatment of hair loss using plant extracts. Mesenchymal stem cell therapy (MSCT) has also been proposed in several previous studies as a safe and effective treatment for difficult-to-treat AA [112,113]. Overall, there are currently many new treatment options for severe AA, and as our understanding of AA deepens, more new treatments are expected to emerge. However, even with new and effective treatment options, there is no guarantee that they will be applicable to all patients, and relapse rates are often high after treatment discontinuation [114]. Furthermore, AA is a systemic disease, and its associated comorbidities should be considered during treatment.
Table 8. Emerging treatments for alopecia areata (AA).
Table 8. Emerging treatments for alopecia areata (AA).
BaricitinibJAK1, 2/TYK2 inhibitor [102]
RitlecitinibJAK 2 inhibitor [115]
BrepocitinibJAK1/TYK2 inhibitor [115]
TofacitinibJAK1, 2, 3/TYK2 inhibitor [116]
RuxolitinibJAK1, 2 inhibitor [117]
DelgocitinibJAK1, 2, 3/TYK2 inhibitor [118]
CTP-543JAK1, 2 inhibitor[119]

7. Conclusions

This review summarizes recent genetic studies on AA and provides an overview of genome-wide association studies (GWAS) on AA in Table 4. Understanding the genetic structure and inheritance of AA can help elucidate the disease’s pathogenesis and develop effective treatments. Table 4 reveals that AA is linked to many immune-related genes, such as PTPN22, HLA-DRA, HLA-DRB1, and AIRE. However, recent studies have also found other genes with different physiological functions related to AA, such as MT-ND1, COL6A2, and POLH, suggesting that our understanding of AA remains incomplete. Although AA is known to be an autoimmune disease, its correlation with other diseases requires further investigation. Current research on AA has progressed to analyzing SNPs in different ethnic groups worldwide, which can help us understand the differences in alopecia rates between different populations and improve our understanding of the global prevalence of AA. We have compiled recent SNP studies in Table 5. Understanding subtle genetic variations can help identify susceptible populations and predict treatment responses. Breakthroughs in genetic research have led to the emergence of many promising treatment directions, such as JAK inhibitors, which have undergone late-stage clinical trials and proven to be effective for treating AA. In summary, genetic research plays an important role in understanding the pathogenesis and etiology of AA. With recent advances in research, multiple genes related to AA have been identified, and ongoing genetic research can lead to more effective and targeted treatments. However, due to the existence of multiple subtypes of AA and potential genetic and environmental differences between different ethnic groups, further research, and validation are necessary to establish a more comprehensive and accurate genetic database and related mechanisms, and provide more comprehensive support and help for the clinical diagnosis and treatment of AA.

Author Contributions

Conceptualization—C.-Y.W. (Ching-Ying Wu), C.-Y.H. and J.Y.-F.C. Methodology—C.-Y.H. , C.-Y.W.(Ching-Ying Wu) and C.-Y.W. (Chiu-Yen Wu). Writing—original draft preparation, C.-Y.W. (Ching-Ying Wu), C.-Y.W. (Chiu-Yen Wu) and C.-Y.H. Writing—review and editing, J.Y.-F.C. and C.-Y.W. (Ching-Ying Wu) All authors have read and agreed to the published version of the manuscript.


This research was funded by Kaohsiung Municipal Ta-Tung Hospital, grant number KMTTH-108-056, KMTTH-110-056, and KMTTH-111-041 to Ching-Ying Wu, and funded by Kaohsiung Medical University, grant number KMU-M12010 to Jeff Yi-Fu Chen.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Juárez-Rendón, K.J.; Rivera Sánchez, G.; Reyes-López, M.; García-Ortiz, J.E.; Bocanegra-García, V.; Guardiola-Avila, I.; Altamirano-García, M.L. Alopecia Areata. Current situation and perspectives. Arch. Argent. Pediatr. 2017, 115, e404–e411. [Google Scholar] [CrossRef]
  2. Mostaghimi, A.; Gao, W.; Ray, M.; Bartolome, L.; Wang, T.; Carley, C.; Done, N.; Swallow, E. Trends in Prevalence and Incidence of Alopecia Areata, Alopecia Totalis, and Alopecia Universalis Among Adults and Children in a US Employer-Sponsored Insured Population. JAMA Dermatol. 2023, 159, 411–418. [Google Scholar] [CrossRef]
  3. Rencz, F.; Gulácsi, L.; Péntek, M.; Wikonkál, N.; Baji, P.; Brodszky, V. Alopecia areata and health-related quality of life: A systematic review and meta-analysis. Br. J. Dermatol. 2016, 175, 561–571. [Google Scholar] [CrossRef]
  4. Rajabi, F.; Drake, L.A.; Senna, M.M.; Rezaei, N. Alopecia areata: A review of disease pathogenesis. Br. J. Dermatol. 2018, 179, 1033–1048. [Google Scholar] [CrossRef]
  5. Simakou, T.; Butcher, J.P.; Reid, S.; Henriquez, F.L. Alopecia areata: A multifactorial autoimmune condition. J. Autoimmun. 2019, 98, 74–85. [Google Scholar] [CrossRef] [Green Version]
  6. Malki, L.; Sarig, O.; Romano, M.T.; Méchin, M.C.; Peled, A.; Pavlovsky, M.; Warshauer, E.; Samuelov, L.; Uwakwe, L.; Briskin, V.; et al. Variant PADI3 in Central Centrifugal Cicatricial Alopecia. N. Engl. J. Med. 2019, 380, 833–841. [Google Scholar] [CrossRef]
  7. Seneschal, J.; Boniface, K.; Jacquemin, C. Alopecia areata: Recent advances and emerging therapies. Ann. Dermatol. Venereol. 2022, 149, 222–227. [Google Scholar] [CrossRef]
  8. Darwin, E.; Hirt, P.A.; Fertig, R.; Doliner, B.; Delcanto, G.; Jimenez, J.J. Alopecia Areata: Review of Epidemiology, Clinical Features, Pathogenesis, and New Treatment Options. Int. J. Trichol. 2018, 10, 51–60. [Google Scholar] [CrossRef]
  9. Villasante Fricke, A.C.; Miteva, M. Epidemiology and burden of alopecia areata: A systematic review. Clin. Cosmet. Investig. Dermatol. 2015, 8, 397–403. [Google Scholar] [CrossRef] [Green Version]
  10. Afford, R.; Leung, A.K.C.; Lam, J.M. Pediatric Alopecia Areata. Curr. Pediatr. Rev. 2021, 17, 45–54. [Google Scholar] [CrossRef]
  11. Sy, N.; Mastacouris, N.; Strunk, A.; Garg, A. Overall and Racial and Ethnic Subgroup Prevalences of Alopecia Areata, Alopecia Totalis, and Alopecia Universalis. JAMA Dermatol. 2023, 159, 419–423. [Google Scholar] [CrossRef] [PubMed]
  12. Campos-Alberto, E.; Hirose, T.; Napatalung, L.; Ohyama, M. Prevalence, comorbidities, and treatment patterns of Japanese patients with alopecia areata: A descriptive study using Japan medical data center claims database. J. Dermatol. 2023, 50, 37–45. [Google Scholar] [CrossRef] [PubMed]
  13. Andersen, Y.M.F.; Nymand, L.; DeLozier, A.M.; Burge, R.; Edson-Heredia, E.; Egeberg, A. Patient characteristics and disease burden of alopecia areata in the Danish Skin Cohort. BMJ Open 2022, 12, e053137. [Google Scholar] [CrossRef] [PubMed]
  14. Harries, M.; Macbeth, A.E.; Holmes, S.; Chiu, W.S.; Gallardo, W.R.; Nijher, M.; de Lusignan, S.; Tziotzios, C.; Messenger, A.G. The epidemiology of alopecia areata: A population-based cohort study in UK primary care. Br. J. Dermatol. 2022, 186, 257–265. [Google Scholar] [CrossRef]
  15. Alshahrani, A.A.; Al-Tuwaijri, R.; Abuoliat, Z.A.; Alyabsi, M.; AlJasser, M.I.; Alkhodair, R. Prevalence and Clinical Characteristics of Alopecia Areata at a Tertiary Care Center in Saudi Arabia. Dermatol. Res. Pract. 2020, 2020, 7194270. [Google Scholar] [CrossRef] [Green Version]
  16. Al-Ajlan, A.; Alqahtani, M.E.; Alsuwaidan, S.; Alsalhi, A. Prevalence of Alopecia Areata in Saudi Arabia: Cross-Sectional Descriptive Study. Cureus 2020, 12, e10347. [Google Scholar] [CrossRef]
  17. Benigno, M.; Anastassopoulos, K.P.; Mostaghimi, A.; Udall, M.; Daniel, S.R.; Cappelleri, J.C.; Chander, P.; Wahl, P.M.; Lapthorn, J.; Kauffman, L.; et al. A Large Cross-Sectional Survey Study of the Prevalence of Alopecia Areata in the United States. Clin. Cosmet. Investig. Dermatol. 2020, 13, 259–266. [Google Scholar] [CrossRef] [Green Version]
  18. Lee, H.H.; Gwillim, E.; Patel, K.R.; Hua, T.; Rastogi, S.; Ibler, E.; Silverberg, J.I. Epidemiology of alopecia areata, ophiasis, totalis, and universalis: A systematic review and meta-analysis. J. Am. Acad. Dermatol. 2020, 82, 675–682. [Google Scholar] [CrossRef]
  19. Soh, B.W.; Kim, S.M.; Kim, Y.C.; Choi, G.S.; Choi, J.W. Increasing prevalence of alopecia areata in South Korea. J. Dermatol. 2019, 46, e331–e332. [Google Scholar] [CrossRef]
  20. Mirzoyev, S.A.; Schrum, A.G.; Davis, M.D.P.; Torgerson, R.R. Lifetime incidence risk of alopecia areata estimated at 2.1% by Rochester Epidemiology Project, 1990–2009. J. Investig. Dermatol. 2014, 134, 1141–1142. [Google Scholar] [CrossRef] [Green Version]
  21. Guzmán-Sánchez, D.A.; Villanueva-Quintero, G.D.; Alfaro Alfaro, N.; McMichael, A. A clinical study of alopecia areata in Mexico. Int. J. Dermatol. 2007, 46, 1308–1310. [Google Scholar] [CrossRef]
  22. Tan, E.; Tay, Y.K.; Goh, C.L.; Chin Giam, Y. The pattern and profile of alopecia areata in Singapore—A study of 219 Asians. Int. J. Dermatol. 2002, 41, 748–753. [Google Scholar] [CrossRef]
  23. Sharma, V.K.; Dawn, G.; Kumar, B. Profile of alopecia areata in Northern India. Int. J. Dermatol. 1996, 35, 22–27. [Google Scholar] [CrossRef] [PubMed]
  24. Safavi, K.H.; Muller, S.A.; Suman, V.J.; Moshell, A.N.; Melton, L.J., III. Incidence of alopecia areata in Olmsted County, Minnesota, 1975 through 1989. Mayo Clin. Proc. 1995, 70, 628–633. [Google Scholar] [CrossRef]
  25. Price, V.H. Alopecia areata: Clinical aspects. J. Investig. Dermatol. 1991, 96, 68S. [Google Scholar] [CrossRef] [Green Version]
  26. Chu, S.Y.; Chen, Y.J.; Tseng, W.C.; Lin, M.W.; Chen, T.J.; Hwang, C.Y.; Chen, C.C.; Lee, D.D.; Chang, Y.T.; Wang, W.J.; et al. Comorbidity profiles among patients with alopecia areata: The importance of onset age, a nationwide population-based study. J. Am. Acad. Dermatol. 2011, 65, 949–956. [Google Scholar] [CrossRef] [PubMed]
  27. Goh, C.; Finkel, M.; Christos, P.J.; Sinha, A.A. Profile of 513 patients with alopecia areata: Associations of disease subtypes with atopy, autoimmune disease and positive family history. J. Eur. Acad. Dermatol. Venereol. 2006, 20, 1055–1060. [Google Scholar] [CrossRef]
  28. Yang, S.; Yang, J.; Liu, J.B.; Wang, H.Y.; Yang, Q.; Gao, M.; Liang, Y.H.; Lin, G.S.; Lin, D.; Hu, X.L.; et al. The genetic epidemiology of alopecia areata in China. Br. J. Dermatol. 2004, 151, 16–23. [Google Scholar] [CrossRef]
  29. Bertolini, M.; McElwee, K.; Gilhar, A.; Bulfone-Paus, S.; Paus, R. Hair follicle immune privilege and its collapse in alopecia areata. Exp. Dermatol. 2020, 29, 703–725. [Google Scholar] [CrossRef]
  30. Hong, S.; Van Kaer, L. Immune privilege: Keeping an eye on natural killer T cells. J. Exp. Med. 1999, 190, 1197–1200. [Google Scholar] [CrossRef] [Green Version]
  31. Naik, P.P.; Farrukh, S.N. Association between alopecia areata and thyroid dysfunction. Postgrad. Med. 2021, 133, 895–898. [Google Scholar] [CrossRef] [PubMed]
  32. Blaumeiser, B.; van der Goot, I.; Fimmers, R.; Hanneken, S.; Ritzmann, S.; Seymons, K.; Betz, R.C.; Ruzicka, T.; Wienker, T.F.; De Weert, J.; et al. Familial aggregation of alopecia areata. J. Am. Acad. Dermatol. 2006, 54, 627–632. [Google Scholar] [CrossRef] [PubMed]
  33. Zhou, C.; Li, X.; Wang, C.; Zhang, J. Alopecia Areata: An Update on Etiopathogenesis, Diagnosis, and Management. Clin. Rev. Allergy Immunol. 2021, 61, 403–423. [Google Scholar] [CrossRef] [PubMed]
  34. Duvic, M.; Nelson, A.; de Andrade, M. The genetics of alopecia areata. Clin. Dermatol. 2001, 19, 135–139. [Google Scholar] [CrossRef]
  35. Rodriguez, T.A.; Fernandes, K.E.; Dresser, K.L.; Duvic, M. Concordance rate of alopecia areata in identical twins supports both genetic and environmental factors. J. Am. Acad. Dermatol. 2010, 62, 525–527. [Google Scholar] [CrossRef]
  36. Petukhova, L.; Christiano, A.M. The genetic architecture of alopecia areata. J. Investig. Dermatol. Symp. Proc. 2013, 16, S16–S22. [Google Scholar] [CrossRef] [Green Version]
  37. Lee, S.; Paik, S.H.; Kim, H.J.; Ryu, H.H.; Cha, S.; Jo, S.J.; Eun, H.C.; Seo, J.S.; Kim, J.I.; Kwon, O.S. Exomic sequencing of immune-related genes reveals novel candidate variants associated with alopecia universalis. PLoS ONE 2013, 8, e53613. [Google Scholar] [CrossRef] [Green Version]
  38. Forstbauer, L.M.; Brockschmidt, F.F.; Moskvina, V.; Herold, C.; Redler, S.; Herzog, A.; Hillmer, A.M.; Meesters, C.; Heilmann, S.; Albert, F.; et al. Genome-wide pooling approach identifies SPATA5 as a new susceptibility locus for alopecia areata. Eur. J. Hum. Genet. 2012, 20, 326–332. [Google Scholar] [CrossRef]
  39. Petukhova, L.; Christiano, A.M. Functional Interpretation of Genome-Wide Association Study Evidence in Alopecia Areata. J. Investig. Dermatol. 2016, 136, 314–317. [Google Scholar] [CrossRef] [Green Version]
  40. Tafazzoli, A.; Forstner, A.J.; Broadley, D.; Hofmann, A.; Redler, S.; Petukhova, L.; Giehl, K.A.; Kruse, R.; Blaumeiser, B.; Böhm, M.; et al. Genome-Wide MicroRNA Analysis Implicates miR-30b/d in the Etiology of Alopecia Areata. J. Investig. Dermatol. 2018, 138, 549–556. [Google Scholar] [CrossRef] [Green Version]
  41. Erjavec, S.O.; Gelfman, S.; Abdelaziz, A.R.; Lee, E.Y.; Monga, I.; Alkelai, A.; Ionita-Laza, I.; Petukhova, L.; Christiano, A.M. Whole exome sequencing in Alopecia Areata identifies rare variants in KRT82. Nat. Commun. 2022, 13, 800. [Google Scholar] [CrossRef]
  42. Tabatabaei-Panah, P.S.; Moravvej, H.; Arian, S.; Fereidonpour, I.; Behravesh, N.; Atoon, A.; Ludwig, R.J.; Akbarzadeh, R. Overlapping and Distinct FAS/FASLG Gene Polymorphisms in Alopecia Areata in an Iranian Population. Immunol. Investig. 2020, 49, 204–214. [Google Scholar] [CrossRef]
  43. Shehata, W.A.; Maraee, A.; Kamal, H.; Tayel, N.; Azmy, R. Protein tyrosine phosphatase nonreceptor type 22 gene polymorphism in alopecia areata: Does it have an association with disease severity? J. Cosmet. Dermatol. 2020, 19, 3138–3144. [Google Scholar] [CrossRef] [PubMed]
  44. Salinas-Santander, M.; Sánchez-Domínguez, C.; Cantú-Salinas, C.; Gonzalez-Cárdenas, H.; Cepeda-Nieto, A.C.; Cerda-Flores, R.M.; Ortiz-López, R.; Ocampo-Candiani, J. Association between PTPN22 C1858T polymorphism and alopecia areata risk. Exp. Ther. Med. 2015, 10, 1953–1958. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Gil-Quiñones, S.R.; Sepúlveda-Pachón, I.T.; Sánchez Vanegas, G.; Gutierrez-Castañeda, L.D. Effect of PTPN22, FAS/FASL, IL2RA and CTLA4 genetic polymorphisms on the risk of developing alopecia areata: A systematic review of the literature and meta-analysis. PLoS ONE 2021, 16, e0258499. [Google Scholar] [CrossRef] [PubMed]
  46. Shin, J.M.; Kim, K.H.; Kim, S.M.; Hong, D.; Park, J.; Lee, H.Y.; Lim, W.J.; Shin, Y.A.; Kim, C.D.; Seo, Y.J.; et al. Exome sequencing reveals novel candidate gene variants associated with clinical characteristics in alopecia areata patients. J. Dermatol. Sci. 2020, 99, 216–220. [Google Scholar] [CrossRef]
  47. Al-Eitan, L.N.; Alghamdi, M.A.; Al Momani, R.O.; Aljamal, H.A.; Abdalla, A.M.; Mohammed, H.M. Genetic predisposition of alopecia areata in jordanians: A case-control study. Heliyon 2022, 8, e09184. [Google Scholar] [CrossRef]
  48. Shi, J.; Peng, P.; Liu, W.; Mi, P.; Xing, C.; Ning, G.; Feng, S. Bioinformatics analysis of genes associated with the patchy-type alopecia areata: CD2 may be a new therapeutic target. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech. Repub. 2020, 164, 380–386. [Google Scholar] [CrossRef] [Green Version]
  49. Maher, S.A.; Ismail, N.A.; Toraih, E.A.; Habib, A.H.; Gouda, N.S.; Gomaa, A.H.A.; Fawzy, M.S.; Helal, G.M. Hair Follicle-Related MicroRNA-34a Serum Expression and rs2666433A/G Variant in Patients with Alopecia: A Cross-Sectional Analysis. Biomolecules 2022, 12, 602. [Google Scholar] [CrossRef]
  50. Biran, R.; Zlotogorski, A.; Ramot, Y. The genetics of alopecia areata: New approaches, new findings, new treatments. J. Dermatol. Sci. 2015, 78, 11–20. [Google Scholar] [CrossRef]
  51. Ismail, N.A.; Toraih, E.A.; Ameen, H.M.; Gomaa, A.H.A.; Marie, R.E.M. Association of Rs231775 Genetic Variant of Cytotoxic T-lymphocyte Associated Protein 4 with Alopecia Areata Disease in Males: A Case-Control Study. Immunol. Investig. 2021, 50, 977–986. [Google Scholar] [CrossRef] [PubMed]
  52. Marie, R.E.M.; Atwa, M.A.; Gomaa, A.H.; Abdelhamid, A.E.S.; Eyada, M.M. The alterations of gene expression of interleukin-36α and interleukin-37 between alopecia areata patients and healthy controls. Australas. J. Dermatol. 2021, 62, e432–e435. [Google Scholar] [CrossRef] [PubMed]
  53. Kang, H.; Wu, W.Y.; Yu, M.; Shapiro, J.; McElwee, K.J. Increased expression of TLR7 and TLR9 in alopecia areata. Exp. Dermatol. 2020, 29, 254–258. [Google Scholar] [CrossRef] [PubMed]
  54. Won, Y.Y.; Haw, S.; Chung, J.H.; Lew, B.L.; Sim, W.Y. Association between EGF and EGFR Gene Polymorphisms and Susceptibility to Alopecia Areata in the Korean Population. Ann. Dermatol. 2019, 31, 489–492. [Google Scholar] [CrossRef] [Green Version]
  55. Tabatabaei-Panah, P.S.; Moravvej, H.; Delpasand, S.; Jafari, M.; Sepehri, S.; Abgoon, R.; Ludwig, R.J.; Akbarzadeh, R. IL12B and IL23R polymorphisms are associated with alopecia areata. Genes Immun. 2020, 21, 203–210. [Google Scholar] [CrossRef]
  56. Alghamdi, M.A.; Al-Eitan, L.N.; Aljamal, H.A.; Shati, A.A.; Alshehri, M.A. Genetic association of IL2RA, IL17RA, IL23R, and IL31RA single nucleotide polymorphisms with alopecia areata. Saudi J. Biol. Sci. 2022, 29, 103460. [Google Scholar] [CrossRef]
  57. Ji, C.; Liu, S.; Zhu, K.; Luo, H.; Li, Q.; Zhang, Y.; Huang, S.; Chen, Q.; Cao, Y. HLA-DRB1 polymorphisms and alopecia areata disease risk: A systematic review and meta-analysis. Medicine 2018, 97, e11790. [Google Scholar] [CrossRef]
  58. Hayran, Y.; Gunindi Korkut, M.; Öktem, A.; Şen, O.; Gür Aksoy, G.; Özmen, F. Evaluation of HLA class I and HLA class II allele profile and its relationship with clinical features in patients with alopecia areata: A case-control study. J. Dermatol. Treat. 2022, 33, 2175–2181. [Google Scholar] [CrossRef]
  59. Fawzi, M.M.; Mahmoud, S.B.; Shaker, O.G.; Saleh, M.A. Assessment of tissue levels of dickkopf-1 in androgenetic alopecia and alopecia areata. J. Cosmet. Dermatol. 2016, 15, 10–15. [Google Scholar] [CrossRef] [Green Version]
  60. Rajabi, F.; Amoli, M.M.; Robati, R.M.; Almasi-Nasrabadi, M.; Jabalameli, N.; Moravvej, H. The Association between Genetic Variation in Wnt Transcription Factor TCF7L2 (TCF4) and Alopecia Areata. Immunol. Investig. 2019, 48, 555–562. [Google Scholar] [CrossRef]
  61. Celik, S.D.; Ates, O. Genetic analysis of interleukin 18 gene polymorphisms in alopecia areata. J. Clin. Lab. Anal. 2018, 32, e22386. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Sayed Mahmoud Marie, R.E.; Abd El-Fadeel, N.M.; El-Sayed Marei, Y.; Atef, L.M. Gene Expression of CD70 and CD27 Is Increased in Alopecia Areata Lesions and Associated with Disease Severity and Activity. Dermatol. Res. Pract. 2022, 2022, 5004642. [Google Scholar] [CrossRef] [PubMed]
  63. Faisal, S.; Toraih, E.A.; Atef, L.M.; Hassan, R.; Fouad, M.M.; Al Ageeli, E.; Fawzy, M.S.; Abdalla, H.A. MicroRNA-17-92a-1 Host Gene (MIR17HG) Expression Signature and rs4284505 Variant Association with Alopecia Areata: A Case-Control Study. Genes 2022, 13, 505. [Google Scholar] [CrossRef] [PubMed]
  64. Eitan, L.N.A.; Alghamdi, M.A.; Al Momani, R.O.; Aljamal, H.A.; Elsy, B.; Mohammed, H.M.; Abdalla, A.M. Genetic Association between Interleukin Genes and Alopecia Areata in Jordanian Patients. Oman Med. J. 2022, 37, e421. [Google Scholar] [CrossRef]
  65. Karami, H.; Nomiri, S.; Ghasemigol, M.; Mehrvarzian, N.; Derakhshani, A.; Fereidouni, M.; Mirimoghaddam, M.; Safarpour, H. CHAC1 as a novel biomarker for distinguishing alopecia from other dermatological diseases and determining its severity. IET Syst. Biol. 2022, 16, 173–185. [Google Scholar] [CrossRef]
  66. Wang, D.; Xu, X.; Li, X.; Shi, J.; Tong, X.; Chen, J.; Lu, J.; Huang, J.; Yang, S. CCL13 is upregulated in alopecia areata lesions and is correlated with disease severity. Exp. Dermatol. 2021, 30, 723–732. [Google Scholar] [CrossRef]
  67. Saeki, H.; Kuwata, S.; Nakagawa, H.; Etoh, T.; Yanagisawa, M.; Miyamoto, M.; Tokunaga, K.; Juji, T.; Shibata, Y. HLA and atopic dermatitis with high serum IgE levels. J. Allergy Clin. Immunol. 1994, 94, 575–583. [Google Scholar] [CrossRef]
  68. Dubin, C.; Del Duca, E.; Guttman-Yassky, E. The IL-4, IL-13 and IL-31 pathways in atopic dermatitis. Expert. Rev. Clin. Immunol. 2021, 17, 835–852. [Google Scholar] [CrossRef]
  69. Narbutt, J.; Wojtczak, M.; Zalińska, A.; Salinski, A.; Przybylowska-Sygut, K.; Kuna, P.; Majak, P.; Sysa-Jedrzejowska, A.; Lesiak, A. The A/A genotype of an interleukin-17A polymorphism predisposes to increased severity of atopic dermatitis and coexistence with asthma. Clin. Exp. Dermatol. 2015, 40, 11–16. [Google Scholar] [CrossRef]
  70. Tabatabaei-Panah, P.S.; Moravvej, H.; Hajihasani, M.; Mousavi, M.; Ludwig, R.J.; Akbarzadeh, R. The MCP-1 rs1024611 and MTHFR rs1801133 gene variations and expressions in alopecia areata: A pilot study. Immun. Inflamm. Dis. 2022, 10, 209–217. [Google Scholar] [CrossRef]
  71. Al-Eitan, L.N.; Al Momani, R.O.; Al Momani, K.K.; Al Warawrah, A.M.; Aljamal, H.A.; Alghamdi, M.A.; Muhanna, A.M.; Al-Qarqaz, F.A. Candidate Gene Analysis Of Alopecia Areata In Jordanian Population Of Arab Descent: A Case-Control Study. Appl. Clin. Genet. 2019, 12, 221–228. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Conteduca, G.; Rossi, A.; Megiorni, F.; Parodi, A.; Ferrera, F.; Tardito, S.; Altosole, T.; Fausti, V.; Occella, C.; Kalli, F.; et al. Single-nucleotide polymorphisms in 3’-untranslated region inducible costimulator gene and the important roles of miRNA in alopecia areata. Skin Health Dis. 2021, 1, e34. [Google Scholar] [CrossRef] [PubMed]
  73. Abd El-Raheem, T.; Mahmoud, R.H.; Hefzy, E.M.; Masoud, M.; Ismail, R.; Aboraia, N.M.M. Tumor necrosis factor (TNF)-α- 308 G/A gene polymorphism (rs1800629) in Egyptian patients with alopecia areata and vitiligo, a laboratory and in silico analysis. PLoS ONE 2020, 15, e0240221. [Google Scholar] [CrossRef] [PubMed]
  74. Lei, Z.X.; Chen, W.J.; Liang, J.Q.; Wang, Y.J.; Jin, L.; Xu, C.; Kang, X.J. The association between rs2476601 polymorphism in PTPN22 gene and risk of alopecia areata: A meta-analysis of case-control studies. Medicine 2019, 98, e15448. [Google Scholar] [CrossRef]
  75. Kalkan, G.; Seçkin, H.Y.; Benli, İ.; Akbaş, A.; Baş, Y.; Karakus, N.; Bütün, İ.; Özyurt, H. Relationship between manganese superoxide dismutase (MnSODAla-9Val) and glutathione peroxidase (GPx1 Pro 197 Leu) gene polymorphisms and alopecia areata. Int. J. Clin. Exp. Med. 2015, 8, 21533–21540. [Google Scholar]
  76. Kim, H.K.; Lee, H.; Lew, B.L.; Sim, W.Y.; Kim, Y.O.; Lee, S.W.; Lee, S.; Cho, I.K.; Kwon, J.T.; Kim, H.J. Association between TAP1 gene polymorphisms and alopecia areata in a Korean population. Genet. Mol. Res. 2015, 14, 18820–18827. [Google Scholar] [CrossRef]
  77. Conteduca, G.; Rossi, A.; Megiorni, F.; Parodi, A.; Ferrera, F.; Tardito, S.; Battaglia, F.; Kalli, F.; Negrini, S.; Pizzuti, A.; et al. Single nucleotide polymorphisms in the promoter regions of Foxp3 and ICOSLG genes are associated with Alopecia areata. Clin. Exp. Med. 2014, 14, 91–97. [Google Scholar] [CrossRef]
  78. Kim, S.K.; Park, H.J.; Chung, J.H.; Kim, J.W.; Seok, H.; Lew, B.L.; Sim, W.Y. Association between interleukin 18 polymorphisms and alopecia areata in Koreans. J. Interferon Cytokine Res. 2014, 34, 349–353. [Google Scholar] [CrossRef] [Green Version]
  79. Seok, H.; Suh, D.W.; Jo, B.; Lee, H.B.; Jang, H.M.; Park, H.K.; Lew, B.L.; Chung, J.H.; Sim, W.Y. Association between TLR1 polymorphisms and alopecia areata. Autoimmunity 2014, 47, 372–377. [Google Scholar] [CrossRef]
  80. Seok, H.; Jeon, H.S.; Park, H.J.; Kim, S.K.; Choi, J.H.; Lew, B.L.; Chung, J.H.; Sim, W.Y. Association of HSPA1B SNP rs6457452 with Alopecia Areata in the Korean population. Immunol. Investig. 2014, 43, 212–223. [Google Scholar] [CrossRef]
  81. Wu, M.; Xu, C.; Jiang, J.; Xu, S.; Xiong, J.; Fan, X.; Ji, K.; Zhao, Y.; Ni, H.; Wang, Y.; et al. JAM-A facilitates hair follicle regeneration in alopecia areata through functioning as ceRNA to protect VCAN expression in dermal papilla cells. Precis. Clin. Med. 2022, 5, pbac020. [Google Scholar] [CrossRef]
  82. Goksin, S. Retrospective evaluation of clinical profile and comorbidities in patients with alopecia areata. North Clin. Istanb. 2022, 9, 451–458. [Google Scholar] [CrossRef] [PubMed]
  83. Alamoudi, S.M.; Marghalani, S.M.; Alajmi, R.S.; Aljefri, Y.E.; Alafif, A.F. Association Between Vitamin D and Zinc Levels With Alopecia Areata Phenotypes at a Tertiary Care Center. Cureus 2021, 13, e14738. [Google Scholar] [CrossRef] [PubMed]
  84. Trüeb, R.M.; Dias, M. Alopecia Areata: A Comprehensive Review of Pathogenesis and Management. Clin. Rev. Allergy Immunol. 2018, 54, 68–87. [Google Scholar] [CrossRef] [PubMed]
  85. Alhanshali, L.; Buontempo, M.G.; Lo Sicco, K.I.; Shapiro, J. Alopecia Areata: Burden of Disease, Approach to Treatment, and Current Unmet Needs. Clin. Cosmet. Investig. Dermatol. 2023, 16, 803–820. [Google Scholar] [CrossRef]
  86. Barton, V.R.; Toussi, A.; Awasthi, S.; Kiuru, M. Treatment of pediatric alopecia areata: A systematic review. J. Am. Acad. Dermatol. 2022, 86, 1318–1334. [Google Scholar] [CrossRef]
  87. Ito, T. Advances in the management of alopecia areata. J. Dermatol. 2012, 39, 11–17. [Google Scholar] [CrossRef]
  88. Sterkens, A.; Lambert, J.; Bervoets, A. Alopecia areata: A review on diagnosis, immunological etiopathogenesis and treatment options. Clin. Exp. Med. 2021, 21, 215–230. [Google Scholar] [CrossRef]
  89. Meah, N.; Wall, D.; York, K.; Bhoyrul, B.; Bokhari, L.; Sigall, D.A.; Bergfeld, W.F.; Betz, R.C.; Blume-Peytavi, U.; Callender, V.; et al. The Alopecia Areata Consensus of Experts (ACE) study: Results of an international expert opinion on treatments for alopecia areata. J. Am. Acad. Dermatol. 2020, 83, 123–130. [Google Scholar] [CrossRef]
  90. Ramos, P.M.; Anzai, A.; Duque-Estrada, B.; Melo, D.F.; Sternberg, F.; Santos, L.D.N.; Alves, L.D.; Mulinari-Brenner, F. Consensus on the treatment of alopecia areata—Brazilian Society of Dermatology. An. Bras. Dermatol. 2020, 95 (Suppl. S1), 39–52. [Google Scholar] [CrossRef]
  91. Cranwell, W.C.; Lai, V.W.; Photiou, L.; Meah, N.; Wall, D.; Rathnayake, D.; Joseph, S.; Chitreddy, V.; Gunatheesan, S.; Sindhu, K.; et al. Treatment of alopecia areata: An Australian expert consensus statement. Australas. J. Dermatol. 2019, 60, 163–170. [Google Scholar] [CrossRef] [PubMed]
  92. Rossi, A.; Muscianese, M.; Piraccini, B.M.; Starace, M.; Carlesimo, M.; Mandel, V.D.; Alessandrini, A.; Calvieri, S.; Caro, G.; D’Arino, A.; et al. Italian Guidelines in diagnosis and treatment of alopecia areata. G. Ital. Dermatol. Venereol. 2019, 154, 609–623. [Google Scholar] [CrossRef] [PubMed]
  93. Messenger, A.G.; McKillop, J.; Farrant, P.; McDonagh, A.J.; Sladden, M. British Association of Dermatologists’ guidelines for the management of alopecia areata 2012. Br. J. Dermatol. 2012, 166, 916–926. [Google Scholar] [CrossRef] [PubMed]
  94. Strazzulla, L.C.; Wang, E.H.C.; Avila, L.; Lo Sicco, K.; Brinster, N.; Christiano, A.M.; Shapiro, J. Alopecia areata: An appraisal of new treatment approaches and overview of current therapies. J. Am. Acad. Dermatol. 2018, 78, 15–24. [Google Scholar] [CrossRef]
  95. Sharma, A.N.; Michelle, L.; Juhasz, M.; Muller Ramos, P.; Atanaskova Mesinkovska, N. Low-dose oral minoxidil as treatment for non-scarring alopecia: A systematic review. Int. J. Dermatol. 2020, 59, 1013–1019. [Google Scholar] [CrossRef]
  96. Phan, K.; Ramachandran, V.; Sebaratnam, D.F. Methotrexate for alopecia areata: A systematic review and meta-analysis. J. Am. Acad. Dermatol. 2019, 80, 120–127.e122. [Google Scholar] [CrossRef]
  97. Nowaczyk, J.; Makowska, K.; Rakowska, A.; Sikora, M.; Rudnicka, L. Cyclosporine With and Without Systemic Corticosteroids in Treatment of Alopecia Areata: A Systematic Review. Dermatol. Ther. 2020, 10, 387–399. [Google Scholar] [CrossRef] [Green Version]
  98. Ghandi, N.; Daneshmand, R.; Hatami, P.; Abedini, R.; Nasimi, M.; Aryanian, Z.; Vance, T.M. A randomized trial of diphenylcyclopropenone (DPCP) combined with anthralin versus DPCP alone for treating moderate to severe alopecia areata. Int. Immunopharmacol. 2021, 99, 107971. [Google Scholar] [CrossRef]
  99. Sakai, K.; Fukushima, S.; Mizuhashi, S.; Jinnin, M.; Makino, T.; Inoue, Y.; Ihn, H. Effect of topical immunotherapy with squaric acid dibutylester for alopecia areata in Japanese patients. Allergol. Int. 2020, 69, 274–278. [Google Scholar] [CrossRef]
  100. Fukuyama, M.; Ito, T.; Ohyama, M. Alopecia areata: Current understanding of the pathophysiology and update on therapeutic approaches, featuring the Japanese Dermatological Association guidelines. J. Dermatol. 2022, 49, 19–36. [Google Scholar] [CrossRef]
  101. Zheng, C.; Tosti, A. Alopecia Areata: New Treatment Options Including Janus Kinase Inhibitors. Dermatol. Clin. 2021, 39, 407–415. [Google Scholar] [CrossRef] [PubMed]
  102. King, B.; Ohyama, M.; Kwon, O.; Zlotogorski, A.; Ko, J.; Mesinkovska, N.A.; Hordinsky, M.; Dutronc, Y.; Wu, W.S.; McCollam, J.; et al. Two Phase 3 Trials of Baricitinib for Alopecia Areata. N. Engl. J. Med. 2022, 386, 1687–1699. [Google Scholar] [CrossRef] [PubMed]
  103. King, B.; Ko, J.; Forman, S.; Ohyama, M.; Mesinkovska, N.; Yu, G.; McCollam, J.; Gamalo, M.; Janes, J.; Edson-Heredia, E.; et al. Efficacy and safety of the oral Janus kinase inhibitor baricitinib in the treatment of adults with alopecia areata: Phase 2 results from a randomized controlled study. J. Am. Acad. Dermatol. 2021, 85, 847–853. [Google Scholar] [CrossRef] [PubMed]
  104. Messenger, A.; Harries, M. Baricitinib in Alopecia Areata. N. Engl. J. Med. 2022, 386, 1751–1752. [Google Scholar] [CrossRef]
  105. Yan, D.; Fan, H.; Chen, M.; Xia, L.; Wang, S.; Dong, W.; Wang, Q.; Niu, S.; Rao, H.; Chen, L.; et al. The efficacy and safety of JAK inhibitors for alopecia areata: A systematic review and meta-analysis of prospective studies. Front. Pharmacol. 2022, 13, 950450. [Google Scholar] [CrossRef]
  106. Lensing, M.; Jabbari, A. An overview of JAK/STAT pathways and JAK inhibition in alopecia areata. Front. Immunol. 2022, 13, 955035. [Google Scholar] [CrossRef]
  107. Mikhaylov, D.; Pavel, A.; Yao, C.; Kimmel, G.; Nia, J.; Hashim, P.; Vekaria, A.S.; Taliercio, M.; Singer, G.; Karalekas, R.; et al. A randomized placebo-controlled single-center pilot study of the safety and efficacy of apremilast in subjects with moderate-to-severe alopecia areata. Arch. Dermatol. Res. 2019, 311, 29–36. [Google Scholar] [CrossRef]
  108. Gupta, A.K.; Wang, T.; Polla Ravi, S.; Bamimore, M.A.; Piguet, V.; Tosti, A. Systematic review of newer agents for the management of alopecia areata in adults: Janus kinase inhibitors, biologics and phosphodiesterase-4 inhibitors. J. Eur. Acad. Dermatol. Venereol. 2023, 37, 666–679. [Google Scholar] [CrossRef]
  109. Sheng, Y.; Qi, S.; Hu, R.; Zhao, J.; Rui, W.; Miao, Y.; Ma, J.; Yang, Q. Identification of blood microRNA alterations in patients with severe active alopecia areata. J. Cell Biochem. 2019, 120, 14421–14430. [Google Scholar] [CrossRef]
  110. Qi, S.; Sheng, Y.; Hu, R.; Xu, F.; Miao, Y.; Zhao, J.; Yang, Q. Genome-wide expression profiling of long non-coding RNAs and competing endogenous RNA networks in alopecia areata. Math. Biosci. Eng. 2020, 18, 696–711. [Google Scholar] [CrossRef]
  111. Pekmezci, E.; Dundar, C.; Turkoglu, M. Proprietary Herbal Extract Downregulates the Gene Expression of IL-1α in HaCaT Cells: Possible Implications Against Nonscarring Alopecia. Med. Arch. 2018, 72, 136–140. [Google Scholar] [CrossRef]
  112. Elmaadawi, I.H.; Mohamed, B.M.; Ibrahim, Z.A.S.; Abdou, S.M.; El Attar, Y.A.; Youssef, A.; Shamloula, M.M.; Taha, A.; Metwally, H.G.; El Afandy, M.M.; et al. Stem cell therapy as a novel therapeutic intervention for resistant cases of alopecia areata and androgenetic alopecia. J. Dermatol. Treat. 2018, 29, 431–440. [Google Scholar] [CrossRef]
  113. Lee, Y.J.; Park, S.H.; Park, H.R.; Lee, Y.; Kang, H.; Kim, J.E. Mesenchymal Stem Cells Antagonize IFN-Induced Proinflammatory Changes and Growth Inhibition Effects via Wnt/β-Catenin and JAK/STAT Pathway in Human Outer Root Sheath Cells and Hair Follicles. Int. J. Mol. Sci. 2021, 22, 4581. [Google Scholar] [CrossRef]
  114. Ramírez-Marín, H.A.; Tosti, A. Emerging drugs for the treatment of alopecia areata. Expert Opin. Emerg. Drugs 2022, 27, 379–387. [Google Scholar] [CrossRef]
  115. King, B.; Guttman-Yassky, E.; Peeva, E.; Banerjee, A.; Zhu, L.; Zhu, H.; Cox, L.A.; Vincent, M.S.; Sinclair, R. Safety and Efficacy of Ritlecitinib and Brepocitinib in Alopecia Areata: Results from the Crossover Open-Label Extension of the ALLEGRO Phase 2a Trial. JID Innov. 2022, 2, 100156. [Google Scholar] [CrossRef] [PubMed]
  116. Jabbari, A.; Sansaricq, F.; Cerise, J.; Chen, J.C.; Bitterman, A.; Ulerio, G.; Borbon, J.; Clynes, R.; Christiano, A.M.; Mackay-Wiggan, J. An Open-Label Pilot Study to Evaluate the Efficacy of Tofacitinib in Moderate to Severe Patch-Type Alopecia Areata, Totalis, and Universalis. J. Investig. Dermatol. 2018, 138, 1539–1545. [Google Scholar] [CrossRef] [Green Version]
  117. Mackay-Wiggan, J.; Jabbari, A.; Nguyen, N.; Cerise, J.E.; Clark, C.; Ulerio, G.; Furniss, M.; Vaughan, R.; Christiano, A.M.; Clynes, R. Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata. JCI Insight 2016, 1, e89790. [Google Scholar] [CrossRef] [Green Version]
  118. Mikhaylov, D.; Glickman, J.W.; Del Duca, E.; Nia, J.; Hashim, P.; Singer, G.K.; Posligua, A.L.; Florek, A.G.; Ibler, E.; Hagstrom, E.L.; et al. A phase 2a randomized vehicle-controlled multi-center study of the safety and efficacy of delgocitinib in subjects with moderate-to-severe alopecia areata. Arch. Dermatol. Res. 2023, 315, 181–189. [Google Scholar] [CrossRef]
  119. King, B.; Mesinkovska, N.; Mirmirani, P.; Bruce, S.; Kempers, S.; Guttman-Yassky, E.; Roberts, J.L.; McMichael, A.; Colavincenzo, M.; Hamilton, C.; et al. Phase 2 randomized, dose-ranging trial of CTP-543, a selective Janus Kinase inhibitor, in moderate-to-severe alopecia areata. J. Am. Acad. Dermatol. 2022, 87, 306–313. [Google Scholar] [CrossRef]
Table 1. Prevalence and incidence of AA according to epidemiological studies of different regions.
Table 1. Prevalence and incidence of AA according to epidemiological studies of different regions.
StudyRegionIncidence, %Prevalence, %Reference
2023, MostaghimiUSA0.09290.22[2]
2023, SyUSA-0.17[11]
2023, Campos-AlbertoJapan-0.27[12]
2022, AndersenDenmark-0.9[13]
2022, HarriesUK0.0260.2[14]
2020, AlshahraniSaudi Arabia-2.3[15]
2020, AbdulmajedSaudi Arabia-5.25[16]
2020, BenignoUSA-2.51[17]
2020, LeeChicago 1.72.13[18]
2019, SohSouth Korea0.9850.15[19]
2014, MirzoyevUSA2.1-[20]
2007, Guzmán-SánchezMexico0.57-[21]
2002, TanSingapore3.8-[22]
1996, SharmaIndia0.7-[23]
1995, SafaviUSA1.7-[24]
1991, PriceUSA and Britain2-[25]
Table 2. Prevalence of AA by age group according to epidemiological studies.
Table 2. Prevalence of AA by age group according to epidemiological studies.
Age Groups *Reference
2023, SyUSA0.[11]
2023, MostaghimiUSA0.[2]
* Approximate prevalence of patients with AA in each age group.
Table 3. The average age of diagnosis/Onset of alopecia areata globally.
Table 3. The average age of diagnosis/Onset of alopecia areata globally.
StudyRegionAge of Diagnosis/OnsetReference
2020, AlshahraniSaudi Arabia25.6[15]
2020, AbdulmajedSaudi Arabia19[16]
2013, MirzoyevUSA33.6[20]
2011, ChuTaiwan32.2[26]
2006, GohUSA36.3[27]
2002, TanSingapore25.2[22]
2004, YangChina29[28]
Table 4. Genes with strong association with alopecia areata.
Table 4. Genes with strong association with alopecia areata.
LocationGeneAssociated FunctionConnection to Other Diseases *Reference
Chromosome 1FASLGActivation-induced cell death (AICD) of T cells Not defined[42]
PTPN22Regulating CBL function in the T-cell receptor signaling pathwayT1D, RA, SLE, GD[43,44,45]
CLCNKASalt reabsorption in the kidney and potassium recycling in the inner earBartter syndrome, type 4b [46]
CLCNKBRenal salt reabsorptionNot defined[46]
CPT2Oxidization of long-chain fatty acids in the mitochondriaCarnitine palmitoyltransferase II deficiency, infantile [46]
PINK1Protection of cells from stress-induced mitochondrial dysfunctionPD [46]
SUCOCollagen biosynthetic processMesial temporal lobe epilepsy [46]
USH2ADevelopment and homeostasis of the inner ear and retinaDeafness [46]
MASP2Coagulation cascadeNot defined[47]
CD2Immune recognitionNot defined[48]
MIR34ATumor suppressor Not defined[49]
Chromosome 2CTLA4Co-stimulationT1D, RA, CeD, MS, SLE, GD [5,39,45,47,50,51]
ICOSCo-stimulationT1D, MS[5,39,50]
Apoptosis, autophagy regulation T1D, IgA nephropathy, primary sclerosing cholangitis[5]
IL36AInflammatory responseAllergic contact dermatitis, AD, acne, hidradenitis suppurativa[52]
ALS2A guanine nucleotide exchange factor for the small GTPase RAB5ALS[46]
CYP27A1Drug metabolism and synthesis of cholesterol, steroids, and other lipidsCTX, Cholestanol storage disease [46]
IRS1Encoding a protein that is phosphorylated by insulin receptor tyrosine kinaseDM[46]
COL4A4The structural component of basement membranesThin basement membrane disease[46]
TPOThyroid gland functionCongenital hypothyroidism [46]
HOXD13Morphogenesis in all multicellular organismsSynpolydactyly [46]
Chromosome 3CHRNB2Regulation of synaptic vesicle exocytosisAD[46]
COLQEncoding the subunit of a collagen-like moleculeCongenital myasthenic syndrome [46]
TLR9Pathogen recognition and activation of innate immunityNot defined[53]
Chromosome 4 IL-21Th17 and NK cell proliferationT1D, RA, CeD, PS[5,39,50]
IL-2T and B cell proliferationT1D, RA, CeD, PS[5,39,50]
Cxcl9Chemoattractant for lymphocytesRA, T1D, PS, SLE[5]
Cxcl10Chemokine: monocyte, NK and, T cell stimulationRA, T1D, PS, SLE[5]
Cxcl11Chemokine: chemotaxis of activated T cellsRA, T1D, PS, SLE[5]
TLR1Pathogen recognition and activation of innate immunityNot defined[47,50]
EGFGrowth, proliferation, and differentiation of numerous cell typesNot defined[54]
Chromosome 5 IL-13/IL-4Th2 differentiationNot defined[5,50]
IL12BMediation of long-term protection to an intracellular pathogenMS[55]
IL7RV(D)J recombination during lymphocyte developmentPIDDs[46]
IL31RAType I cytokine receptor familyNot defined[56]
VCANTissue morphogenesis and maintenanceRetinitis pigmentosa [46]
Chromosome 6NOTCH4T cell differentiation T1D, RA, MS[5]
C6orf10Unknown function in vivo T1D, RA, PS, GV[5,50]
BTNL2Co-stimulationT1D, RA, UC, CD, SLE, MS[5,50]
HLA-DRAAntigen presentation (MHC II) T1D, RA, CeD, MS, GV[5,50]
HLA-DRB1*04Antigen presentation (MHC II) Not defined[57]
HLA-DRB1*16Antigen presentation (MHC II)Not defined[57]
HLA-DRB1*11Antigen presentation (MHC II)Not defined[57]
HLA-DQA1Antigen presentation (MHC II) T1D, RA, UC, CD, SLE, MS, CeD, GD [5,50]
HLA-DQA2Antigen presentation (MHC II)T1D, RA[5,50]
HLA-DQB2Antigen presentation (MHC II) RA[5,50]
HLA-DOBAntigen presentation (MHC II) SLE[5]
HLA-AAntigen presentation (MHC I) T1D, MS, PS, GD[50]
HLA-B*13Antigen presentation (MHC I) Not defined[58]
KLRK1NK and T cell activation (NKG2D)T1D, RA, MS, CD, CeD, SLE[5]
MICANKG2D Activating ligandT1D, RA, UC, CeD, PS, SLE[5,50]
ULBP6NKG2D Activating ligandNot defined[5,50]
ULBP3NKG2D Activating ligandNot defined[5,50]
TNFAProinflammatory cytokineRA, MS, IBD, SLE[5]
PPP1R18Targeting the enzyme to different cellular locations Not defined[40]
TNXBLocalizing to the major histocompatibility complex (MHC) class IIINot defined[40]
POLHA member of the Y family of specialized DNA polymerasesXP, variant type [46]
COL9A1Assembly of type IX collagen moleculesNot defined[46]
Chromosome 7 IL-6Inflammatory cytokineT1D, RA, CeD[5]
SLC26A4No knownEnlarged vestibular aqueduct, Pendred’s syndrome [46]
EGFRProtein kinase superfamilyLung cancer,
severe form of coronavirus disease 2019 (COVID-19)
Chromosome 8LPLEncodes lipoprotein lipaseHyperlipoproteinemia, type I [46]
Chromosome 9 STX17No known inflammatory role. It is involved in premature hair greying Not defined[5,50]
GNEInitiates and regulates the biosynthesis of N-acetylneuraminic acid (NeuAc)Inclusion body myopathy 2 [46]
Chromosome 10 IL-2RAT-cell proliferationT1D, MS, GD, GV[5,45,50]
TWNKmtDNA replicationAtaxia [46]
DKK1Embryonic developmentNot defined[59]
TCF7L2Wnt signaling pathwayDM[60]
Chromosome 11 PRDX5Antioxidant enzyme with roles in inflammationMS[5,50]
IL-18Proinflammatory cytokine that augments natural killer cell activity and stimulates IFNγ production in T-helper type I cellsRA, SLE [5,61]
GARP (LRRC32)Treg differentiation and activity IBD, Allergies [5]
SLC22A12Regulation of urate levels in bloodRenal hypouricemia [46]
TYR Encoding tyrosinaseOculocutaneous albinism [46]
Chromosome 12 IL-26T cell differentiationMS[5]
IFNGRegulation of immune responsesSLE[5]
KRT82A member of the keratin gene familyNot defined[41]
CD27T cell immunity and regulating B-cell activationNot defined [62]
WNT10BImplicated in oncogenesis and in several developmental processesOligodontia [46]
Chromosome 13MIR17HGCell survival, proliferation, differentiation, and angiogenesisNot defined [63]
Chromosome 15IL16The modulator of T cell activation and an inhibitor of HIV replicationNot defined[64]
CHAC1Promotion neuronal differentiationNot defined[65]
Chromosome 16 SOCS1STAT inhibitor, regulator of IFN-γ responseT1D, CeD[5]
FUS Regulation of gene expression, maintenance of genomic integrity, and mRNA/microRNA processingALS[46]
Chromosome 17CCL13Chemotactic activity for monocytes, lymphocytes, basophils, and eosinophilsNot defined[66]
Chromosome 18 PTPN2Phosphatase involved in cell signalingT1D, CeD[5]
Chromosome 19CD70Enhances T helper and cytotoxic T cell activationNot defined [62]
NPHS1Ultrafilter to exclude albumin and other plasma macromolecules in the formation of urineFinnish congenital nephrotic syndrome [46]
Chromosome 20PIGTGlycosylphosphatidylinositol (GPI)-anchor biosynthesisMultiple congenital anomalies-hypotonia- seizures syndrome 3 [46]
RTEL1Encodes a DNA helicaseDyskeratosis congenita [46]
Chromosome 21 AIREAutoimmune regulator, selection of auto-reactive cellsAPECED, T1D, GV, HT [5]
COL6A2Encodes one of the three α chains of type VI collagenMuscular dystrophy [46]
Chromosome 22CELSR1Cell adhesion and receptor-ligand interactionsNeural tube defects [46]
IL17RAInducer of the maturation of CD34-positive hematopoietic precursors into neutrophils.RA[56]
Chromosome X Cxcr3Chemokine receptorRA, T1D, PS, SLE[5]
MAMLD1Transcriptional co-activator46XY disorder of sex development [46]
TLR7Pathogen recognition and activation of innate immunity. [53]
Chromosome MTMT-ND1Mitochondrial electron transportAD, PD[46]
* Abbreviation: Type 1 diabetes (T1D), rheumatoid arthritis (RA), systemic lupus erythematous (SLE), Graves’ disease (GD), Parkinson’s disease (PD), celiac disease (CeD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), cerebrotendinous xanthomatosis (CTX), psoriasis (PS), primary immunodeficiency diseases (PIDDs), generalized vitiligo (GV), ulcerative colitis (UC), Crohn’s disease (CD), inflammatory bowel disease (IBD), xeroderma pigmentosum (XP), Hashimoto thyroiditis (HT).
Table 5. Genes associated with both alopecia areata and other diseases.
Table 5. Genes associated with both alopecia areata and other diseases.
Type 1 DiabetesPTPN22, CTLA4, ACOXL/BCL2L11, IL-21, IL-2, Cxcl9, Cxcl10, Cxcl11, NOTCH4, C6orf10, BTNL2, HLA-DRA, HLA-DQA1, HLA-DQA2, HLA-A, KLRK1, MICA, IL-6, IL-2RA, SOCS1, PTPN2, Cxcr3[5,50]
Rheumatoid ArthritisPTPN22, CTLA4, IL-21, IL-2, Cxcl9, Cxcl10, Cxcl11, NOTCH4, C6orf10, BTNL2, HLA-DRA, HLA-DQA1, HLA-DQA2, HLA-DQB2, KLRK1, MICA, TNFA, IL-6, IL-18, IL17RA, Cxcr3[5,50]
Systemic Lupus ErythematousPTPN22, CTLA4, Cxcl9, Cxcl10, Cxcl11, BTNL2, HLA-DQA1, HLA-DOB, KLRK1, MICA, TNFA, IL-18, IFNG, Cxcr3[5,50]
Graves’ DiseasePTPN22, CTLA4, HLA-DQA1, HLA-A, IL-2RA,[5,50]
Parkinson’s DiseasePINK1, MT-ND1[5,46]
Celiac DiseaseCTLA4, IL-21, IL-2, HLA-DRA, HLA-DQA1, KLRK1, MICA, IL-6, SOCS1, PTPN2[5,50]
Ulcerative ColitisBTNL2, HLA-DQA1, MICA,[5]
Multiple SclerosisCTLA4, ICOS, IL12B, NOTCH4, BTNL2, HLA-DRA, HLA-DQA1, HLA-A, KLRK1, TNFA, IL-2RA, PRDX5, IL-26[5,50,55]
Amyotrophic Lateral SclerosisALS2, FUS[5,46]
Generalized VitiligoC6orf10, HLA-DRA, IL-2RA, AIRE[5]
Inflammatory Bowel DiseaseTNFA, GARP (LRRC32)[5]
Atopic DermatitisHLA-DQB1, HLA-DRB1, HLA-DQA1, IL-4, IL-13, IL-17, IL-23R[67,68,69]
Table 6. Associated-SNP studies with Alopecia Areata.
Table 6. Associated-SNP studies with Alopecia Areata.
2022, AlghamdiNot definedIL17RArs879575Not associated with AA susceptibility among Jordanian patients[56]
2021, Gil-QuiñonesNot definedPTPN22rs2476601T allele is a risk factor for developing AA[45]
2021, ConteducaItalianICOSrs4404254
Carrying the 3’ UTR alleles was more frequently observed in AA patients[72]
2021, IsmailEgyptianCTLA4rs231775Significantly higher in AA patients[51]
2020, Abd El-RaheemEgyptianTNFα
promoter region
rs1800629No association with AA[73]
2020, EitanJordanianIL16 exon regionrs11073001The A-allele was distributed more frequently[64]
IL16 promoter regionrs17875491A difference was found between the patients and the controls
2019, LeiNot definedPTPN22rs2476601Significantly correlated with AA. The C-allele and CC-genotype carriers at this locus have a lower risk of AA.[74]
JordanianTNFαrs1800629Significantly associated with AA in the heterozygous and rare homozygous genotypes[71]
TurkishIL 18rs1946518Distribution of CC + CA genotypes and frequency of -607/allele C were higher in AA[61]
rs187238Distribution of GG genotype and frequency of -137/allele G were higher in AA
2015, KalkanTurkishMnSODAla-9ValNo association with AA[75]
GPx1 Pro 198 LeuNo association with AA
2015, KimKoreanTAP1
promoter region
rs2071480Association with AA[76]
2015, Salinas-SantanderMexicanPTPN22C1858TT allele as a genetic risk factor for patchy AA[44]
2014, ConteducaNot definedFOXP3rs2294020Reduced relative gene expression in AA patients[77]
2014, KimKoreanIL18rs187238
Associated with the development of AA[78]
2014, SeokKoreanTLR1 missense regionrs4833095Significantly associated with the development of AA[79]
promoter region
rs5743557Weakly associated with the development of AA
2014, SeokKoreanHSPA1Brs6457452Weakly related to the age of onset of AA[80]
rs2763979Weakly related to AA
intronic region
rs304650Significant association with AA[38]
Table 7. Standard treatments for alopecia areata (AA).
Table 7. Standard treatments for alopecia areata (AA).
TherapyAdministrationSide EffectsReference
Intralesional corticosteroidsTopical
Injected directly into the skin
Pain, skin atrophy, contact allergic dermatitis [88,94,100]
Topical corticosteroidsTopical foam or cream Folliculitis, skin atrophy, acne, telangiectasia[88,94,100]
Systemic corticosteroidsOral intake or intravenous or intramuscular injectionSuppression of the pituitary–adrenal axis, weight gain, osteoporosis, ocular changes hypertension, diabetes[88,94,100]
Topical minoxidil Topical foam or cream Itching and dermatitis, hypertrichosis, acne[88,94,100]
MethotrexateOral intake alone or in conjunction with corticosteroids Nausea and vomiting, mucositis, liver toxicity, leukopenia[88,94]
CyclosporineOral intake alone or in conjunction with corticosteroids Hypertension, hypertrichosis, nephrotoxicity[88,94]
Contact immunotherapy
diphenylcyclopropenone (DPCP)
squaric acid dibutylester (SADBE)
Topical cream Lymphadenopathy, generalized eczema, vitiligo[88,94,100]
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Ho, C.-Y.; Wu, C.-Y.; Chen, J.Y.-F.; Wu, C.-Y. Clinical and Genetic Aspects of Alopecia Areata: A Cutting Edge Review. Genes 2023, 14, 1362.

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Ho C-Y, Wu C-Y, Chen JY-F, Wu C-Y. Clinical and Genetic Aspects of Alopecia Areata: A Cutting Edge Review. Genes. 2023; 14(7):1362.

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Ho, Chih-Yi, Chiu-Yen Wu, Jeff Yi-Fu Chen, and Ching-Ying Wu. 2023. "Clinical and Genetic Aspects of Alopecia Areata: A Cutting Edge Review" Genes 14, no. 7: 1362.

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