Genetics of Alopecia Areata: History
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Subjects: Dermatology
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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 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.

  • molecular genetics
  • alopecia universalis
  • genome-wide association study (GWAS)
  • DNA genotyping
  • disease
  • alopecia areata

1. Introduction

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. 

2. 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].

3. 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 1 and Table 2. 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 2 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 2, the manifestation of AA can be considered an aiding biomarker for diagnosing the underlying immune disease.
Table 1. Genes with strong association with alopecia areata.

4. 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.

5. 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 3.

6. 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.

This entry is adapted from the peer-reviewed paper 10.3390/genes14071362

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