Genomic Markers and Personalized Medicine in Androgenetic Alopecia: A Comprehensive Review

Abstract

Androgenetic alopecia (AGA) is the most common form of hair loss, significantly affecting both men and women worldwide. Characterized by progressive hair thinning and loss, AGA is primarily mediated by dihydrotestosterone (DHT). Recent research has identified numerous single-nucleotide polymorphisms (SNPs) associated with AGA, particularly in genes involved in androgen metabolism, prostaglandin pathways, and vasodilation. These genetic markers offer insights into AGA pathophysiology and potential therapeutic targets. Pharmacogenetics, the study of how genetic variations influence drug response, holds promise for personalized AGA treatment. Identifying SNPs that affect the efficacy of treatments like minoxidil and finasteride enables the development of tailored therapeutic strategies. For instance, genetic variants in the SRD5A2 gene, which affects DHT metabolism, can predict responsiveness to 5-alpha-reductase inhibitors. Beyond pharmacogenetics, RNA interference (RNAi) technologies, e.g., small interfering RNAs (siRNAs), present new therapeutic avenues. Studies have shown the efficacy of RNAi-based treatments in targeting androgen receptors, promoting hair growth in AGA models. Integrating genetic and pharmacogenetic research into clinical practice can transform AGA management, enhancing treatment efficacy and patient outcomes. In conclusion, genetic and pharmacogenetic insights are crucial for developing personalized treatments for AGA, while emerging RNAi technologies offer promising new interventions. These advancements represent significant steps toward more effective and individualized AGA therapies.

1. Introduction

Androgenetic alopecia (AGA) is the most common form of hair loss, affecting a significant portion of both male and female populations worldwide. In men, AGA often begins between adolescence and 30 years of age, with early onset associated with a more severe progression [1]. For women, AGA typically manifests around two peak periods: premenopausal in their 20s and postmenopausal around their 50s [1]. This condition is characterized by progressive hair thinning and loss, primarily mediated by dihydrotestosterone (DHT), a potent androgen hormone [2,3]. The prevalence of AGA underscores its relevance as a major dermatological concern, necessitating effective treatment strategies and further understanding of its underlying mechanisms [4,5].

The genetic basis of AGA has been a focal point of research, aiming to uncover the specific genetic variants that contribute to its development and progression. Single-nucleotide polymorphisms (SNPs) have been identified as significant markers associated with AGA, with particular attention given to genes involved in androgen metabolism and hair follicle regulation [1,6,7]. For instance, variations in the androgen receptor gene and other loci such as 2q35, 3q25.1, 5q33.3, and 12p12.1 have been linked to AGA susceptibility [7]. These genetic factors are crucial for developing targeted therapies and improving patient outcomes by tailoring treatments based on individual genetic profiles [1]. Notably, the identification of SNPs in genes like SRD5A2 and PTGFR has provided insights into the mechanisms driving AGA, further highlighting the importance of genetic research in this field [8,9].

Current therapeutic approaches for AGA include pharmacological treatments like minoxidil and finasteride [10,11]. However, the success of these treatments is often limited by individual differences in response, side effects, and patient adherence [1,11]. Meta-analyses have shown that while these treatments are generally more effective than placebos, their overall impact on hair regrowth and patient satisfaction remains inconsistent [12,13]. For example, a 12-month observational study demonstrated that a 5% minoxidil topical solution decreased the affected area in 62.0% of subjects, with hair regrowth rated as effective or very effective in 63.7% of patients [14,15,16]. Despite these benefits, physicians and patients often perceive the efficacy of treatments differently, underscoring the need for personalized approaches to improve outcomes [13,17].

The integration of genetic information into the treatment of diseases represents a significant advancement in personalized medicine. In the context of AGA, pharmacogenetics offers the potential to tailor treatments based on an individual’s genetic profile, thereby improving efficacy and minimizing adverse effects [1,18]. Genetic markers can provide insights into how patients metabolize drugs, respond to therapies, and predict treatment outcomes [7,19,20]. This approach not only enhances therapeutic effectiveness but also optimizes patient care by considering the genetic diversity that influences disease progression and treatment response [11,21,22]. The relevance of genetics in disease treatment is exemplified by the role of SNPs in predicting responses to AGA treatments, highlighting the need for further research and clinical integration of genetic data [18].

Pharmacogenetics, the study of how genetic variations influence drug response, holds great promise for the management of AGA. By identifying specific SNPs that affect treatment outcomes, researchers can develop more precise and effective therapeutic strategies [16,20]. Genetic variants in enzymes involved in drug metabolism or in receptors targeted by treatments like minoxidil can inform personalized treatment plans [10]. Future research aims to validate these genetic associations and integrate them into clinical practice, paving the way for personalized medicine to become a standard approach in AGA treatment [11,15]. This shift towards individualized care promises to enhance treatment efficacy, patient satisfaction, and overall health outcomes for those affected by AGA [1,11,19,20].

2. Androgenetic Alopecia

Androgenetic alopecia (AGA) is the most common cause of hair loss in both men and women, affecting a significant portion of the global population. Epidemiological studies have shown that AGA affects approximately 50% of men by the age of 50 and up to 80% by the age of 70 [4,22]. In women, the prevalence is lower, affecting about 40% by the age of 70 [4,22]. The onset of AGA in men can occur as early as late adolescence, with a progressive thinning of hair primarily at the temples and crown, leading to a characteristic “M”-shaped hairline [23]. In women, AGA typically presents as diffused thinning over the crown, with the frontal hairline often spared [23].

Genetic factors play a crucial role in the development of AGA, with several genetic loci, including the androgen receptor (AR) gene and the ectodysplasin A2 receptor (EDA2R) locus, being strongly implicated [7]. Additionally, environmental and hormonal factors, such as the conversion of testosterone to dihydrotestosterone (DHT) by the enzyme 5α-reductase, contribute to the miniaturization of hair follicles, a hallmark of AGA [21].

The prevalence of AGA varies among different ethnic groups, with studies indicating higher rates in Caucasians compared to Asians and Africans [17,24]. Moreover, AGA has been associated with various systemic conditions, including metabolic syndrome, cardiovascular diseases, and polycystic ovary syndrome (PCOS) in women, further highlighting its clinical significance [23].

Given the high prevalence and significant impact of AGA on affected individuals, it is epidemiologically relevant to explore this condition in detail. This review aims to address the critical aspects of AGA, including its genetic underpinnings, current pharmacological treatments, and the potential of pharmacogenetics to personalize treatment approaches. By examining these topics, we hope to enhance the understanding and management of AGA, paving the way for improved therapeutic strategies tailored to individual genetic profiles.

2.1. Genetics and Androgenetic Alopecia

The genetic basis of androgenetic alopecia (AGA) has been extensively studied, revealing numerous genetic variants associated with the condition. A significant proportion of these genetic markers are single-nucleotide polymorphisms (SNPs) that have been identified through genome-wide association studies (GWASs). These studies have highlighted the role of the androgen receptor (AR) gene, located on the X chromosome, as a major genetic determinant of AGA [7,25]. The AR gene contains several SNPs, such as rs12558842 and rs2497938, which have been strongly associated with AGA. These genetic variants affect androgen metabolism, influencing the miniaturization of hair follicles, a characteristic feature of AGA [26,27]. Furthermore, Chen et al. (2023) noted that prediction models using these SNPs can effectively differentiate between varying degrees of hair loss severity, underscoring their clinical relevance [27].

In addition to the AR gene, other genetic loci have been implicated in AGA. For instance, SNPs within the ectodysplasin A2 receptor (EDA2R) gene, located on chromosome 1, have been associated with an increased risk of AGA [18]. Moreover, GWASs have identified several other loci, such as 2q35, 3q25.1, 5q33.3, and 12p12.1, that contribute to the genetic architecture of AGA [28,29]. These loci include genes involved in hair follicle development and cycling, indicating a complex interplay of multiple genetic factors in the pathogenesis of AGA [30]. Notably, the study by Heilmann-Heimbach et al. (2017) identified 63 distinct genetic loci, further reinforcing the multifactorial nature of AGA [25]. Understanding these genetic associations is crucial for developing targeted therapies and improving patient outcomes.

The role of androgen metabolism in AGA is further underscored by the involvement of the SRD5A2 gene, which encodes the enzyme 5α-reductase type 2. This enzyme is responsible for converting testosterone to dihydrotestosterone (DHT), a potent androgen that binds to the AR and initiates the miniaturization of hair follicles [2]. SNPs in the SRD5A2 gene, such as rs523349, have been shown to influence enzyme activity and, consequently, the severity of AGA [9]. This genetic variant will be further discussed in the context of pharmacogenetics and its potential use in personalized treatment approaches. In addition, genetic variants in the prostaglandin D2 synthase (PTGDS) gene have been associated with AGA, implicating prostaglandin pathways in the condition’s pathophysiology [12]. As previously discussed, genetics plays a very important role in the pathogenesis of AGA as well as in the mechanisms associated with hair growth and therapy. In order to better present the relevant literature findings,

Table 1. Summary of key genetic variants associated with androgenetic alopecia (AGA).

Gene	SNP	Chromosome Location	Functional Role	Study References
AR	rs12558842	X	Major determinant of AGA; affects androgen metabolism	[31,32,33,34,35]
AR	rs2497938	X	Influences severity of hair loss through androgen receptor activity	[26,34,36,37]
SRD5A2	rs523349	2p23.1	Encodes 5α-reductase type 2, converts testosterone to DHT	[9,38,39]
EDA2R	rs1385699	1p36.12	Associated with increased risk of AGA, involved in hair follicle development	[33,36,40,41]
PTGDS	rs245324	9q34.2	Involved in prostaglandin pathways affecting hair growth	[1,12,15,42,43,44]
WNT10A	rs7349332	2q35	Implicated in hair follicle development through WNT signaling pathway	[1,7,33,38,44,45,46,47,48,49]
APCDD1	rs7349333	18p11.22	Inhibits WNT signaling, affecting hair follicle growth and cycling	[39,42,49]
LINC01475	rs7349341	6q23.2	Non-coding RNA influencing hair follicle function	[27,30,50]
HDAC9	rs12021639	7p21.1	Histone deacetylase affecting gene expression in hair follicles	[38,51,52]
SULT2A1	rs11085258	19q13.3	Sulfotransferase involved in DHT metabolism	[30,38,53]
TERT	rs2736098	5p15.33	Involved in telomere maintenance, associated with cellular aging and hair loss	[31,38]
TGFBR2	rs6784615	3p24.1	Transforming growth factor-beta receptor, involved in cell growth and differentiation	[34,54]
FOXO1	rs4946936	13q14.11	Forkhead box protein O1, involved in cell cycle regulation and apoptosis	[55]
RUNX3	rs2456449	1p36.11	Involved in hair follicle morphogenesis	[56,57,58,59]
PAX3	rs619847	2q36.1	Paired box 3, involved in early development of hair follicles	[58]
SOX13	rs7717630	1q32.1	SRY-box 13, transcription factor involved in hair growth	[38,51]
MUC1	rs4072037	1q22	Mucin 1, cell surface-associated, involved in cell adhesion and signaling	[1,31]
ACE	rs4343	17q23.3	Angiotensin I-converting enzyme, involved in blood pressure regulation	[60]
COL1A1	rs1800012	17q21.33	Collagen type I alpha 1 chain, involved in collagen structure	[1,7,25]
PTGFR	rs10782665	1p31.1	Prostaglandin F receptor, involved in prostaglandin signaling	[55]
EBF1	rs17643057	5q33.3	Involved in B-cell development	[25,31]
GPR44	rs533116	9q34.3	Prostaglandin D2 receptor, involved in hair growth inhibition	[1,11]

summarizes the main genetic variants and their relevance in AGA.

Emerging genetic markers have also been identified through recent GWASs, providing new insights into the genetic basis of AGA. Yap et al. (2018) identified 624 genetic loci associated with AGA in a large cohort of UK Biobank participants. These loci include genes involved in WNT signaling, prostaglandin metabolism, and inflammatory pathways, highlighting the multifactorial nature of AGA [30]. The identification of these genetic markers not only advances our understanding of the disease but also opens new avenues for therapeutic interventions targeting these pathways [11]. Another significant finding is the identification of SNPs in the APCDD1 gene, which is involved in WNT signaling and hair follicle development, further supporting the role of this pathway in AGA [46,47].

Further research is needed to validate these genetic associations and understand their functional implications. Integrating genetic data with clinical phenotypes and treatment responses will be crucial in developing personalized medicine approaches for AGA. By leveraging the power of genetics, we can enhance the efficacy of existing treatments and identify novel therapeutic targets, ultimately improving patient outcomes [1]. The following table provides a comprehensive summary of key genetic variants associated with AGA, their functional roles, and the implications for future research and treatment strategies.

2.2. Pharmacological Therapy of Androgenetic Alopecia

The treatment of androgenetic alopecia (AGA) primarily involves pharmacological interventions such as topical minoxidil and oral finasteride. Minoxidil, a vasodilator, promotes hair growth and slows hair loss by prolonging the anagen phase of the hair cycle and increasing follicular size [61]. This effect is achieved through the opening of potassium channels in the smooth muscle cells surrounding the hair follicles, leading to hyperpolarization of the cell membrane and increased blood flow to the hair follicles, which ultimately stimulates hair growth. Multiple studies have shown that minoxidil is effective in both men and women, with the 5% solution generally providing better results compared to the 2% solution [59,61]. Finasteride, a 5-alpha-reductase inhibitor, prevents the conversion of testosterone to dihydrotestosterone (DHT), a key androgen involved in AGA pathogenesis. This reduction in DHT levels has been proven to significantly slow the progression of hair loss and, in some cases, promote hair regrowth [61,62,63]. Dutasteride, another 5-alpha-reductase inhibitor, has demonstrated efficacy in treating AGA, particularly in patients unresponsive to finasteride. Dutasteride inhibits both type 1 and type 2 5-alpha-reductase enzymes, leading to a more comprehensive reduction in DHT levels, which has been shown to be more effective in treating AGA than finasteride [64,65].

Recent advancements have introduced novel therapies such as low-level laser therapy (LLLT), platelet-rich plasma (PRP) injections, and microneedling. LLLT is believed to stimulate hair growth by enhancing cellular activity and blood flow in the scalp, likely through the activation of cytochrome c oxidase, which increases ATP production and triggers downstream effects that promote hair follicle health [60,61,62]. PRP involves injecting concentrated platelets from the patient’s blood into the scalp, releasing growth factors that may stimulate hair follicles and improve hair density and thickness [52,61,64]. Studies have shown that PRP can significantly increase hair count and thickness in patients with AGA, although the treatment protocols vary widely, and the results are often dependent on the specific PRP preparation used [58,60]. Microneedling, often combined with topical treatments, induces controlled micro-injuries that promote wound healing and enhance the penetration of topical agents like minoxidil [60]. The addition of microneedling to a treatment regimen has been shown to improve the efficacy of minoxidil, likely by enhancing its absorption through the skin [60,61].

However, the efficacy of these treatments varies significantly among individuals. While minoxidil and finasteride are effective for many, a significant subset of patients does not respond to these therapies. The variability in response can be attributed to genetic differences, underlying health conditions, and other individual factors [65,66]. Additionally, treatments such as PRP and LLLT, although promising, lack standardized protocols and robust evidence from large-scale randomized controlled trials to fully establish their efficacy. This has led to a situation where some patients experience substantial benefits, while others see little to no improvement [58,59,60]. Furthermore, long-term adherence to treatments is often poor due to the slow onset of visible results, the need for continuous application, and potential side effects. The chronic nature of AGA requires ongoing treatment, which can be burdensome for patients and may lead to discontinuation of therapy [62,63,64,65].

Given the limited efficacy of current treatments and the individual variability in response, ongoing research is crucial to develop more effective and personalized therapies. Emerging therapies, such as clascoterone, a topical androgen receptor inhibitor currently in clinical trials, offer hope for more targeted treatments. Clascoterone works by directly inhibiting the androgen receptor, thus blocking the effects of DHT on hair follicles without affecting systemic hormone levels. This could potentially offer a safer and more effective treatment option for patients with AGA, particularly those who are unable to tolerate the side effects of oral medications like finasteride [32,61]. The complex nature of AGA requires a multifaceted approach to treatment, combining existing therapies with emerging ones, and tailoring them to individual patient needs and genetic profiles. The subsequent section will delve into the potential of pharmacogenetics to revolutionize the treatment of AGA, providing insights into how genetic markers can guide therapeutic decisions and improve patient outcomes [57,61].

Moreover, the efficacy of AGA treatments is a critical consideration for both clinicians and patients. Studies indicate that while minoxidil and finasteride are generally effective, their impact on hair regrowth and patient satisfaction can vary widely. For example, a long-term study found that minoxidil resulted in significant hair regrowth in approximately 60% of men with AGA, with the greatest efficacy observed in the vertex area of the scalp [61]. In contrast, finasteride has been shown to halt the progression of hair loss in 90% of men and promote regrowth in about 65%, particularly in the crown region [35,66]. However, these treatments are less effective in the frontal scalp area, which is often the most concerning for patients. This highlights the need for individualized treatment plans that consider the specific pattern of hair loss and patient preferences. The advent of new therapies, including those targeting different pathways involved in hair loss, holds promise for improving treatment efficacy and expanding the options available to patients with AGA [19].

2.3. Potential Use of Pharmacogenetics to Treat Androgenetic Alopecia

Pharmacogenetics, the study of how genetic variations influence individual responses to drugs, has the potential to revolutionize the treatment of androgenetic alopecia (AGA). By understanding the genetic basis of drug response, it is possible to develop personalized treatments that are more effective and have fewer side effects. Pharmacogenetics aims to tailor medical treatment to the individual characteristics of each patient, including their genetic makeup, to predict their response to specific medications and adjust treatment accordingly [62].

Numerous single-nucleotide polymorphisms (SNPs) have been associated with AGA and its therapeutic management. Specifically, SNPs such as rs13283456 (PTGES2) and rs4343 (ACE) have been closely linked to mechanisms that regulate the vasodilatory system [63]. A statistical analysis examining the correlation between these SNPs has shown a significant association, highlighting the role of functional alterations in genes involved in vasodilation control in the development of alopecia. Minoxidil, a commonly used initial treatment for alopecia, primarily works through vasodilation by opening potassium channels in the smooth muscles of peripheral arteries, leading to hyperpolarization of the cell membrane [10,62,64]. Individuals with genetic polymorphisms that result in reduced PTGES2 and ACE activity may have a better response to minoxidil, suggesting that genetic factors influencing vasodilation may contribute to differences in treatment outcomes.

Additionally, analysis has focused on SNPs involved in testosterone metabolism, such as rs2470152 (CYP19A1), rs39848 (SRD5A1), and rs523349 (SRD5A2). Among these, rs523349, associated with the type 2 5-alpha-reductase enzyme, has shown a strong link with AGA. The increased activity of SRD5A2 is related to elevated DHT production, a hormone known to bind to its receptors in hair follicle cells, leading to decreased follicle function [63]. This finding supports the clinical effectiveness of finasteride and dutasteride, given that this enzyme is essential in their mechanisms of action. Previous research has also linked the activity of SRD5A2 and the SNP rs523349 with AGA and other testosterone metabolism alterations [64,65,66].

Emerging treatments for alopecia, e.g., cetirizine and phytotherapeutic products derived from Nigella sativa [67], are associated with the modulation of prostaglandin D2 (PGD2) levels and responses. The hormonal sensitivity of PTGDS in various systems and the presence of PGD2 receptors in the hair follicle’s outer root sheath further underscore the crucial role of prostaglandins in AGA. The elevated levels of PGD2 may contribute to the increased size of sebaceous glands seen in this condition. The SNPs rs533116 and rs545659 in the prostaglandin D2 receptor are significant genetic findings related to AGA, supporting mechanisms previously linked to the disease’s pathogenesis [13]. The importance of these SNPs is emphasized by the recognized role of prostaglandins in regulating hair functions, including the opposing effects of PGE2 and PGF2a in promoting hair growth and PGD2 in inhibiting it [15]. Figure 1 provides an overview of the molecular targets for treatment and the genomic markers that might be used to predict therapeutic success.

The potential of pharmacogenetics in AGA treatment lies in identifying these genetic markers and integrating them into clinical practice to guide therapeutic decisions. This personalized approach promises to enhance treatment efficacy and patient satisfaction, marking a significant step towards individualized alopecia management. Further research is needed to validate these genetic associations and explore additional genetic markers that may contribute to the variability in treatment response [1].

3. Discussion and Conclusions

The exploration of genetic and pharmacogenetic research has revealed significant insights into the pathogenesis and treatment of androgenetic alopecia (AGA). This condition, with its high prevalence and profound impact on individuals’ quality of life, necessitates effective therapeutic strategies. Genetic studies have identified numerous single-nucleotide polymorphisms (SNPs) associated with AGA, highlighting key genes involved in androgen metabolism, prostaglandin pathways, and vasodilation. These genetic markers not only enhance our understanding of AGA but also present potential targets for innovative treatments.

Pharmacogenetics offers a promising approach to personalize AGA treatment. The identification of SNPs that influence the response to drugs like minoxidil and finasteride opens new avenues for individualized therapy. For instance, patients with specific genetic variants in the SRD5A2 gene, affecting dihydrotestosterone (DHT) metabolism, may respond better to 5-alpha-reductase inhibitors. Similarly, genetic polymorphisms in genes related to vasodilation and prostaglandin pathways can guide the use of minoxidil and other emerging therapies. These pharmacogenetic insights pave the way for more personalized and effective approaches to AGA management.

The future of AGA treatment extends beyond traditional pharmacogenetics. Recent advancements in RNA interference (RNAi) technology, particularly the use of small interfering RNAs (siRNAs) and asymmetric siRNAs (asiRNAs), hold significant promise. Studies such as those by Moon et al. (2022) have demonstrated the potential of cholesterol-conjugated, chemically modified cp-asiAR to significantly reduce androgen receptor (AR) mRNA and protein levels. This novel approach has shown efficacy in promoting hair growth in AGA mouse models and ex vivo human scalp tissues. RNAi-based treatments could provide a highly specific and localized intervention, offering a promising alternative for patients who do not respond well to traditional therapies or experience systemic side effects [68,69].

In conclusion, integrating genetic and pharmacogenetic research into clinical practice has the potential to transform the treatment landscape for androgenetic alopecia. The identification of genetic markers and their role in drug response enables personalized therapeutic strategies that enhance treatment outcomes and patient satisfaction. Furthermore, the exploration of RNAi technology presents an exciting frontier in dermatology, promising more effective and tailored solutions for individuals suffering from androgenetic alopecia.