Genetic polymorphisms and their association with atopic dermatitis in skin of color – A comprehensive review

INTRODUCTION

Atopic dermatitis (AD) is a chronic inflammatory skin condition with a multi-factorial etiology. It has significant global health implications, especially in children. Skin of color (SOC) refers to Asian, including Indian skin, African, Latin, Hawaiian, Pacific Islanders, Native Americans, Chinese, Japanese, Hispanics, and other people of Indigenous descent.^[1] SOC is generally under-represented across all dermatological conditions, especially in AD. There are variations in the genetic make-up, pathogenesis, epidemiology, clinical features, complications, and management of AD in SOC, compared to Caucasian skin.^[2] A combination of genetic predisposition and environmental triggers contributes to the onset and progression of AD within an individual. This intricate interplay accounts for the wide variation seen in the disease’s presentation, severity, and progression. Factors such as ethnicity, geographic location, climate, pollution levels, and occupational exposures play key roles in shaping these differences.^[3] Genetic factors play a pivotal role in the pathogenesis of AD, accounting for almost 82% of the risk.^[4] Children with a strong family history of atopy in both parents are at a 5 times higher risk of developing early-onset AD.^[5] Genetic risk factors vary across ethnic groups, indicating the need for population-specific studies. Recognizing the distinct clinical manifestations of AD across various ethnic groups, along with the genetic polymorphisms that affect disease susceptibility and treatment response, is essential for effectively managing a growingly diverse patient population. Studying AD in SOC populations presents unique challenges due to underrepresentation in clinical and genetic research. Variations in pigmentation can mask classic signs like erythema, leading to delayed or missed diagnoses.^[6] Differences in healthcare access and cultural perceptions of skin disease further contribute to disparities. In addition, most genomic studies have focused on European populations, limiting the applicability of findings to diverse ethnic groups.^[7] This review aims to cover the genetic basis and specific genetic polymorphisms of AD in the under-represented SOC, with more focus on genetic variability in Indian skin.

GENETIC BASIS OF AD

Heritability estimates from family and twin studies suggest that genetic factors contribute significantly (70–80%) to the risk of developing AD, underscoring its polygenic and multifactorial nature rather than a simple familial inheritance. Monozygotic twins exhibit concordance rates as high as 86%, compared to 21–23% in dizygotic twins. A landmark discovery in the genetics of AD is the identification of loss-of-function mutations in the Filaggrin (FLG) gene, which compromise skin barrier function. These mutations are common in Northern Europeans but occur at much lower frequencies in populations of African ancestry. Beyond FLG, several other genetic variants have been linked to AD, particularly those involved in the Th2 immune pathway, including interleukin-4 (IL-4), IL-13, and IL4R, as well as serine protease inhibitor Kazal type 5 (SPINK5), which is implicated in Netherton syndrome. Genome-wide association studies (GWAS) have further expanded the genetic landscape of AD, identifying over 30 risk loci, many associated with epidermal barrier integrity and immune regulation. Some loci are located in non-coding regions, indicating the need for functional follow-up studies. Phenome-wide association studies have demonstrated that FLG mutations are also associated with other atopic conditions such as asthma and allergic rhinitis. Whole-exome and genome sequencing efforts have revealed rare variants in genes such as general transcription factor IIH subunit 5(GTF2H5), A disintegrin and metalloproteinase domain containing protein 33 (ADAM33), envoplakin (EVPL), NLR family pyrin domain containing 1 (NLRP1), underscoring the genetic heterogeneity of AD and the need for ancestry-specific research.^[8]

The epidermal differentiation complex (EDC), located on chromosome 1q21, is a key genomic region involved in maintaining skin barrier structure and function. This region spans about 1.9 megabases and includes nearly 45 genes, which are mainly categorized into three groups: Cornified envelope precursor proteins such as loricrin, involucrin, and late-stage small proline-rich proteins; the S100 calcium-binding protein family; and the S100 fused-type proteins (SFTPs), which include FLG, FLG-2, trichohyalin, trichohyalin-like protein 1, hornerin, repetin, and cornulin. Among these, the SFTP family is particularly significant in the context of AD, due to its central role in skin differentiation and immune barrier function. Beyond the genes located within the EDC, whole genome sequencing has highlighted SID1 transmembrane family member 2 (SIDT2) (on chromosome 11q23.3) and RBBP8NL (on 20q13.33) as important modulators of keratinocyte-mediated antiviral defense, particularly in response to herpes simplex virus type 1.^[9]

ROLE OF FLG IN AD

The FLG gene, situated on chromosome 1q21 within the EDC, encodes FLG, a critical protein in the stratum corneum (SC). Research from European and Asian populations has consistently shown that FLG loss-of-function mutations are a major risk factor for AD, identified in nearly 50% of European and about 27% of Asian patients with the condition.^[23] Individuals carrying these mutations often present with an earlier onset of AD, more severe symptoms, increased susceptibility to eczema herpeticum, and a higher likelihood of other atopic conditions compared to those without the mutations.^[24]

FLG-2, a member of the S-100 protein family and part of the polyfilament group, is derived from profilaggrin through processes involving dephosphorylation and proteolytic cleavage. A deficiency of FLG-2 has been associated with abnormalities in the structural organization and maturation of the lipid bilayers, a reduction in the cohesion of corneocytes, and increased permeability of the SC.^[25] In vitro experiments using reconstructed human epidermal models demonstrated that silencing FLG2 expression through short hairpin RNA (shRNA) resulted in a significant reduction of natural moisturizing factor (NMF) components such as urocanic acid and pyrrolidone carboxylic acid, which are essential for absorbing ultraviolet (UV) radiation and contribute to protection against UVB-induced damage. Furthermore, reduced FLG2 expression led to structural changes in the epidermis, including a denser SC with parakeratosis, the presence of abnormal intracellular vesicles, and an increase in surface pH, which are features consistent with a weakened skin barrier and could predispose to conditions like AD.^[26] However, there are no studies currently that directly link standalone mutations in FLG2 and the development of AD.

The most prevalent FLG mutations (R501X, 2282del4, S3247X, and R2447X) are found in 7–10% of White Europeans, whereas Asian populations tend to have distinct FLG null mutations specific to their ethnic backgrounds. In populations of African descent, the link between FLG mutations and AD remains less definitive. FLG mutations appear to be approximately 6 times less frequent in African Americans than in European Americans. The four most common FLG null mutations are found in fewer than 5.8% of African-Americans, compared to 27.5% in European Americans. Interestingly, the mutation frequency is higher among African-Americans diagnosed with both AD and ichthyosis vulgaris, with one study reporting a 22.2% mutation rate in this subgroup. Similar to European populations, lower intragenic copy number in FLG is associated with more severe disease in African-Americans, with each additional FLG monomer reducing the risk of AD by 12%.

CLINICAL IMPLICATIONS OF GENETIC POLYMORPHISMS

Effect of FLG deficiency on the epidermis: Loss-of-function mutations in the FLG gene result in truncated profilaggrin that cannot be processed into functional FLG monomers. This deficiency disrupts the skin barrier by affecting keratin filament organization, lamellar body secretion, and lipid layering in the SC. It also impairs tight junction formation by reducing the expression of key proteins such as (Zonula Occludens 1) ZO-1 and occludin, weakening the skin’s structural integrity. FLG breakdown products contribute to NMFs, and their absence increases transepidermal water loss, raises skin pH, and reduces hydration. Elevated pH further impairs lipid-processing enzymes, worsening the barrier defect. Moreover, a weakened barrier allows allergens to penetrate more easily, triggering local inflammation and systemic sensitization. Studies in FLG-deficient mice have demonstrated enhanced allergen absorption and elevated antigen-specific IgE levels. This supports the idea that FLG mutations can accelerate progression along the atopic march by facilitating allergic sensitization through the skin.^[34] Understanding the clinical implications of genetic polymorphisms in AD is crucial for moving toward a personalized approach to diagnosis, prognosis, and therapy. Specific gene variants can influence not only susceptibility to AD but also its severity, chronicity, and response to treatment. Identifying such polymorphisms, particularly in populations with SOC, allows for better risk stratification and may guide tailored interventions in the future. Table 4 summarizes key single-nucleotide polymorphisms (SNPs) found to be associated with either increased risk or protective effects.^[35]

CONCLUSION

The study of gene mutations in atopic dermatitis affecting skin of color is still an under-represented area of research. This review throws light on certain genetic mutations specific to Indian and other ethnic skin populations, compared to the western cohort. Clinically recognizing these genetic differences may pave the way for risk prediction, and improved patient outcomes. Further research on region specific bio-banks and inclusive genomic studies in Indian skin are essential to bridge the knowledge gap.