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Vitiligo is an acquired skin disorder characterized by the selective destruction of melanocytes in the skin, resulting in the development of depigmented macules and patches. This study investigates the potential role of Liver X Receptor-α (LXR-α) gene polymorphism (rs2279238) (C>T) in vitiligo pathogenesis among Egyptian patients. We conducted genetic analysis on 25 vitiligo patients aged 12 to 50, comparing them with 25 age and sex-matched controls. The study revealed a significant association between LXR-α gene polymorphism and vitiligo in Egyptian patients. However, there was no correlation found between this polymorphism and the severity or activity of vitiligo.
These findings suggest that LXR-α gene polymorphism may play a role in the development of vitiligo among Egyptian patients.
Vitiligo is an acquired skin disorder resulting from the selective destruction of melanocytes in the skin, leading to the development of depigmented macules and patches[1]. It typically presents as bilaterally symmetric depigmented areas, with a preference for periorificial and trauma-prone skin regions.
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Commonly affected sites include the eyelids, ears, nostrils, perioral skin, axillae, wrists, elbows, hands, fingers, areolae, periumbilical skin, genitals, inguinal folds, ankles, knees, and toes[1].
Various theories have been proposed to elucidate the pathogenesis of vitiligo, including genetic, autoimmune, oxidative stress, autocytotoxic, neurohumoral, and convergence theories[2]. However, none of these theories has provided a comprehensive understanding of the disorder's development.
More than 150 genes have been identified that influence pigmentation in the skin, hair, and eyes, in addition to numerous signaling, transcriptional, and biological factors involved in regulatory pathways[3][4].
The focus of this study is the Liver X Receptor (LXR), a ligand-activated nuclear transcription factor that regulates the expression of genes involved in various physiological processes. LXR exists in two isoforms: LXR-α and LXR-β[5]. While LXR-α is highly expressed in metabolically active tissues such as the liver, adipose tissue, macrophages, and intestine, LXR-β is ubiquitously expressed in most tissues[5][6].
The relevance of LXR-α in vitiligo development arises from its functional link between keratinocytes and melanocytes. LXRs serve as transcription factors that regulate genes associated with lipid biosynthesis, immunity, and inflammation. Cutaneous LXRs are implicated in the regulation of melanocyte and keratinocyte functions[7][8].
Although melanocytes express LXR, the precise functions of LXR in these cells remain unclear. Kumar et al. noted a significant increase in LXR-α expression in melanocytes obtained from perilesional skin compared to normal skin in vitiligo patients[7].
The study was conducted on a cohort of 25 vitiligo patients aged between 12 and 50, comprising both genders and encompassing various clinical types of vitiligo. Additionally, 25 age and sex-matched controls were included in the study.
Participants, both patients and controls, were recruited from the Dermatology Outpatient Clinic of Alexandria Main University Hospital in Egypt. Ethical approval for the study was granted by the institutional ethics committee, and all participants provided informed written consent.
Exclusion criteria were applied to eliminate individuals with the following conditions: inflammatory bowel disease, cancer, diabetes, polycystic ovary syndrome, obesity, and cardiovascular disease.
The genotyping process involved several steps:
The vitiligo group comprised 14 females (56%) and 11 males (44%), with a mean age of 32.68 ± 11.09 years. No statistically significant differences were observed between the patient and control groups concerning age and sex. Additional characteristics of both groups are summarized in Tables (1) and (2).
There were no statistically significant differences between the patients and the control group regarding Random Blood Glucose (RBG) (P=0.095), Triglycerides (TG) (P=0.355), Low-Density Lipoprotein (LDL) (P=0.072), and High-Density Lipoprotein (HDL) (P=0.725).
The genotype distribution of the LXR gene single nucleotide polymorphism (SNP) (rs2279238) in the vitiligo and control groups was consistent with Hardy-Weinberg equilibrium. Hardy-Weinberg Equilibrium is a genetic law that states that allele or genotype frequencies in a given population will remain constant from generation to generation in the absence of evolutionary events such as immigration, random mating, selection, and genetic flow.
The observed genotype frequencies, including the TT mutant genotype, the heterozygous SNP (CT) genotype, and the (CC) wild genotype, were in agreement with the Hardy-Weinberg equilibrium in the overall population (P=0.051).
The distribution of genotypes for the Liver X Receptor-alpha gene (rs2279238) among the vitiligo group was as follows: TT mutant genotype was detected in 2 cases (8%), the heterozygous SNP (CT) genotype in 20 cases (80%), and finally, the (CC) wild genotype in 3 cases (12%).
On the other hand, the distribution of genotypes for the Liver X Receptor-alpha gene (rs2279238) among the control group revealed that no one carried the (TT) mutant genotype, the heterozygous SNP (CT) genotype was detected in 14 controls (56%), and finally, the (CC) wild genotype was detected in 11 controls (44%).
A statistically significant difference was observed between the two groups with regard to the (rs2279238) genotype (P=0.014) (see Table 3).
There were no statistically significant differences between the three genotypes regarding smoking (P=0.060).
All cases carrying the homozygous wild group (TT) had generalized vitiligo, while in the SNP heterozygous group (CT), 15 cases had generalized vitiligo, and 5 cases had segmental vitiligo. Meanwhile, all cases carrying the (CC) mutant genotype had segmental vitiligo.
There were no statistically significant differences between the three genotypes regarding VIDA (P=0.615), VASI score (P=0.131), family history of vitiligo (P=0.336), UV radiation exposure (P=0.241), or psychological stress (P=0.009).
The observed minor allele frequency (T) of (rs2279238) was detected in 48% of cases, while in controls, it was detected in 28%. Conversely, the frequency of the (C) allele was found in 52% of cases, while in controls, it was 72% (see Table 4).
There was a statistically significant increase in the minor allele (T) frequency of (rs2279238) in vitiligo patients compared to controls (P=0.039). The minor allele (T) was found to be associated with a statistically significant increased risk of vitiligo.
In this study, the Liver X Receptor-alpha gene polymorphism (rs2279238) adhered to Hardy-Weinberg equilibrium, which aligns with the findings of Agarwal S et al. (13). They also reported that Liver X receptor-α polymorphisms (rs11039155 and rs2279238) followed Hardy-Weinberg equilibrium and were associated with vitiligo susceptibility. However, this contradicts Rogers et al. (14), who suggested that one of the primary causes of deviation from Hardy-Weinberg equilibrium is the association of genetic polymorphisms with disease pathogenesis.
Statistically significant differences were observed between the vitiligo and control groups regarding the (rs2279238) genotype, which corroborates the results of Agarwal S et al. (13). They reported that Liver X Receptor-α polymorphisms (rs2279238) are associated with vitiligo susceptibility. These findings are consistent with studies by Bakry OA et al. (15), Hong I et al. (16), and Kumar et al. (17), all of which reported elevated LXR-α expression in melanocytes from perilesional skin compared to normal skin in vitiligo patients. Bakry OA et al. (18) also found that LXR activation induces keratinocyte differentiation and inhibits proliferation, affecting melanocyte growth and survival. Similarly, Lee CS et al. (19) reported that Liver X receptor activation inhibits melanogenesis.
Regarding allele frequency, the observed minor allele frequency (T) of (rs2279238) was significantly higher in vitiligo patients (48%) compared to controls (28%). Conversely, the frequency of the (C) allele was more prevalent in cases (52%) than controls (72%). These findings are in line with Agarwal S et al. (13), who reported that Liver X Receptor-α polymorphisms (rs2279238) allele frequency is associated with vitiligo susceptibility. The minor allele (T) was found to be significantly linked to an increased risk of vitiligo, with an Odds ratio of 0.039.
There were no statistically significant differences between the three genotypes regarding family history of vitiligo (P=0.336), consistent with Hilding et al. (20), who found no association between LXR genotyping and family history of disease in a similar study on diabetes.
Regarding smoking, there were no statistically significant differences between the three genotypes (P=0.060). This differs from findings by Jung CG et al. (21), who reported clear induction of LXR mRNA and increased translocation after exposure to cigarette smoking. It also contrasts with Rigamonti E et al. (22), who demonstrated increased ABCA1 expression (both mRNA and protein levels) in human cells after cigarette smoking exposure, leading to liver X receptor (LXR) translocation and activation, which in turn increases ABCA1 gene expression. These conflicting results may be attributed to differences in nucleotide sequences and the study's ethnic groups.
Regarding ultraviolet radiation (UVR) exposure, there were no statistically significant differences between patients and controls (P=0.241). This aligns with Ken C. N. Chang (23), who demonstrated that LXR signaling is down-regulated in cell-based models of photoaging, such as UV-activated keratinocytes and tumor necrosis factor (TNF_ α ) activated dermal fibroblasts. Similarly, Marionnet et al. (24) reported that gene expression changes induced by daily ultraviolet light require chronic successive exposure and can be prevented by broad-spectrum sunscreen. However, this contradicts with Thomas L. Des Marais et al. (25), who observed global changes in gene expression and associated pathways in human keratinocytes exposed to UVR. It also contradicts with Zhang, X. et al. (26), who reported that solar simulated ultraviolet radiation induces global histone hypoacetylation in human keratinocytes, leading to alterations in transcription factors and stress response genes. Furthermore, Takeuchi, et al. (27) conducted a study illustrating that mitotic genes are transcriptionally upregulated in fibroblasts exposed to very low doses of UVR.
Regarding psychological stress, there was a statistically significant difference between the three genotypes (P=0.009). This is consistent with Marsland AL et al. (28), who reported that persistent stress is accompanied by an increase in cytokines, oxidative stress, reactive oxygen species (ROS), and reactive nitrogen species (RNS) production, all of which can interfere with the regulatory mechanisms of liver regeneration and the regulation of nuclear receptors (NRs), especially the liver X receptor. Similarly, Nguyen ET et al. (29) found a correlation between psychological stress and liver X receptor regulation.
This study sheds light on the potential role of Liver X Receptor-alpha gene polymorphism (rs2279238) in the pathogenesis of vitiligo among Egyptian patients. Several significant findings emerged from our investigation:
Our findings align with previous research, supporting the notion that Liver X Receptor-alpha gene polymorphism (rs2279238) may contribute to vitiligo susceptibility. However, further studies with larger sample sizes and diverse populations are needed to confirm our results and explore the mechanisms underlying this genetic association.
Understanding the genetic basis of vitiligo is essential for developing targeted therapies and interventions that could potentially mitigate the impact of this challenging skin disorder.
Vitiligo and LXR-α Gene Polymorphism. (2024, Jan 18). Retrieved from https://studymoose.com/document/vitiligo-and-lxr-gene-polymorphism
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