The Overlap between Genetic Susceptibility to COVID-19 and Skin Diseases.

Coronavirus disease 2019 (COVID-19) mainly affects the respiratory system, but the involvement of other organ systems has also been commonly reported. Acute acro-ischemia or chilblain like lesions were among the first recognized dermatological presentations of COVID-19. Though the occurrence of such lesions has been attributed to the similar interferon-1 mediated immune response in both COVID-19 and systemic lupus erythematosus, we propose another possible explanation based on a common genetic background. In a recent genome-wide association study, the 3p21.31 region was found to be associated with COVID-19 severity. This region also contains the TREX1 gene. Missense mutations of the TREX1 gene are responsible for familial chilblain lupus and its genetic polymorphisms have been implicated in the pathogenesis of systemic lupus erythematosus. Based on this observation, herein we have reviewed other COVID-19 risk loci for potential overlap with dermatological conditions.

Immunological aspects of COVID-19-related skin manifestations: Revisiting pathogenic mechanism in the light of new evidence.

The newly emerged coronavirus disease 2019 (COVID-19), induced by a novel strain of the coronavirus family, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a rapidly spreading global threat. This virus affects a fair number of tissues in the human body by availing itself of potential target receptors like Angiotensin-Converting Enzyme 2 (ACE2). Presenting with diverse clinical manifestations, COVID-19 has raised the urge for extensive research in different medical fields, including dermatology. Developing a comprehensive knowledge of cutaneous manifestations is highly important as it can help us in early diagnosis and better management of the ongoing pandemic. The dermatological presentations of COVID-19 are classified into main categories of vascular and non-vascular (exanthematous) patterns. Though not yet fully confirmed, the pathogenesis of these cutaneous presentations has been suggested to be more related to the overactivation of the immune system. In this review, we discuss in detail the clinical features of the diverse skin lesions in COVID-19 patients and the imperative role of the immune system in their pathogenesis and development. Furthermore, we will discuss the reasons behind the accentuation of skin lesions in COVID-19 compared to the same virus family predecessors.

Ichthyosis follicularis syndromes in patients with mutations in GJB2.

Ichthyosis follicularis (IF) manifests as generalized spiny follicular projections found in syndromic diseases secondary to SREBF1 and MBTPS2 mutations. We sought the genetic cause of IF in two distinct families from a cohort of 180 patients with ichthyosis. In Family 1, the proband (Patient 1) presented with IF, bilateral sensorineural hearing loss and punctate palmoplantar keratoderma. Using DNA from peripheral blood lymphocytes, two compound heterozygous mutations, c.526A>G and c.35delG, were discovered in GJB2. In Family 2, the proband (Patient 2) presented with a previously unreported IF phenotype in the context of keratitis-ichthyosis-deafness syndrome, and whole-exome sequencing found a de novo heterozygous mutation, c.148G>A in GJB2. Histopathology was consistent with porokeratotic eccrine ostial and dermal duct naevus (PEODDN) and IF in Patients 1 and 2, respectively. Our findings add to the clinical and histopathological spectrum of IF and emphasize the association of PEODDN-like entities with GJB2 variants.

The Concept of Immunogenetics.

Genetics plays a major role in shaping the immune responses in both physiological and pathological states such as psoriasis, alopecia areata, and other immune-mediated dermatological conditions. The genes encoding the elements of the immune system and its regulators are among the most polymorphous loci in the genome. Subtle variations in these genes can thus alter the balanced defensive responses of the immune system and make an individual liable to diseases and environmental triggers. Immunogenetics deals with finding the precise set of liability genes involved in the pathogenesis of specific complex diseases. In this chapter, we will briefly discuss the basic principles of genetic polymorphisms, the methods used in scanning these polymorphisms, and the strategies employed to find the role of these polymorphisms in complex diseases.

The Immunogenetics of Alopecia areata.

Alopecia areata (AA) is an autoimmune disease that targets the hair follicles (HF) and results in non-scarring hair loss. AA results from the collapse of the HF's immune privilege due to a combination of environmental and genetic factors that either change the local HF dynamics or dysregulate the central immune tolerance. Multiple genetic studies have attempted to identify AA susceptibility genes through candidate gene approaches and genome-wide analysis. These studies were able to show an association between AA and multiple immune-related genes such as those encoding cytokines, chemokines, molecules involved in regulatory T-cell functions, and adaptor molecules along with genes involved in autophagy, melanogenesis, and hair cycling pathways. This chapter aims to explore these genes and their contribution to the pathogenesis of the AA.

The Immunogenetics of Systemic Sclerosis.

Systemic sclerosis (SSc) is a rare disease with a prevalence ranging from 7 to 700 cases per million. Like with most autoimmune diseases, both environmental and genetic factors are involved in the pathogenesis of the SSc. Though the incidence of SSc in the family members of those affected and the concordance rate in twins is very low, inheritance is still the strongest risk factor of SSc. Thus, multiple studies have been conducted to identify the genes responsible for this inheritance including candidate gene association studies and genome-wide analyses. Variations and mutations in the genes encoding cytokines, adhesion molecules, and signaling proteins involved in the interaction between endothelial cells, fibroblasts, and immune cells have been found to be associated with SSc susceptibility. In this chapter, these genes and their contribution to the pathogenesis of the SSc are discussed in detail. These genes are categorized into five major groups of HLA genes, genes involved in the innate immune responses, genes affecting adaptive immune responses, genes with a role in the fibrogenesis pathways, and apoptosis, autophagy, and pyroptosis-related genes.

Immunogenetics of Lupus Erythematosus.

Lupus erythematosus (LE) is a heterogeneous disease with a wide range of manifestations ranging from localized lesions in cutaneous lupus erythematosus (CLE) to severe disseminated disease in systemic lupus erythematosus (SLE).Lupus results from a complex interaction between genetic and epigenetic backgrounds and environmental triggers that cause loss of tolerance to self-antigens and the formation of autoantibodies. Genetic susceptibility plays a key role in the pathogenesis of lupus erythematosus. In most cases, multiple common alleles with modest effect sizes are combined to result in the polygenic inheritance of the disease but monogenic variants of lupus have also been described. Genes from the innate and adaptive immune system along with genes involved in apoptosis and immunoglobulin clearance have been linked to SLE. This chapter aims to explore the functions of these genes and their contribution to the pathogenesis of the disease.

COVID-19 and exacerbation of dermatological diseases: A review of the available literature.

Since the emergence of the new coronavirus disease 19 (COVID-19) pandemic, there has been a concern for the patients with chronic autoimmune diseases including dermatological conditions over the potential exacerbation of these underlying conditions after infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV2). We performed a systematic review to evaluate presentations, postinfection change in the manifestation, diagnosis, and management of flare-ups of underlying dermatologic disease in patients with COVID-19. A total of 17 articles were recovered reporting on flare-ups of dermatological disease including pemphigus vulgaris, psoriasis, subacute cutaneous lupus erythematosus, acrodermatitis continua of Hallopeau, systemic sclerosis sine scleroderma, and Sézary syndrome (SS). Out of these, psoriasis and alopecia areata were the most common conditions. However, most cases of psoriasis could have been attributed to either antimalarial agents that were initially used for the treatment of COVID-19 or discontinuation of treatment following SARS-CoV2 infection.

The Association between Genetic Variation in Wnt Transcription Factor TCF7L2 (TCF4) and Alopecia Areata.

Background: Alopecia areata (AA) is a non-scarring hair loss with a polymorphous presentation ranging from patchy lesions to involvement of the entire scalp. The disease is the consequence of an autoimmune attack on hair bulbs that results in a premature transition of hair follicles to catagen and telogen. Thus the Wnt/ß-catenin signaling pathway that regulates the hair cycling might be involved in the pathogenesis of AA. Genetic variations in the components of Wnt/ß-catenin could greatly alter their adaptive mechanisms against an immunologic attack. Objectives: Our aim was to investigate the association between AA and genetic polymorphisms in the TCF7L2 gene, one of the most important components of the Wnt/ß-catenin pathway. Methods: This is a case-control study of 145 patients with AA and 152 healthy controls. Genotyping of the TCF7L2 gene (rs7903146) was performed via the ARMS-PCR method (amplification refractory mutation system- polymerase chain reaction). The allele and genotype distribution was compared between the two groups. Results: The frequency of the T allele (0.38 vs. 0.28, odds ratio = 1.56, 95% CI = 1.09-2.17, p = 0.013) and TT + CT genotypes (0.68 vs. 0.53, odds ratio = 1.88, 95% CI = 1.17-3.02, p = 0.008) were significantly higher in AA patients. Conclusions: This study indicates that the TCF7L2 gene variant is associated with AA. Its contribution to disease pathogenesis could either be through a hair cycling defect or dendritic cell dysregulation.

Is the +405 G/C single nucleotide polymorphism of the vascular endothelial growth factor (VEGF) gene associated with late-onset vitiligo?

The increasing body of evidence for the relationship between the vascular endothelial growth factor (VEGF) polymorphism and autoimmune disorders combined with the enhanced expression of this angiogenic factor in vitiligo makes VEGF a very interesting candidate gene to be investigated in vitiligo. The aim of this study was to evaluate the possible associations between the +405 G/C single nucleotide polymorphisms (SNP) of the VEGF gene (rs2010963) and vitiligo. The independent case-control population sample of 152 patients with vitiligo and 152 matched controls was evaluated in this study. A questionnaire was completed for each vitiligo patient to document the demographic and clinical characteristics of the patients. All enrolled individuals had a venous blood sample collected. Genotype frequencies for +405 G/C VEGF gene polymorphism were determined using polymerase chain reaction (PCR) amplification and restriction fragment length polymorphism (RFLP) analysis. There were no significant differences in genotype or allele distributions for this SNP between cases and controls. However, we observed a significant association between GG genotype and higher age at onset of vitiligo (p = 0.04). Moreover, patients stratification revealed a significant increase in the frequency of GG genotype compared to CC + CG genotypes in patients with the late onset (≥20 years) vitiligo (p = 0.05). Although these results are not conclusive, they could potentially lead to considering the angiogenic factors as a potential target for therapy in late-onset vitiligo.

Interleukin-4 and Interleukin-4 Receptor Alpha Gene Polymorphisms in Recurrent Aphthous Stomatitis.

BACKGROUND: Recurrent aphthous stomatitis (RAS) is a common oral condition with a major impact on the quality of life. The condition is thought to be due to the overexpression of T helper-1(Th1)-related cytokines. Since interleukin-4 (IL-4) and its receptor (IL-4Rα) are antagonistic to Th-1 pathways, polymorphisms in their genes may also be involved in the pathogenesis of aphthous stomatitis. METHODS: Sixty-four patients diagnosed with minor RAS and 141 (age- and sex-matched) healthy controls were assessed for 3 single-nucleotide polymorphisms (SNPs) within the promoter region of the IL-4 gene (-1098G/T, -590C/T, and -33C/T), and 1 SNP in IL-4Rα gene (+1902 A/G). RESULTS: No significant differences were detected between the patient and the control group regarding IL-4 allele frequencies. However, the patient group demonstrated a higher frequency of IL-4 -590 CC genotype and a lower rate of IL-4 -590 TC genotype. The TCT, GTT, GCT, and GTC haplotypes of the IL-4 gene (-1098, -590, -33) were significantly more frequent in the patients and the GCC, and TTT haplotypes were more common in healthy controls. No significant differences were found in IL-4Rα gene polymorphism between the 2 groups. CONCLUSIONS: Certain polymorphisms of IL4 gene could predispose individuals to RAS.

Economic feasibility of solar-powered reverse osmosis water desalination: a comparative systemic review.

Due to disparities in the allocation of rainwater and drought, extreme exploitation of groundwater reservoirs has depleted water supplies in many locations. In addition, improper disposal of domestic and industrial waste leads to poor drainage and deterioration of water quality. According to studies, desalination methods are an effective solution for treating unconventional water, i.e., sea and brackish water, and making it usable in daily life. Solar-powered desalination has recently received a great deal of attention around the world. Herein, we summarized challenges and future perspectives associated with solar-powered desalination units. Some hybrid technologies are also discussed like solar-wind desalination and RO-ED crystallizer technology in Morocco and the Middle East and North Africa (MENA) region. Previously, most experimental studies focused on the use of solar energy in traditional desalination methods such as multistage flash and multi-effect distillation. Desalination with reverse osmosis has become popular due to membrane technology improvement and benefits like high recovery ratios and low energy consumption. Furthermore, it has been seen that solar energy is less expensive than the energy obtained from traditional fuels in the MENA area. This article aims to comparatively and systematically review the economic feasibility of the use of solar photovoltaic reverse osmosis in desalination in the MENA region.

Quality of life among Iranian adults before and after rhinoplasty.

BACKGROUND: Despite developments in the therapeutic field of cosmetic surgery, there is a little information about the effects of cosmetic procedures on quality of life (QOL), especially in Iran. Rhinoplasty is one of the most common cosmetic surgeries. This type of surgery has remarkable effects on physical and mental health and also improves nasal functioning. The purpose of this study was to survey QOL among Iranian adults before and after rhinoplasty. METHODS: In this descriptive and analytical cross-sectional study, from March 2009 to March 2010, data were collected from 75 subjects, 16 years old and above, before and 6 months after rhinoplasty. A trained interviewer interviewed and completed standardized questionnaires investigating QOL, including the SF-36 version 2, NOSE, and Rosenberg questionnaires. Data analysis was conducted using SPSS ver. 16. Results before and after surgery were compared. RESULTS: The mean age of the subjects was 26.05 ± 7.78 years, with a median of 24 years. The female-to-male ratio was 4.35:1. In all cases and all questionnaires, QOL was improved after rhinoplasty. Significant differences were observed on the NOSE questionnaire (p = 0.005) and the Rosenberg questionnaire (p = 0.002). On the SF-36 questionnaire, significant differences were observed in four subscales, including physical functioning (p = 0.047), role of emotion (p = 0.01), bodily pain (p = 0.01), and vitality (p = 0.05). CONCLUSIONS: According to this study, QOL is improved after rhinoplasty in Iranian adult patients. With proper patient selection and a successful operation, improvement of physical and mental health can be expected.

Correlation between Carotid Artery Mean Intima-Media Thickness and brain Natriuretic Peptide in Patients with Psoriasis.

Background: Numerous studies have documented an association between psoriasis and subclinical atherosclerosis. Objective: We aimed to investigate the effects of psoriasis on the levels of N-terminal prohormone B type natriuretic peptide (NT-proBNP) and clarify whether this factor correlates with the evaluations of subclinical atherosclerosis, measured with mean intima-media thickness (MIMT) of the carotid artery. Methods: Sixty-one psoriatic patients and sixty-one healthy, age and sex-matched volunteers were enrolled. MIMT was assessed via ultrasonography and serum NT-proBNP level were measured by electrochemiluminescence. Results: Both NT-proBNP and MIMT were significantly higher in psoriasis patients. This remained true even after controlling for the effects of age and gender. MIMT was positively correlated with age and serum NT-proBNP level in both groups. Conclusions: In conclusion, NT-proBNP levels may be used as a predictor of subclinical atherosclerosis in patients with psoriasis.

Cutaneous Lymphadenoma: A Case of Recurrence after Shave Excision.

Cutaneous lymphadenoma (CL) is a rare skin tumor supposedly derived from the pilosebaceous unit. Since its description in 1987, fewer than 60 cases have been documented. Herein we report a case of CL presenting as a small nodule on the forehead of a young female. The lesion recurred two years after shave excision of a similar lesion. The histopathological examination revealed interconnected islands, sheets, and trabeculae consisting of two distinct types of cells within a sclerotic stroma, a peripheral rim of palisading basophilic cells, and central epithelial cells with eosinophilic to clear cytoplasm. A dense infiltration with prominent lymphocytes and few plasma cells dominated the stroma and permeated the epithelial nests. This case represents the recurrence of this type of skin tumor after shave excision and thus highlights the importance of complete margin-free excision of such lesions.

Arrhythmogenic right ventricular cardiomyopathy in patients with biallelic JUP-associated skin fragility.

Arrhythmogenic right ventricular cardiomyopathy (ARVC), with skin manifestations, has been associated with mutations in JUP encoding plakoglobin. Genotype-phenotype correlations regarding the penetrance of cardiac involvement, and age of onset have not been well established. We examined a cohort of 362 families with skin fragility to screen for genetic mutations with next-generation sequencing-based methods. In two unrelated families, a previously unreported biallelic mutation, JUP: c.201delC; p.Ser68Alafs*92, was disclosed. The consequences of this mutation were determined by expression profiling both at tissue and ultrastructural levels, and the patients were evaluated by cardiac and cutaneous work-up. Whole-transcriptome sequencing by RNA-Seq revealed JUP as the most down-regulated gene among 21 skin fragility-associated genes. Immunofluorescence showed the lack of plakoglobin in the epidermis. Two probands, 2.5 and 22-year-old, with the same homozygous mutation, allowed us to study the cross-sectional progression of cardiac involvements in relation to age. The older patient had anterior T wave inversions, prolonged terminal activation duration (TAD), and RV enlargement by echocardiogram, and together with JUP mutation met definite ARVC diagnosis. The younger patient had no evidence of cardiac disease, but met possible ARVC diagnosis with one major criterion (the JUP mutation). In conclusion, we identified the same biallelic homozygous JUP mutation in two unrelated families with skin fragility, but cardiac findings highlighted age-dependent penetrance of ARVC. Thus, young, phenotypically normal patients with biallelic JUP mutations should be monitored for development of ARVC.

Patients with alopecia areata show signs of insulin resistance.

Alopecia areata (AA) is an autoimmune disease associated with high levels of proinflammatory cytokines. Since chronic inflammation plays a major role in the pathogenesis of insulin resistance, AA can theoretically increase the risk of diabetes. We sought to investigate this theory by conducting a case-control study. Sixty patients with alopecia areata and 60 healthy volunteers (matched for age, sex, and body mass index) were evaluated. Fasting blood glucose (FBS), C-peptide, plasma insulin, and homeostasis model assessment for insulin resistance (HOMA-IR) were measured for each individual. Plasma levels of insulin [median (interquartile range IQR): 11.22 (7.28-18.15) µIU/ml vs. 4.80 (3.20-9.00), p < 0.0001)], C-peptide [median (IQR): 2.10 (1.61-3.00) ng/ml vs. 1.40 (1.20-1.88), p < 0.0001)] and HOMA-IR [median (IQR): 2.70 (1.58-3.96) µIU/ml vs. 1.01 (0.64-1.98, p < 0.0001)] were significantly higher in patients with AA compared to controls. The differences remained significant even after controlling for age, gender, and BMI. Patients with a more severe disease (alopecia totalis/universalis) had higher levels of insulin [median (IQR): 15.80 (9.68-21.55) vs. 9.30 (5.33-14.40), p = 0.02)] and HOMA-IR [median (IQR): 3.30 (2.20-4.84) vs. 2.15 (1.29-3.52), p = 0.01] compared to those with patchy hair loss. Our data suggest that individuals with AA are at a higher risk of developing insulin resistance. This may be due to common inflammatory pathogenesis or a shared genetic background.

Macrophage migration inhibitory factor polymorphism (rs755622) in alopecia areata: a possible role in disease prevention.

Alopecia areata (AA) is an organ-specific autoimmune disease that targets the bulb of the hair follicles and results in non-scarring hair loss that can range from patchy lesions to involvement of the entire scalp. AA develops when the hair follicles lose their physiologic state of immune privilege. One of the key factors that help in maintaining this immune privilege by suppressing natural killer cells is macrophage migration inhibitory factor (MIF). Surprisingly, MIF is also known to provoke autoimmunity by upregulating cytokines. To address this dilemma and understand the exact nature of the involvement of MIF in disease pathogenesis we investigated the association of MIF gene polymorphisms (- 173 G > C, rs755622) with AA by conducting a case-control study of 274 subjects. We observed that the frequency of the C allele in the patients was significantly lower than the control group (0.15, 0.23, respectively, p = 0.01) and the combined frequencies of the CC and GC genotypes (dominant Mendelian pattern) had the most prevalent difference between the two groups (odds ratio 0.60, 95% confidence interval 0.36-0.99; p = 0.048).Since the C allele is associated with higher MIF transcription levels, this could infer that MIF is more likely to attribute to the preservation of the immune privilege rather than acting as a proinflammatory factor.

CDH1 and DDR1 common variants confer risk to vitiligo and autoimmune comorbidities.

The weaker expression of the two main proteins adhering melanocytes to the epidermis basal layer, Epithelial Cadherin (E-cadherin) and Discoidin Domain Receptor Tyrosine kinase 1 (DDR1), has been implicated as one of the aggravating factors in the loss of melanocytes in vitiligo. The present study was designed to assess the association between single nucleotide polymorphisms (SNP) in the genes encoding these proteins, CDH1 and DDR1, and the risk of developing vitiligo. The independent case-control study was conducted on the sample including152 patients with vitiligo and 152 matched controls. A questionnaire was completed for recording demographic and clinical characteristics of vitiligo patients. Venous blood samples were taken from all the subjects. Genotype frequencies were determined for CDHI C/T (rs 10431924) and DDRI A/C (rs 2267641) genes polymorphisms using polymerase chain reaction (PCR) amplification method and Restriction Fragment Length Polymorphism (RFLP) analysis. The CDH1 CC genotype was found to be significantly associated with the risk of developing vitiligo. The results of stratified analysis revealed a correlation between CDH1 CC genotype and late age of onset, clinical type of vitiligo, the absence of autoimmune comorbidities and family history of autoimmune disorders. However, the expression level of CDH1 TT genotype increased significantly in patients with autoimmune comorbidities. There was also a significant relationship between the DDR1 CC genotype and the risk of developing vitiligo. The results of stratified analysis revealed a correlation between DDR1 CC genotype and early age of onset, clinical type of vitiligo and absence of family history of autoimmune disorders. The findings of the study confirm the conjecture previously made in the literature regarding the melanocytes' adhesion deficit as an initial step for pigment loss in vitiligo and emphasize the substantial role of friction and koebner phenomenon in the pathogenesis of vitiligo. Moreover, a probable association can be proposed between the adhesion deficit involved in vitiligo and autoimmune disorders.