Genome‐wide association study of psoriasis in an Egyptian population

Psoriasis is a chronic inflammatory disorder of the skin, with genetic factors reportedly involved in the disease pathogenesis. Numerous studies reported psoriasis candidate genes. However, these tend to involve mostly in the European and Asian populations. Here, we report the first genome‐wide association study (GWAS) in an Egyptian population, identifying susceptibility variants for psoriasis using a two‐stage case‐control design. In the first discovery stage, we carried out a genome‐wide association analysis using the Infinium^® Global Screening Array‐24 v1.0, on 253 cases and 449 control samples of Egyptian descent. In the second replication stage, 26 single‐nucleotide polymorphisms (SNPs) were selected for replication in additional 321 cases and 253 controls. In concordance with the findings from previous studies on other populations, we found a genome‐wide significant association between the MHC locus and the disease at rs12199223 (P_comb = 6.57 × 10^?18) and rs1265181 (P_comb = 1.03 × 10^?10). Additionally, we identified a novel significant association with the disease at locus, 4q32.1 (rs12650590, P_comb = 4.49 × 10^?08) in the vicinity of gene GUCY1A3, and multiple suggestive associations, for example rs10832027 (P_comb = 7.28 × 10^?06) and rs3770019 (P_comb = 1.02 × 10^?05). This proposes the existence of important interethnic genetic differences in psoriasis susceptibility. Further studies are necessary to elucidate the downstream pathways of the new candidate loci.     

Melanoma risk alleles are associated with downregulation of the MTAP gene and hypermethylation of a CpG island upstream of the gene in dermal fibroblasts

Several association studies and GWAS on melanoma skin cancer risk have reported statistically significant signals on 9p21.3 region, where MTAP gene maps. None of the associated SNPs identified in these studies lie in the coding region of the gene and the causative relation of risk alleles with melanoma predisposition has not been elucidated. MTAP has a tumor suppressor activity and epigenetic silencing has been described in melanoma cell lines. In the present study, we show that melanoma risk alleles correlate with a MTAP allele‐specific hyper‐methylation and down‐regulation of gene expression.     

Novel gene identified in an exome‐wide association study of tanning dependence

Growing evidence suggests that some individuals may exhibit symptoms of dependence to ultraviolet light, a known carcinogen, in the context of tanning. Genetic associations with tanning dependence (TD) have not yet been explored. We conducted an exome‐wide association study in 79 individuals who exhibited symptoms of TD and 213 individuals with volitional exposure to ultraviolet light, but who were not TD based on three TD scales. A total of 300 000 mostly exomic single nucleotide polymorphisms primarily in coding regions were assessed using an Affymetrix Axiom array. We performed a gene burden test with Bonferroni correction for the number of genes examined (P < 0.05/14 904 = 3.36 × 10^?6). One gene, patched domain containing 2 (PTCHD2), yielded a statistically significant P‐value of 2.5 × 10^?6 (OR = 0.27) with fewer individuals classified as TD having a minor allele at this locus. These results require replication, but are the first to support a specific genetic association with TD.     

Variation at HLA‐DPB1 is associated with dermatomyositis in Chinese population

Dermatomyositis (DM) is a polygenic disorder characterized by inflammation of skeletal muscle and skin. To date, the exact etiopathogenesis of DM remains elusive. To explore the genetic basis of DM, we conducted genome‐wide genotyping analysis of 127 patients and 1566 healthy controls by Illumina Human OmniZhongHua‐8 BeadChips in the Chinese Han population. We investigated whether the three SNP ( rs7750458 , rs9501251 and rs9500928 ) at 6p21.32 in the HLA‐DPB1 gene were significantly associated with DM (P < 5 × 10^?8) and identified two susceptibility loci at 7q34 (PIP, rs9986765 , P = 7.45 × 10^?7, odds ratio [OR] = 2.71) and 10q24.2 (CPN1, rs3750716 , P = 9.04 × 10^?7, OR = 4.39) with suggestive evidence. We imputed 6674 classical human leukocyte antigen (HLA) alleles, amino acids and SNP from the discovery dataset, and stepwise analysis revealed that HLA‐DPB1*17 in class II HLA genes were significantly associated with DM susceptibility. This study represents the first genome‐wide association study (GWAS) of DM in the Chinese Han population. For the first time, HLA‐DPB1 was found to be associated with DM in this population. Moreover, we identified two novel suggestive susceptibility loci (PIP and CPN1) and confirmed four previously reported genes (DMB, DQA1, DQB1 and DRB1) having potential associations with DM in the Chinese Han population. Our GWAS results in this population should provide important information regarding the genetic etiopathogenesis of DM and facilitate the development of new therapies for the treatment of DM and the prevention of DM progression.     

Polymorphisms within the CTLA4 gene are associated with infant atopic dermatitis

BACKGROUND: Atopic dermatitis (AD) is one of the most common childhood disorders. It can have a significant impact on the physical and psychological well-being of affected individuals. Although environmental triggers are important, AD also has a strong genetic component. Identifying genes associated with AD may help to understand better the basis of this disorder and its relationship with other allergic disorders such as asthma. OBJECTIVES: Polymorphisms in the gene encoding the inhibitory CTLA4 receptor, an important regulator of T cells, are associated with asthma as well as autoimmune disorders. We have now tested whether polymorphisms in the CTLA4 gene are also associated with early childhood AD. METHODS: A family-based cohort of 112 children and their parents was recruited from Western Sydney, Australia. All children were seen by a paediatric dermatologist and presented with AD within the first 3 years of life. Using the transmission disequilibrium test, individual and haplotypic associations with the +49 and CT60 polymorphisms in exon 1 and the 3' nontranslated DNA of the CTLA4 gene were tested. RESULTS: Single tests of association revealed significant association of the +49(A) [P = 0.037, odds ratio (OR) 1.59, 95% confidence interval (CI) 1-2.55] and borderline significance of the CT60(A) alleles (P = 0.055, OR 1.51, 95% CI 1-2.38). Significant association of the +49(A)/CT60(A) haplotype was detected (P = 0.002, OR 1.78, 95% CI 1.2-2.65). CONCLUSIONS: Polymorphisms within the gene encoding CTLA4 were associated with early onset infant AD. This is in agreement with findings from asthmatic cohorts, suggesting that the +49(A)/CT60(A) haplotype is a genetic risk factor common to asthma and AD.     

A study of differences in surface roughness between sun-exposed and unexposed skin with age

BACKGROUND: To understand and separate the roles of age and solar ultraviolet exposure (sun damage) on the surface roughness of skin. OBJECTIVES: To determine the effects of age and site (sun exposed vs. unexposed) on skin roughness in normal healthy subjects. SUBJECTS/METHODS: Using a stylus profilometer and silicone skin surface replicas, we have measured skin surface roughness parameters on habitually exposed (back of hand) and habitually unexposed (upper buttock) skin sites from the same individual in a sample of 73 subjects from the normal population. We compared the two sites in order to determine any differences in roughness caused, we postulate, by the effect of solar ultraviolet exposure on the exposed site. RESULTS: We found that the two sites are indistinguishable in roughness until after 30 years of age. For the over 30 years group, the difference between exposed and unexposed skin roughness correlated strongly with age. For all ages, skin roughness showed a positive correlation with age on the unexposed, but not the exposed, site. On the hand site subjects aged 40 years and older had significantly smoother skin than those aged less than 40 years, as measured by one roughness parameter. On the back, the older group had significantly rougher skin than the younger group measured by two roughness parameters. CONCLUSIONS: We propose that on the back of the hands, solar damage reverses or reduces the increase in roughness which would otherwise be caused by intrinsic ageing.     

Potential association of single nucleotide polymorphisms in pigmentation genes with the development of basal cell carcinoma

The risk of developing skin cancers is dependent on a combination of environmental factors and personal genetic predispositions. Basal cell carcinoma (BCC) has been associated with single nucleotide polymorphisms in several pigmentation genes; however, there is still controversy concerning the mechanism by which these variants may increase the risk of BCC. The pathway may lead to pigmentation alone, but evidence for their independent influence is growing. Using a single base extension protocol, candidate polymorphisms within 11 known pigment-related genes were studied for their association with BCC in a population sample consisting of 164 patients and 707 controls. The significance of variation within the MC1R gene was confirmed and, in addition, position rs12203592 within the IRF4 gene was shown to be associated with BCC. These associations remained significant after adjustment for skin color. Gene-gene interactions were found to influence susceptibility to BCC. Among interacting genes are the two above-mentioned loci with main effect on BCC risk and additionally KITLG, TYRP1, ASIP and TYR. The obtained results indicate that polymorphism at MC1R and IRF4 constitute pigmentation-independent risk factor in the development of BCC. Moreover, susceptibility to BCC may be influenced by epistatic effects between pigmentation genes.     

Inherited palmoplantar keratoderma and sensorineural deafness associated with A7445G point mutation in the mitochondrial genome

We report a French pedigree with members having an inherited combination of non-epidermolytic palmoplantar keratoderma (NEPPK) and sensorineural deafness. The penetrance of both features was incomplete. Additional ectodermal defects were absent. The expression of numerous epidermal proteins (keratins, fillagrin, cornified envelope proteins, intercellular junction proteins including connexin 26, and loricrin) defined with immunolabelling was normal in the proband. The combination was shown to be associated with the A7445G point mutation in the mitochondrial genome (mtDNA). This mutation is responsible for a subtype of NEPPK which is so far the only mtDNA mutation-associated keratoderma.     

Selected variants of the steroid-5-alpha-reductase isoforms SRD5A1 and SRD5A2 and the sex steroid hormone receptors ESR1, ESR2 and PGR: no association with female pattern hair loss identified

Female pattern hair loss (FPHL) is a common disorder with a complex mode of inheritance. Although understanding of its etiopathogenesis is incomplete, an interaction between genetic and hormonal factors is assumed to be important. The involvement of an androgen-dependent pathway and sex steroid hormones is the most likely hypothesis. We therefore selected a total of 21 variants from the steroid-5-alpha-reductase isoforms SRD5A1 and SRD5A2, the sex steroid hormone receptors ESR1, ESR2 (oestrogen receptor) and PGR (progesterone receptor) and genotyped these in a case-control sample of 198 patients (145 UK; 53 German patients) and 329 controls (179 UK; 150 German). None of these variants showed any significant association, either in the overall UK and German samples or in the subgroup analyses. In summary, the present results, while based on a limited selection of gene variants, do not point to the involvement of SRD5A1, SRD5A2, ESR1, ESR2 or PGR in FPHL.     

The A5.1 allele of the major histocompatibility complex class I chain-related gene A is associated with psoriasis vulgaris in Chinese

Background Recent studies have demonstrated an association of a polymorphic (GCT)_n triplet repeat in the transmembrane (TM) region of the major histocompatibility complex (MHC) class I chain‐related gene A (MICA), one of the MHC class I chain‐related (MIC) family members, with some autoimmune diseases, including Behçet’s disease, acute anterior uveitis, Takayasu’s arteritis and others. Objectives The aim of this study was to examine whether the MICA gene is associated with psoriasis vulgaris (PS) in Chinese. Patients and methods The (GCT)_n polymorphism of the MICA gene was investigated in 200 healthy Chinese of Han origin and 300 patients with PS by polymerase chain reaction amplification and denaturing polyacrylamide gel electrophoresis. Results Five alleles, namely A4, A5, A6, A9 and A5.1 were found in both groups. Comparison of the data from both groups revealed that the A5.1 allele was present at a significantly higher frequency in the patient group (41·5%) than in the control group (23·0%) (Pc < 0·0001, Pc means the probability of a comparison with the control group). The frequency of A5.1‐positive cases was also significantly increased in the patient group (68·0%) as compared with the controls (38·0%) (Pc < 0·0001). Furthermore, the carrier frequency of A5.1‐positive was significantly increased in psoriatic patients with a positive family history and with early onset as compared with sporadic cases (Pc = 0·0005) and with late onset PS (Pc = 0·002). Conclusions These results suggest that the MICA gene may be associated with the development of PS in Chinese.     

A novel mutation in the SCN9A gene associated with congenital insensitivity to pain,anhidrosis, and mild cognitive impairment

Congenital insensitivity to pain (CIP) is a rare phenotype characterized by the inability to perceive pain stimuli with subsequent self-injuries, whereas CIP associated with anhidrosis (CIPA) is an overlapping phenotype mainly characterized by insensitivity to noxious stimuli and anhidrosis. CIP is primarily associated with pathogenetic variants in the SCN9A gene while CIPA is associated with pathogenetic variants in NGF and NRTK genes. However, in recent years, a significant overlap between these two disorders has been observed highlighting the presence of anhidrosis in SCN9A variants. We report the cases of two siblings (age 4 and 6 years) born from consanguineous parents presenting with a previously undescribed phenotype due to a novel pathogenic variant in SCN9A clinically characterized by congenital insensitivity to pain, anhidrosis, and mild cognitive impairment.     

Psoriasis is associated with increased risk of bullous pemphigoid: A nationwide population‐based cohort study in Taiwan

Psoriasis may coexist with bullous pemphigoid (BP); however, no cohort studies have investigated the relationship between psoriasis and the risk of BP. This study aims to investigate the relationship between psoriasis and the risk of BP in Taiwan. This cohort study consists of 109 777 psoriatic patients and 109 777 matched non‐exposed controls. Psoriatic patients diagnosed between 2002 and 2012 were identified from the Taiwan National Health Insurance Research Database. The age‐, sex‐ and index date‐matched non‐exposed group was selected from the same database. The relationship between psoriasis and the risk of BP was investigated using Cox proportional hazards analyses. Psoriasis was significantly associated with an increased risk of BP (hazard ratio, 3.05; 95% confidence interval, 2.10–4.43; P < 0.001). The mean interval between the diagnoses of psoriasis and BP was 2.86 years, with the highest occurrence in the first year after psoriasis diagnosis, and gradually decreasing with each year of observation. Psoriatic patients with BP were significantly younger than BP patients in the non‐exposed group (71.6 ± 13.9 vs 76.6 ± 7.7 years, respectively; P = 0.030). A higher proportion of patients with coexisting psoriasis and BP received phototherapy (20%). In conclusion, psoriasis was independently associated with a 3.05‐fold increased risk of BP, and psoriatic patients with BP were younger, with over one‐third of BP cases diagnosed in the first year after incident psoriasis. Therefore, clinicians treating patients with psoriasis may be aware of the possibility of the development of BP.