Evaluation of androgen receptor gene as a candidate gene in female androgenetic alopecia

Background  Genetic polymorphisms of the androgen receptor (AR) gene have been studied in male androgenetic alopecia (AGA); however, little is known about gene polymorphism and female AGA.
Aim  To evaluate the AR gene as a candidate gene for female AGA.
Methods  Thirty premenopausal Egyptian female patients with AGA (mean age, 32.3 ± 7 years) and 11 age- and sex-matched controls were included. All subjects underwent laboratory and pelvic ultrasound evaluation to exclude other precipitating cause(s) of hair loss. Scalp biopsy was taken and the AR gene was evaluated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
Results  According to Ludwig's classification, all patients had type II AGA. Statistical analysis showed no statistically significant difference in genotype (χ² = 5.513, P  ≥ 0.05) or allele frequency (χ² = 1.312, P  ≥ 0.05) between patients and controls. There was also no statistically significant difference between the genotype and allele frequency with disease duration.
Conclusion  In contrast with male AGA, no association was found between type II AGA in Egyptian women and the AR gene. Therefore, the genetic study of this gene does not serve as a biomarker for the identification of women with a predisposition to AGA.     

The Wiskott-Aldrich syndrome gene as a candidate gene for atopic dermatitis.

Atopic dermatitis is a multifactorial disorder probably caused by environmental factors in combination with susceptibility genes. The clinical similarity between atopic dermatitis and the eczema manifestation in patients with Wiskott-Aldrich syndrome made the previously identified WAS gene in chromosome sub-band Xpl 1.23 an interesting candidate gene for atopic dermatitis. We studied linkage and association to the WAS gene region using four polymorphic microsatellite markers in 406 Swedish families with at least two siblings affected with atopic dermatitis (in total 1514 individuals). In the analyses, we studied two qualitative traits: atopic dermatitis and elevated allergen-specific serum IgE antibodies, and one quantitative trait, a severity score of atopic dermatitis. We found that the marker MAOB gave positive linkage with a maximum lod score of 1.68 (p<0.05) to the severity score of atopic dermatitis. Association could not be seen to atopic dermatitis nor to elevated allergen-specific serum IgE antibodies in this region using the transmission disequilibrium test. Our results indicate that either the WAS gene or another gene in the area contributes to the severity of atopic dermatitis.     

Haplotype sharing analysis identifies a retroviral dUTPase as candidate susceptibility gene for psoriasis

The psoriasis susceptibility locus 1 (PSORS1) mutation is assumed to reside within a region around human leukocyte antigen-C spanning 250 kb, termed risk haplotype (RH) 1/2. By re-analyzing a published data set with a previously developed method, the haplotype sharing statistic, we confirm localization of PSORS1 to the RH1 region and refine its location to marker M6S168. We replicate this result in an independent patient sample. The target region harbors fragments of a human endogenous retrovirus K (HERV-K) endogenous retrovirus. Two single-nucleotide polymorphisms with alleles differing between high- and low-risk haplotypes are located within the HERV-K dUTPase. One of these encodes a predicted non-conserved Glu-Arg exchange. The HERV-K dUTPase is expressed in peripheral blood and in normal as well as lesional psoriatic skin. Our results indicate that an endogenous retroviral dUTPase constitutes a candidate gene for the PSORS1 mutation.     

Exclusion of CARD15/NOD2 as a candidate susceptibility gene to psoriasis in the Italian population

Psoriasis is a chronic inflammatory skin disorder showing multifactorial inheritance. Linkage studies have mapped disease susceptibility loci to several genomic regions, including the chromosome 16 interval that contains the CARD15/NOD2 gene. CARD15 has been involved in Crohn's Disease (CD) susceptibility and it has been hypothesised that it may also contribute to the pathogenesis of psoriasis. To test this hypothesis we studied the distribution of 3 CARD15 SNPs in an Italian case-control data set. We failed to observe any significant difference between patients and controls, thereby excluding the presence of a strong genetic association between CARD15 gene polymorphisms and psoriasis, in the Italian population.     

Susceptibility variants on chromosome 7p21.1 suggest HDAC9 as a new candidate gene for male-pattern baldness

Background Male‐pattern baldness (androgenetic alopecia, AGA) is the most common form of hair loss among humans. Research has shown that it is caused by genetic factors. Numerous studies have unequivocally identified two major genetic risk loci for AGA: the X‐chromosomal AR/EDA2R locus, and the PAX1/FOXA2 locus on chromosome 20. Objectives To identify further candidate genes for AGA, and thus gain further insights into this phenotype. Methods A German sample of 581 severely affected cases and 617 controls was used to perform a genome‐wide association study. The identified associated locus was further analysed by fine‐mapping, and then independently replicated in an Australian sample. Expression and pathway analyses were performed to characterize the susceptibility gene identified. Results The most significant association signal was obtained for rs756853 (P = 1·64 × 10^?7), which is located intronically in the histone deacetylase 9 (HDAC9) gene. Fine‐mapping and a family‐based analysis revealed that rs756853 and the 6‐kb distal rs2249817 were the most highly associated single nucleotide polymorphisms. The association finding was replicated in an independent Australian sample, when the analysis was restricted to severely affected cases and unaffected controls (P = 0·026). Analysis of rs2249817 in a combined sample of severely affected German and Australian cases and unaffected controls revealed a strong association signal (P = 9·09 × 10^?8). Tissue expression studies demonstrated HDAC9 expression in various tissues, including tissues of relevance to AGA. No strong genotypic effects were observed in genotype‐specific expression or splice studies. Pathway analyses supported the hypothesis that HDAC9 plays a functional role in AGA via interaction with the AR gene. Conclusions The present study suggests that HDAC9 is the third AGA susceptibility gene.     

Investigation of the chromosome 17q25 PSORS2 locus in atopic dermatitis

Psoriasis and atopic dermatitis (AD) are strongly genetic and inherited as multi-factorial traits. In both diseases, linkage has been reported to chromosome 17q25. For psoriasis, the locus has been labelled PSORS2. Two peaks of association here contain the psoriasis candidate genes SLC9A3R (solute carrier family 9, isoform 3 regulatory factor), NAT9 (N-acetyltransferase superfamily), and RAPTOR (rapamycin (TOR)). We genotyped 14 of the most significantly associated single-nucleotide polymorphisms (SNPs) in these genes in a panel of 148 families (ECZ1) identified through a proband with active AD. The panel contains 350 siblings and 245 sib-pairs. Replication of positive findings was sought in a second panel, MRC-E, comprising of 278 families, 634 siblings, and 470 sib-pairs. SNP genotyping was carried out by Sequenom MassArray technology. Using family-based tests of association (transmission disequilibrium test), rs878906, in intron 3 of NAT9, was significantly associated with AD (P = 0.010) in the ECZ1 panel. In the MRC-E panel, rs895691, between the end of exon 6 of SLC9A3R1 and exon 7 of NAT9, was associated with AD (P = 0.037). These were not significant when multiple comparisons were taken into account. Haplotype analysis revealed no significant associations in either population. These results suggest that the psoriasis candidate genes do not account for previously observed linkage of the 17q25 PSORS2 locus to AD.     

Confirmation of PSORS psoriasis susceptibility loci in a Chinese population

We investigated 38 Chinese psoriasis families with 19 reported microsatellite markers. Families comprised a total of 96 affected and 92 unaffected individuals. Genotyping results were analyzed using parametric and nonparametric linkage analysis. Our results confirmed the published linkage with the PSORS1 locus, as well as the PSORS2 locus, which has not been previously shown in the Chinese population. Significant two-point LOD scores were obtained in a parametric linkage analysis with markers D6S1610 and D17S944. Nonparametric linkage values greater than 1.6 ( P<0.05) were obtained with markers D6S1610, D17S944 and D17S785.     

The candidate tumor suppressor gene Ecrg4 as a wound terminating factor in cutaneous injury

The Esophageal cancer-related gene-4 (Ecrg4) is a candidate tumor suppressor gene whose secreted protein product has been implicated in the development and progression of epithelial cancers, neuroprogenitor cell activation after central nervous system injury, cell senescence in neurodegeneration, and the survival of hematopoietic stem cells. Here, we investigated the temporal and spatial localization of Ecrg4 expression in healthy and injured mouse skin, and evaluated the biological activity of Ecrg4 using viral-mediated gene delivery in cutaneous wound healing models. Using in situ hybridization and immunohistochemistry, we found both Ecrg4 mRNA and its protein product localized to the epidermis, dermis, and hair follicles of healthy mouse skin. Upon cutaneous injury, Ecrg4 redistributed to the wound margins where gene microarray and quantitative RT-PCR showed an increased gene expression 5–10 days post-injury as a late phase injury response gene. Ecrg4 over-expression inhibited the directional migration of fibroblasts in modified Boyden chambers in vitro, but had no effect on rates of fibroblast proliferation. Ecrg4 over-expression in vivo at the wound margins delayed the rate of wound closure at 1 and 2 days after full-thickness punch injury. These findings point to the candidate tumor suppressor gene Ecrg4 as a novel, biologically active, constituent of skin and skin injury. The possibility that Ecrg4 serves as a wound termination factor during wound resolution is discussed.     

Human nidogen gene: identification of multiple RFLP and exclusion as candidate gene in a family with epidermolysis bullosa (EBS2) with evidence for linkage to chromosome 1

Epidermolysis bullosa (EB) is a group of heritable blistering diseases affecting the dermal-epidermal basement membrane zone. We have recently provided evidence for genetic linkage of the molecular defect in a large family with dominant simplex, generalized (Koebner) type of EB (EBS2) to the long arm of chromosome 1. Because human nidogen gene has been mapped to chromosomal locus 1q43 in the human genome, we examined the possibility that nidogen, an integral component of all basement membranes, would be the candidate gene in this family of EBS2. Restriction fragment-length polymorphism, which was shown with several restriction endonucleases to be present within the nidogen gene, was utilized for linkage analyses. The results using an informative PvuII polymorphism as a marker of allelic inheritance supported exclusion of the EBS2 locus from approximately 10 cM in either side of the nidogen locus, when Lod score of -2.0 was taken as the limit of exclusion. This study demonstrates the feasibility of examining other families with EB for possible linkage to the nidogen locus.     

A study of PSORS1C1 gene polymorphisms in Chinese patients with psoriasis

BACKGROUND: Although genetic analyses have identified the HLA-Cw*0602 allele as the major risk allele for chronic plaque psoriasis in various ethnic groups, it has been proposed that the association of Cw*0602 is due to linkage disequilibrium and that other nearby genes are involved in susceptibility to psoriasis. The psoriasis susceptibility 1 candidate 1 (PSORS1C1, formerly SEEK1) gene, located 127 kb telomeric to the HLA-C locus, is considered to be one of the potential candidate genes of psoriasis. Up to the present, no association study of the PSORS1C1 gene has been conducted on Chinese patients with psoriasis. OBJECTIVES: We aimed to determine whether the genetic polymorphisms of the PSORS1C1 gene were associated with an increased risk of psoriasis in Chinese patients. METHODS: We investigated the PSORS1C1 gene for disease association by direct sequencing of the PSORS1C1 gene in 143 Chinese patients with chronic plaque psoriasis and 188 control subjects. Genotyping for HLA-Cw*0602 and the alpha-helix coiled-coil rod homologue (C6orf18, formerly HCR) gene was also carried out using a sequence-based typing method. RESULTS: We identified 10 single nucleotide polymorphisms (SNPs) on the PSORS1C1 gene in our subjects; four of these SNPs cause amino acid change. We also detected poly(C) repeat variants from nucleotide positions 386-392 (poly(C)6-8). The poly(C) repeat polymorphisms cause a frame shift mutation. Another poly(C) repeat variant was also found at nucleotide positions 748-751. No significantly different allelic distributions of the PSORS1C1 SNPs or poly(C) repeat polymorphisms could be found between the patients with chronic plaque psoriasis and controls after correction for multiple testing. However, a significant increase of the Cw*0602 allele and tryptophan-tryptophan allele of the C6orf18 gene (HCR*WW) was found in patients with early onset psoriasis (21.9% vs. 4.8%, P < 10(-7)). Haplotype-based association analysis also showed a susceptibility haplotype carrying Cw*0602 and HCR*WW alleles in early onset Chinese patients. CONCLUSIONS: Our results indicate that the PSORS1C1 gene might not play an important role in the causation of chronic plaque psoriasis in Chinese people.     

Fine mapping of the psoriasis susceptibility gene PSORS1: a reassessment of risk associated with a putative risk haplotype lacking HLA-Cw6

Human leukocyte antigen (HLA)-Cw6 has long been associated with psoriasis, and PSORS1 (psoriasis susceptibility 1), a major gene for psoriasis susceptibility, has been mapped to its vicinity. A previous analysis identified multiple risk haplotypes carrying HLA-Cw6 and one haplotype (cluster 17, HLA-Cw8-B65) that appeared to carry risk for psoriasis but did not carry HLA-Cw6. This haplotype was very similar to other risk haplotypes for at least 60 kb telomeric to HLA-C, suggesting identity by descent with the remaining risk chromosomes. The association, however, between psoriasis and this haplotype as assessed by the transmission/disequilibrium test (TDT) was of borderline significance (p-value 0.048). In order to better assess the risk associated with cluster 17, a multicenter collaboration typed additional subjects for a single marker (M6S161) for which one allele (249 bp) was found only on cluster 17. The new sample included 1275 pedigrees as well as 300 cases and 913 controls. Transmission of this allele to affected individuals was examined using the TDT and the pedigree disequilibrium test (PDT), and case-control samples were analyzed by a trend test across genotype categories. By all methods, the newly acquired genotypes failed to confirm the association originally reported, despite adequate power. In contrast, the 248 bp allele, which is found on all HLA-Cw6-positive risk haplotypes as well as several non-risk haplotypes, shows significant excess transmission for all cohorts. Taken together, these results indicate that cluster 17 does not carry a psoriasis-susceptibility allele, and expand the PSORS1 risk interval to approximately 300 kb.     

Evidence for a major psoriasis susceptibility locus at 6p21(PSORS1) and a novel candidate region at 4q31 by genome-wide scan in Chinese hans

Psoriasis is a heterogeneous disease with seven major psoriasis susceptibility loci reported so far on chromosomes 1p, 1q, 3q, 4q, 6p, 17q, and 19p, respectively. To investigate the psoriasis susceptibility loci in Chinese Hans, a genome-wide scan was performed with two-point and multipoint parametric and nonparametric linkage analyses in 61 multiplex families. These families were Chinese Hans residing in east and south-east China, comprising 189 affected and 166 unaffected individuals. We detected evidence for linkage at 6p21 (PSORS1) with nonparametric linkage scores > 3 in the range of 39.9-62.3 cM and a maximum multipoint nonparametric linkage score of 4.58 (p=0.000032). Parametric analysis revealed a maximum two-point heterogeneity lod score of 4.30 with 58% as the proportion of linked families (alpha) and a maximum multipoint heterogeneity lod score of 4.25 (alpha=53%) under the assumption of a dominant model. We could not confirm a previous reported locus (PSORS3) on distal chromosome 4q; however, a region of highly suggestive linkage was identified proximal to this proposed locus. Multipoint nonparametric analysis demonstrated nonparametric linkage scores > 3 throughout a region between 152.5 cM and 165.1 cM (from pter) with a maximum peak of 3.69 (p=0.00033) at 157.9 cM, which locates D4S413. A maximum multipoint heterogeneity lod score of 2.31 (alpha=46%) was reached at 163.1 cM. With two-point parametric linkage analysis, we observed the highest lod score of 2.43 and heterogeneity lod score of 3.94 (alpha=77%) at marker D4S1597. Our results showed that chromosomes 6p and 4q may contain genes involved in the susceptibility to psoriasis vulgaris in a Chinese Han population. Other regions with weaker evidence for linkage could also hide minor susceptibility genes.     

HLA-Cw*0602 associates more strongly to psoriasis in the Swedish population than variants of the novel 6p21.3 gene PSORS1C3

The PSORS1 locus in the major histocompatibility complex region on chromosome 6p21.3 contains a major predisposing factor for psoriasis for which several candidate genes have been tested. The analyses are complicated by strong linkage disequilibrium in the region and the complex genetic background of psoriasis. In the search for an alternative to HLA-C we have identified a novel gene, PSORS1C3, and characterized it with regard to psoriasis. PSORS1C3 is located approximately 7 kb centromeric to POU5F1. A putative protein of 58 amino acids was predicted and expression was detected in both normal and psoriasis skin. Sequencing of the coding region revealed a total of 11 single nucleotide polymorphisms. When comparing the frequencies of PSORS1C3 variants in a case-control material in the Swedish population, three single nucleotide polymorphisms displayed significant association with psoriasis. This association appeared to be HLA-Cw*0602-dependent due to linkage disequilibrium, thus HLA-C remains the strongest associating factor in the region.     

银屑病易感基因位点PSORS1的研究进展

银屑病是一种常见的多基因遗传性皮肤病,通过对不同群体的银屑病患者的基因样本进行全基因组扫描,确定了7个银屑病易感基因位点(PSORS1～PSORSS7),其中位于6p21染色体上的易感基因位点PSORS1是当前银屑病易感基因研究的热点,它包括三个银屑病候选基因:HLA-Cw6,CDSN,HCR.分别对这三个易感基因进行综述.     

Inflammatory peeling skin syndrome caused by homozygous genomic deletion in the PSORS1 region encompassing the CDSN gene

Peeling skin syndrome (PSS) type B is a rare recessive genodermatosis characterized by lifelong widespread, reddish peeling of the skin with pruritus. The disease is caused by small‐scale mutations in the Corneodesmosin gene (CDSN) leading to premature termination codons. We report for the first time a Japanese case resulting from complete deletion of CDSN. Corneodesmosin was undetectable in the epidermis, and CDSN was unamplifiable by PCR. QMPSF analysis demonstrated deletion of CDSN exons inherited from each parent. Deletion mapping using microsatellite haplotyping, CGH array and PCR analysis established that the genomic deletion spanned 49–72 kb between HCG22 and TCF19, removing CDSN as well as five other genes within the psoriasis susceptibility region 1 (PSORS1) on 6p21.33. This observation widens the spectrum of molecular defects underlying PSS type B and shows that loss of these five genes from the PSORS1 region does not result in an additional cutaneous phenotype.     

The major psoriasis susceptibility locus PSORS1 is not a risk factor for late-onset psoriasis

PSORS1 is the major susceptibility locus for psoriasis vulgaris (PV) and lies within an approximately 200 kb segment of the major histocompatibility complex on chromosome 6p21.3. Alleles of candidate genes in this region including human leukocyte antigen (HLA)-C, alpha-helical coiled coil rod (HCR), and corneodesmosin (CDSN) show association with early-onset PV. Late-onset psoriasis (LOP) is defined as a disease with onset after 40 y of age and is typically sporadic. We assessed the role of PSORS1 in genetic susceptibility to LOP. Genotyping for HLA-C alleles and seven single nucleotide polymorphisms (SNP) within the genes HCR and CDSN was performed in LOP (n=145) and normal controls (n=309). Statistical analysis of allelic frequencies included calculation of odds ratio and chi2 comparisons. LOP demonstrated only a weak association to PSORS1 alleles HLA-Cw*6 (p=0.037), CDSN*5 (p=0.041), HCR*WC (p=0.013), and HCR SNP +325 (p=0.038). Patients with age of onset for psoriasis of 50 y or above provided no evidence of association with any of these alleles. These data suggest that the study cohort may include a number of subjects who harbor PSORS1 predisposition to early-onset psoriasis and yet do not present with disease by the age of 40 y. Thus this study demonstrates that PSORS1 is not a major inherited risk factor in the pathogenesis of LOP. These data suggest that the exclusion of LOP subjects from case-control studies will aid further delineation of the PSORS1 locus. Future genome-wide studies will be required to identify loci conferring risk for late-onset disease.     

Thermoreversible gel as a candidate barrier to prevent the transmission of HIV-1 and herpes simplex virus type 2

BACKGROUND: Sexually transmitted diseases (STDs) caused by HIV, herpes simplex virus (HSV), and other pathogens are spreading dramatically. The need to develop active products and vehicles to reduce this epidemic is urgent. GOAL: The efficacy of a thermoreversible gel formulation as a possible barrier to prevent the transmission of pathogens causing STDs was evaluated. STUDY DESIGN: This evaluation investigated the ability of the gel formulation to prevent infection of susceptible cells by HIV-1 and HSV-2 in vitro, the diffusion of radiolabeled herpes virus and micelles of polymer through an insertion membrane, and the electron microscopic appearance of herpes virus and gel alone or mixed together. RESULTS: The gel formulation prevents infection of susceptible cells by HIV-1 and HSV-2. It acts as an effective artificial physical barrier against the herpes virus within the first 4 hours of incubation. Herpes virus is coated by the gel or entrapped within micelles of the gel, which could hinder its attachment to target cells and inhibit its infectivity. CONCLUSION: This thermoreversible gel formulation represents an attractive matrix for the incorporation of microbicides to prevent the spread of STDs.