Functional Interpretation of Genome-Wide Association Study Evidence in Alopecia Areata.
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ABSTRACT:
SUBMITTER: Petukhova L
PROVIDER: S-EPMC4870380 | biostudies-literature | 2016 Jan
REPOSITORIES: biostudies-literature
Publications
Functional Interpretation of Genome-Wide Association Study Evidence in Alopecia Areata.
Petukhova Lynn L Christiano Angela M AM
The Journal of investigative dermatology 20160101 1
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Project description:Genome Wide Association Study of Alopecia Areata
| PRJNA187262 | ENA
Project description:Alopecia areata (AA) is among the most highly prevalent human autoimmune diseases, leading to disfiguring hair loss due to the collapse of immune privilege of the hair follicle and subsequent autoimmune attack. The genetic basis of AA is largely unknown. We undertook a genome-wide association study (GWAS) in a sample of 1,054 cases and 3,278 controls and identified 139 single nucleotide polymorphisms that are significantly associated with AA (P <or= 5 x 10(-7)). Here we show an association with genomic regions containing several genes controlling the activation and proliferation of regulatory T cells (T(reg) cells), cytotoxic T lymphocyte-associated antigen 4 (CTLA4), interleukin (IL)-2/IL-21, IL-2 receptor A (IL-2RA; CD25) and Eos (also known as Ikaros family zinc finger 4; IKZF4), as well as the human leukocyte antigen (HLA) region. We also find association evidence for regions containing genes expressed in the hair follicle itself (PRDX5 and STX17). A region of strong association resides within the ULBP (cytomegalovirus UL16-binding protein) gene cluster on chromosome 6q25.1, encoding activating ligands of the natural killer cell receptor NKG2D that have not previously been implicated in an autoimmune disease. By probing the role of ULBP3 in disease pathogenesis, we also show that its expression in lesional scalp from patients with AA is markedly upregulated in the hair follicle dermal sheath during active disease. This study provides evidence for the involvement of both innate and acquired immunity in the pathogenesis of AA. We have defined the genetic underpinnings of AA, placing it within the context of shared pathways among autoimmune diseases, and implicating a novel disease mechanism, the upregulation of ULBP ligands, in triggering autoimmunity.
| S-EPMC2921172 | biostudies-literature
Project description:PurposeAlopecia areata (AA) is one of the most prevalent autoimmune diseases affecting humans. Given that hair follicles are immune-privileged, autoimmunity can result in disfiguring hair loss. However, the genetic basis for AA in the Taiwanese population remains unknown.Materials and methodsA genome-wide association study was conducted using a cohort of 408 AA cases and 8167 controls. To link variants to gene relationships, we used 882 SNPs (P<1E-05) within 74 genes that were associated with AA group to build the biological networks by IPA software. HLA diplotypes and haplotypes were analyzed using Attribute Bagging (HIBAG)-R package and chi-square analysis.ResultsSeven single nucleotide polymorphisms (SNPs) including LINC02006 (rs531166736, rs187306735), APC (rs112800832_C_CAT), SRP19 (rs139948960, rs144784670), EGFLAM (rs16903975) and LDLRAD3 (rs79874564) were closely associated with the AA phenotype (P<5E-08). Examination of biological networks revealed that these genomic areas are associated with antigen presentation signaling, B cell and T cell development, Th1 and Th2 activation pathways, Notch signaling, crosstalk signaling between dendritic cells and natural killer cells, and phagosome maturation. Based on human leukocyte antigen (HLA) genotype analysis, four HLA genotypes (HLA-B*15:01-*40:01, HLA-DQA1*01:02-*03:03, HLA-DQA1*01:02, and HLA-DQB1*02:01) were found to be associated with AA (adjusted p-value<0.05). HLA-DQA1*01:02 is the most significantly related gene in the Taiwanese population (adjusted p-value = 2.09E-05).ConclusionThis study successfully identified susceptibility loci associated with AA in the Taiwanese population. These findings not only shed light on the origins of AA within the Taiwanese context but also contribute to a comprehensive understanding of the genetic factors influencing AA susceptibility.
| S-EPMC10519225 | biostudies-literature
Project description:Alopecia areata is an autoimmune disorder characterized by transient, non-scarring hair loss and preservation of the hair follicle. Hair loss can take many forms ranging from loss in well-defined patches to diffuse or total hair loss, which can affect all hair-bearing sites. Patchy alopecia areata affecting the scalp is the most common type. Alopecia areata affects nearly 2% of the general population at some point during their lifetime. Skin biopsies of affected skin show a lymphocytic infiltrate in and around the bulb or the lower part of the hair follicle in the anagen (hair growth) phase. A breakdown of immune privilege of the hair follicle is thought to be an important driver of alopecia areata. Genetic studies in patients and mouse models have shown that alopecia areata is a complex, polygenic disease. Several genetic susceptibility loci were identified to be associated with signalling pathways that are important to hair follicle cycling and development. Alopecia areata is usually diagnosed based on clinical manifestations, but dermoscopy and histopathology can be helpful. Alopecia areata is difficult to manage medically, but recent advances in understanding the molecular mechanisms have revealed new treatments and the possibility of remission in the near future.
| S-EPMC5573125 | biostudies-other
Project description:Alopecia areata (AA) is a common hair loss disorder, which is thought to be a tissue-specific autoimmune disease. Previous research has identified a few AA susceptibility genes, most of which are implicated in autoimmunity. To identify new genetic variants and further elucidate the genetic basis of AA, we performed a genome-wide association study using the strategy of pooled DNA genotyping (729 cases, 656 controls). The strongest association was for variants in the HLA region, which confirms the validity of the pooling strategy. The selected top 61 single-nucleotide polymorphisms (SNPs) were analyzed in an independent replication sample (454 cases, 1364 controls). Only one SNP outside of the HLA region (rs304650) showed significant association. This SNP was then analyzed in a second independent replication sample (537 cases, 657 controls). The finding was not replicated on a significant level, but showed the same tendency. A combined analysis of the two replication samples was then performed, and the SNP rs304650 showed significant association with P=3.43 × 10(-4) (OR=1.24 (1.10-1.39)). This SNP maps to an intronic region of the SPATA5 (spermatogenesis-associated protein 5) gene on chromosome 4. The results therefore suggest the SPATA5 locus is a new susceptibility locus for AA.
| S-EPMC3283178 | biostudies-literature
Project description:IntroductionPatients with alopecia areata (AA) experience psychological and psychosocial symptoms including depression, anxiety, anger, social withdrawal, embarrassment, and low self-esteem. While multiple studies have measured the detrimental emotional impact of AA on patient quality of life, evidence of its effect on work productivity loss (WPL) and daily activities is limited. This study aimed to assess the extent of AA-related emotional symptom (ES) burden on work productivity and activity impairment.MethodsA cross-sectional survey of dermatologists and their adult patients with AA was conducted in the USA in 2019. Dermatologists provided assessments of patients' clinical characteristics, while patients completed sociodemographic questionnaires along with two validated patient-reported outcome measures of the Work Productivity and Activity Impairment (WPAI) and the AA Patient Priority Outcomes (AAPPO) ES subscale. The WPAI assessed AA-related WPL (employed respondents) and activity impairment (all respondents), and the AAPPO-ES assessed AA-related frequency of feeling self-conscious, embarrassed, sad, or frustrated. Multiple linear regression models were fitted to both WPAI scores with the AAPPO ES as an independent variable.ResultsA total of 242 patients with a mean (SD) age of 39.2 (13.3) years, treated by 59 dermatologists, were evaluated. Mean (SD) ES score was 2.0 (1.1). Mean (SD) work productivity loss [n = 170] and activity impairment [n = 242] were 12.2% (17.4%) and 13.3% (18.3%), respectively. After adjusting for covariates, WPL increased by 4.1% [95% confidence interval (CI) 1.6-6.7%; p = 0.002] and activity impairment increased by 3.1% (95% CI 0.7-5.4%; p = 0.010) for every 1-point increase in ES. For an average patient, a 1-SD decrease (about 1 point) on the ES scale substantially reduced WPL and activity impairment (by at least 25%).ConclusionsPatients with AA reported significant increases in WPL and activity impairment associated with worsening AA-related ES. These findings underscore the substantial emotional and psychosocial burden among patients with AA and a need for improved treatment options.
| S-EPMC9823171 | biostudies-literature
Project description:BackgroundAlopecia areata (AA) is characterized by hair loss on the scalp and body, significantly impacting patients' quality of life based on its severity.ObjectiveThis study aims to identify crucial factors influencing the perception of severe AA from the patients' viewpoint.MethodsA web-based survey was conducted among AA patients attending dermatology departments at 21 university hospitals in Korea. The survey comprised 17 criteria, exploring both clinical characteristics of AA patients and subjective determinants of disease severity.ResultsA total of 791 AA patients and their caregivers participated in the survey. Approximately 30% of respondents developed AA during childhood, with 43.5% experiencing chronic courses lasting over 3 years. Half of the participants exhibited more than 20% scalp hair loss, and 42% reported additional hair loss on other body parts, such as eyelashes and nose hair. Most respondents agreed that patients with ≥20% scalp hair loss should be categorized as having severe AA. They also identified longer disease duration, involvement of non-scalp body hair, treatment refractoriness, and social or mental impairment requiring medical intervention as factors indicating increased disease severity.ConclusionThis survey underscores the significant impact of AA on patients' quality of life and highlights existing unmet needs in current treatment modalities.
| S-EPMC11621644 | biostudies-literature
Project description:Alopecia areata (AA) is a skin condition in which hair is lost from certain or all areas of the body. This condition has been described as an immune-mediated complex genetic disease, characterized by the presence of lymphocytes that are directed to the hair follicles in the anagen phase. The gene encoding the protein tyrosine phosphatase, non-receptor type 22 (PTPN22), which is exclusively expressed in immune cells, has been considered as a risk factor associated with a number of autoimmune diseases. In AA, the single nucleotide polymorphism, rs2476601, has been identified as a risk factor in several populations. The aim of the present study was to investigate the effect of PTPN22 C1858T inherited genetic polymorphism on the predisposition to severe forms of AA, in a case-control study on individuals. The study included 64 unrelated patients diagnosed with several types of AA, as well as 225 healthy unrelated subjects. The DNA samples were genotyped for PTPN22 C1858T polymorphism using the polymerase chain reaction-restriction fragment length polymorphism technique. Causal associations were determined by χ2 test and their respective odds ratio (OR) was assessed in a 2×2 contingency table. The results demonstrated a significant association of the T allele [P=0.040; OR=3.196; 95% confidence interval (CI), 0.094-10.279] and the CT genotype (P=0.038; OR=3.313; 95% CI, 1.008-10.892) with patchy AA. In conclusion, the results of the present study suggested the possible involvement of the T allele of the PTPN22 C1858T SNP as a genetic risk factor for this type of AA in the population studied.
| S-EPMC4665763 | biostudies-literature
Project description:Alopecia areata (AA) is a prevalent autoimmune disease with 10 known susceptibility loci. Here we perform the first meta-analysis of research on AA by combining data from two genome-wide association studies (GWAS), and replication with supplemented ImmunoChip data for a total of 3,253 cases and 7,543 controls. The strongest region of association is the major histocompatibility complex, where we fine-map four independent effects, all implicating human leukocyte antigen-DR as a key aetiologic driver. Outside the major histocompatibility complex, we identify two novel loci that exceed the threshold of statistical significance, containing ACOXL/BCL2L11(BIM) (2q13); GARP (LRRC32) (11q13.5), as well as a third nominally significant region SH2B3(LNK)/ATXN2 (12q24.12). Candidate susceptibility gene expression analysis in these regions demonstrates expression in relevant immune cells and the hair follicle. We integrate our results with data from seven other autoimmune diseases and provide insight into the alignment of AA within these disorders. Our findings uncover new molecular pathways disrupted in AA, including autophagy/apoptosis, transforming growth factor beta/Tregs and JAK kinase signalling, and support the causal role of aberrant immune processes in AA.
| S-EPMC4451186 | biostudies-literature
Project description:BackgroundMany patients with asthma experience alopecia areata (AA) in their lives. However, it is unclear whether asthma causes or results from AA. Our objective was to investigate the genetic causal relationship between asthma and AA.MethodsTwo-sample Mendelian randomization (MR) was used to assess the causal relationship between asthma and AA based on the largest publicly available genome-wide association study summary statistics. Androgenetic alopecia (AGA) and cicatricial alopecia (CA) were chosen as the control groups for AA. The main estimates were obtained using inverse variance weighting meta-analysis (IVW), Mendelian randomization-Egger (MR-Egger), maximum likelihood estimation, and the weighted median. Sensitivity analyses were conducted using Cochran's Q test, MR-Egger, and leave-one-out methods. Lastly, we conducted a reverse MR analysis to evaluate the possibility of reverse causation.ResultsGenetically, asthma is associated with an increased risk of AA, while the association between genetically predicted AGA or CA and asthma was negative. The risk of AA increased by 1.86 times in patients with asthma under the IVW method (OR = 1.86, 95% CI = 1.31-2.629, p < 0.001). The reverse MR analysis did not find evidence supporting reverse causality from three phenotypes of alopecia to asthma. Sensitivity analyses yielded consistent causal estimates.ConclusionThis study suggests that asthma is causally associated with AA. The findings deepen our understanding of the role of asthma in the pathology of AA, which emphasizes the potential for opening a new vista for the prevention and diagnosis of AA.
| S-EPMC11224124 | biostudies-literature