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OBJECTIVE: Primary sclerosing cholangitis (PSC) is characterised by bile duct strictures and progressive liver disease, eventually requiring liver transplantation. Although the pathogenesis of PSC remains incompletely understood, strong associations with HLA-class II haplotypes have been described. As specific HLA-DP molecules can bind the activating NK-cell receptor NKp44, we investigated the role of HLA-DP/NKp44-interactions in PSC. DESIGN: Liver tissue, intrahepatic and peripheral blood lymphocytes of individuals with PSC and control individuals were characterised using flow cytometry, immunohistochemical and immunofluorescence analyses. HLA-DPA1 and HLA-DPB1 imputation and association analyses were performed in 3408 individuals with PSC and 34 213 controls. NK cell activation on NKp44/HLA-DP interactions was assessed in vitro using plate-bound HLA-DP molecules and HLA-DPB wildtype versus knock-out human cholangiocyte organoids. RESULTS: NKp44+NK cells were enriched in livers, and intrahepatic bile ducts of individuals with PSC showed higher expression of HLA-DP. HLA-DP haplotype analysis revealed a highly elevated PSC risk for HLA-DPA1*02:01~B1*01:01 (OR 1.99, p=6.7×10-50). Primary NKp44+NK cells exhibited significantly higher degranulation in response to plate-bound HLA-DPA1*02:01-DPB1*01:01 compared with control HLA-DP molecules, which were inhibited by anti-NKp44-blocking. Human cholangiocyte organoids expressing HLA-DPA1*02:01-DPB1*01:01 after IFN-γ-exposure demonstrated significantly increased binding to NKp44-Fc constructs compared with unstimulated controls. Importantly, HLA-DPA1*02:01-DPB1*01:01-expressing organoids increased degranulation of NKp44+NK cells compared with HLA-DPB1-KO organoids. CONCLUSION: Our studies identify a novel PSC risk haplotype HLA-DP A1*02:01~DPB1*01:01 and provide clinical and functional data implicating NKp44+NK cells that recognise HLA-DPA1*02:01-DPB1*01:01 expressed on cholangiocytes in PSC pathogenesis.
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Colangitis Esclerosante , Humanos , Haplotipos , Colangitis Esclerosante/genética , Cadenas alfa de HLA-DP/genética , Células Asesinas NaturalesRESUMEN
Psoriasis is a common, debilitating immune-mediated skin disease. Genetic studies have identified biological mechanisms of psoriasis risk, including those targeted by effective therapies. However, the genetic liability to psoriasis is not fully explained by variation at robustly identified risk loci. To move towards a saturation map of psoriasis susceptibility we meta-analysed 18 GWAS comprising 36,466 cases and 458,078 controls and identified 109 distinct psoriasis susceptibility loci, including 45 that have not been previously reported. These include susceptibility variants at loci in which the therapeutic targets IL17RA and AHR are encoded, and deleterious coding variants supporting potential new drug targets (including in STAP2, CPVL and POU2F3). We conducted a transcriptome-wide association study to identify regulatory effects of psoriasis susceptibility variants and cross-referenced these against single cell expression profiles in psoriasis-affected skin, highlighting roles for the transcriptional regulation of haematopoietic cell development and epigenetic modulation of interferon signalling in psoriasis pathobiology.
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Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.
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Enfermedad de Crohn , Enfermedad de Crohn/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
BACKGROUND: Acute pancreatitis (AP) is a serious, mechanistically not entirely resolved side effect of L-asparaginase-containing treatment for acute lymphoblastic leukemia (ALL). To find new candidate variations for AP, we conducted a genome-wide association study (GWAS). METHODS: In all, 1,004,623 single-nucleotide variants (SNVs) were analyzed in 51 pediatric ALL patients with AP (cases) and 1388 patients without AP (controls). Replication used independent patients. RESULTS: The top-ranked SNV (rs4148513) was located within the ABCC4 gene (odds ratio (OR) 84.1; p = 1.04 × 10-14). Independent replication of our 20 top SNVs was not supportive of initial results, partly because rare variants were neither present in cases nor present in controls. However, results of combined analysis (GWAS and replication cohorts) remained significant (e.g., rs4148513; OR = 47.2; p = 7.31 × 10-9). Subsequently, we sequenced the entire ABCC4 gene and its close relative, the cystic fibrosis associated CFTR gene, a strong AP candidate gene, in 48 cases and 47 controls. Six AP-associated variants in ABCC4 and one variant in CFTR were detected. Replication confirmed the six ABCC4 variants but not the CFTR variant. CONCLUSIONS: Genetic variation within the ABCC4 gene was associated with AP during the treatment of ALL. No association of AP with CFTR was observed. Larger international studies are necessary to more conclusively assess the risk of rare clinical phenotypes.
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Killer cell immunoglobulin-like receptors (KIR) regulate immune responses in NK and CD8+ T cells via interaction with HLA ligands. KIR genes, including KIR2DS1, KIR3DL1, and KIR3DS1 have previously been implicated in psoriasis susceptibility. However, these previous studies were constrained to small sample sizes, in part due to the time and expense required for direct genotyping of KIR genes. Here, we implemented KIR*IMP to impute KIR copy number from single-nucleotide polymorphisms (SNPs) on chromosome 19 in the discovery cohort (n=11,912) from the PAGE consortium, University of California San Francisco, and the University of Dundee, and in a replication cohort (n=66,357) from Kaiser Permanente Northern California. Stratified multivariate logistic regression that accounted for patient ancestry and high-risk HLA alleles revealed that KIR2DL2 copy number was significantly associated with psoriasis in the discovery cohort (p ≤ 0.05). The KIR2DL2 copy number association was replicated in the Kaiser Permanente replication cohort. This is the first reported association of KIR2DL2 copy number with psoriasis and highlights the importance of KIR genetics in the pathogenesis of psoriasis.
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Alelos , Variaciones en el Número de Copia de ADN , Psoriasis/genética , Receptores KIR2DL2/genética , Estudios de Casos y Controles , Europa (Continente) , Predisposición Genética a la Enfermedad , Antígenos HLA-A , Antígenos HLA-B , Humanos , Modelos Logísticos , América del Norte , Polimorfismo de Nucleótido SimpleRESUMEN
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such as delineation could not be made because of tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a transethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40 691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analyzed the physicochemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we not only identified consistent associations (regarding effects directions/magnitudes) across different ethnicities but also identified population-specific signals (regarding differences in allele frequencies). We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.
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Colitis Ulcerosa/genética , Etnicidad/genética , Predisposición Genética a la Enfermedad , Antígenos HLA/genética , Antígenos HLA-DQ/genética , Cadenas HLA-DRB1/genética , Péptidos/genética , Alelos , Estudios de Cohortes , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Haplotipos , Humanos , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple , Unión ProteicaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1-3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of-and interplay between-novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.
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Enfermedades de Inmunodeficiencia Primaria/genética , Secuenciación Completa del Genoma , Complejo 2-3 Proteico Relacionado con la Actina/genética , Teorema de Bayes , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/inmunología , Proteína Tirosina Fosfatasa no Receptora Tipo 2/genética , Proteínas de Unión al ARN/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Proteína 1 Supresora de la Señalización de Citocinas/genética , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: Fifteen percent of atopic dermatitis (AD) liability-scale heritability could be attributed to 31 susceptibility loci identified by using genome-wide association studies, with only 3 of them (IL13, IL-6 receptor [IL6R], and filaggrin [FLG]) resolved to protein-coding variants. OBJECTIVE: We examined whether a significant portion of unexplained AD heritability is further explained by low-frequency and rare variants in the gene-coding sequence. METHODS: We evaluated common, low-frequency, and rare protein-coding variants using exome chip and replication genotype data of 15,574 patients and 377,839 control subjects combined with whole-transcriptome data on lesional, nonlesional, and healthy skin samples of 27 patients and 38 control subjects. RESULTS: An additional 12.56% (SE, 0.74%) of AD heritability is explained by rare protein-coding variation. We identified docking protein 2 (DOK2) and CD200 receptor 1 (CD200R1) as novel genome-wide significant susceptibility genes. Rare coding variants associated with AD are further enriched in 5 genes (IL-4 receptor [IL4R], IL13, Janus kinase 1 [JAK1], JAK2, and tyrosine kinase 2 [TYK2]) of the IL13 pathway, all of which are targets for novel systemic AD therapeutics. Multiomics-based network and RNA sequencing analysis revealed DOK2 as a central hub interacting with, among others, CD200R1, IL6R, and signal transducer and activator of transcription 3 (STAT3). Multitissue gene expression profile analysis for 53 tissue types from the Genotype-Tissue Expression project showed that disease-associated protein-coding variants exert their greatest effect in skin tissues. CONCLUSION: Our discoveries highlight a major role of rare coding variants in AD acting independently of common variants. Further extensive functional studies are required to detect all potential causal variants and to specify the contribution of the novel susceptibility genes DOK2 and CD200R1 to overall disease susceptibility.
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Proteínas Adaptadoras Transductoras de Señales/genética , Dermatitis Atópica/genética , Genotipo , Receptores de Orexina/genética , Fosfoproteínas/genética , Piel/metabolismo , Adulto , Estudios de Cohortes , Proteínas Filagrina , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Especificidad de Órganos , Polimorfismo Genético , Riesgo , TranscriptomaRESUMEN
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 (Pcomb = 6.57 × 10-18 ) and rs1265181 (Pcomb = 1.03 × 10-10 ). Additionally, we identified a novel significant association with the disease at locus, 4q32.1 (rs12650590, Pcomb = 4.49 × 10-08 ) in the vicinity of gene GUCY1A3, and multiple suggestive associations, for example rs10832027 (Pcomb = 7.28 × 10-06 ) and rs3770019 (Pcomb = 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.
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Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Psoriasis/genética , Estudios de Casos y Controles , Egipto/epidemiología , Femenino , Genoma Humano , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Inflamación , Complejo Mayor de Histocompatibilidad , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , RiesgoRESUMEN
Genotype imputation of the human leukocyte antigen (HLA) region is a cost-effective means to infer classical HLA alleles from inexpensive and dense SNP array data. In the research setting, imputation helps avoid costs for wet lab-based HLA typing and thus renders association analyses of the HLA in large cohorts feasible. Yet, most HLA imputation reference panels target Caucasian ethnicities and multi-ethnic panels are scarce. We compiled a high-quality multi-ethnic reference panel based on genotypes measured with Illumina's Immunochip genotyping array and HLA types established using a high-resolution next generation sequencing approach. Our reference panel includes more than 1,300 samples from Germany, Malta, China, India, Iran, Japan and Korea and samples of African American ancestry for all classical HLA class I and II alleles including HLA-DRB3/4/5. Applying extensive cross-validation, we benchmarked the imputation using the HLA imputation tool HIBAG, our multi-ethnic reference and an independent, previously published data set compiled of subpopulations of the 1000 Genomes project. We achieved average imputation accuracies higher than 0.924 for the commonly studied HLA-A, -B, -C, -DQB1 and -DRB1 genes across all ethnicities. We investigated allele-specific imputation challenges in regard to geographic origin of the samples using sensitivity and specificity measurements as well as allele frequencies and identified HLA alleles that are challenging to impute for each of the populations separately. In conclusion, our new multi-ethnic reference data set allows for high resolution HLA imputation of genotypes at all classical HLA class I and II genes including the HLA-DRB3/4/5 loci based on diverse ancestry populations.
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Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase I/genética , Negro o Afroamericano/etnología , Negro o Afroamericano/genética , Alelos , Pueblo Asiatico , Benchmarking , Análisis por Conglomerados , Etnicidad , Frecuencia de los Genes , Genotipo , Antígenos HLA/genética , Cadenas HLA-DRB3/genética , Cadenas HLA-DRB4/genética , Cadenas HLA-DRB5/genética , Haplotipos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Polimorfismo de Nucleótido Simple , Estudios Retrospectivos , Población Blanca/etnología , Población Blanca/genéticaRESUMEN
In transplantation, development of humoral alloimmunity against donor HLA is a major cause of organ transplant failure, but our ability to assess the immunological risk associated with a potential donor-recipient HLA combination is limited. We hypothesized that the capacity of donor HLA to induce a specific alloantibody response depends on their structural and physicochemical dissimilarity compared with recipient HLA. To test this hypothesis, we first developed a novel computational scoring system that enables quantitative assessment of surface electrostatic potential differences between donor and recipient HLA molecules at the tertiary structure level [three-dimensional electrostatic mismatch score (EMS-3D)]. We then examined humoral alloimmune responses in healthy females subjected to a standardized injection of donor lymphocytes from their male partner. This analysis showed a strong association between the EMS-3D of donor HLA and donor-specific alloantibody development; this relationship was strongest for HLA-DQ alloantigens. In the clinical transplantation setting, the immunogenic potential of HLA-DRB1 and -DQ mismatches expressed on donor kidneys, as assessed by their EMS-3D, was an independent predictor of development of donor-specific alloantibody after graft failure. Collectively, these findings demonstrate the translational potential of our approach to improve immunological risk assessment and to decrease the burden of humoral alloimmunity in organ transplantation.
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Rechazo de Injerto/inmunología , Antígenos HLA-DQ/química , Cadenas HLA-DRB1/química , Inmunidad Humoral , Isoanticuerpos/biosíntesis , Isoantígenos/química , Trasplante de Riñón , Femenino , Rechazo de Injerto/diagnóstico , Antígenos HLA-DQ/inmunología , Cadenas HLA-DRB1/inmunología , Histocompatibilidad , Prueba de Histocompatibilidad , Humanos , Isoantígenos/inmunología , Masculino , Electricidad Estática , Donantes de Tejidos , Receptores de TrasplantesRESUMEN
OBJECTIVE: Activating mutations in the GUCY2C gene, which encodes the epithelial receptor guanylate cyclase C, cause diarrhea due to increased loss of sodium chloride to the intestinal lumen. Patients with familial GUCY2C diarrhea syndrome (FGDS) are predisposed to inflammatory bowel disease (IBD). We investigated whether genes in the guanylate cyclase C pathway are enriched for association with IBD and reversely whether genetic or transcriptional changes associated with IBD are found in FGDS patients. METHODS: (1) A set of 27 genes from the guanylate cyclase C pathway was tested for enrichment of association with IBD by Gene Set Enrichment Analysis, using genome-wide association summary statistics from 12,882 IBD patients and 21,770 controls. (2) We genotyped 163 known IBD risk loci and sequenced NOD2 in 22 patients with FGDS. Eight of them had concomitant Crohn's disease. (3) Global gene expression analysis was performed in ileal tissue from patients with FGDS, Crohn's disease and healthy individuals. RESULTS: The guanylate cyclase C gene set showed a significant enrichment of association in IBD genome-wide association data. Risk variants in NOD2 were found in 7/8 FGDS patients with concomitant Crohn's disease and in 2/14 FDGS patients without Crohn's disease. In ileal tissue, downregulation of metallothioneins characterized FGDS patients compared to healthy controls. CONCLUSIONS: Our results support a role of guanylate cyclase C signaling and disturbed electrolyte homeostasis in development of IBD. Furthermore, downregulation of metallothioneins in the ileal mucosa of FGDS patients may contribute to IBD development, possibly alongside effects from NOD2 risk variants.
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Diarrea/genética , Enfermedades Inflamatorias del Intestino/genética , Receptores de Enterotoxina/genética , Adulto , Anciano , Estudios de Casos y Controles , Diarrea/metabolismo , Regulación hacia Abajo , Salud de la Familia , Femenino , Expresión Génica , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Íleon/patología , Enfermedades Inflamatorias del Intestino/complicaciones , Masculino , Persona de Mediana Edad , Proteína Adaptadora de Señalización NOD2/genética , Noruega , Plasma/química , Medición de Riesgo , Síndrome , Adulto JovenRESUMEN
Individuals with psychiatric disorders have elevated rates of autoimmune comorbidity and altered immune signaling. It is unclear whether these altered immunological states have a shared genetic basis with those psychiatric disorders. The present study sought to use existing summary-level data from previous genome-wide association studies to determine if commonly varying single nucleotide polymorphisms are shared between psychiatric and immune-related phenotypes. We estimated heritability and examined pair-wise genetic correlations using the linkage disequilibrium score regression (LDSC) and heritability estimation from summary statistics methods. Using LDSC, we observed significant genetic correlations between immune-related disorders and several psychiatric disorders, including anorexia nervosa, attention deficit-hyperactivity disorder, bipolar disorder, major depression, obsessive compulsive disorder, schizophrenia, smoking behavior, and Tourette syndrome. Loci significantly mediating genetic correlations were identified for schizophrenia when analytically paired with Crohn's disease, primary biliary cirrhosis, systemic lupus erythematosus, and ulcerative colitis. We report significantly correlated loci and highlight those containing genome-wide associations and candidate genes for respective disorders. We also used the LDSC method to characterize genetic correlations among the immune-related phenotypes. We discuss our findings in the context of relevant genetic and epidemiological literature, as well as the limitations and caveats of the study.
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Enfermedades Autoinmunes/genética , Trastornos Mentales/genética , Enfermedades Autoinmunes/fisiopatología , Comorbilidad , Bases de Datos Factuales , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/métodos , Humanos , Desequilibrio de Ligamiento , Masculino , Trastornos Mentales/fisiopatología , Herencia Multifactorial , Polimorfismo de Nucleótido Simple , Población Blanca/genéticaRESUMEN
Psoriatic arthritis (PsA) is a complex chronic musculoskeletal condition that occurs in ~30% of psoriasis patients. Currently, no systematic strategy is available that utilizes the differences in genetic architecture between PsA and cutaneous-only psoriasis (PsC) to assess PsA risk before symptoms appear. Here, we introduce a computational pipeline for predicting PsA among psoriasis patients using data from six cohorts with >7000 genotyped PsA and PsC patients. We identify 9 new loci for psoriasis or its subtypes and achieve 0.82 area under the receiver operator curve in distinguishing PsA vs. PsC when using 200 genetic markers. Among the top 5% of our PsA prediction we achieve >90% precision with 100% specificity and 16% recall for predicting PsA among psoriatic patients, using conditional inference forest or shrinkage discriminant analysis. Combining statistical and machine-learning techniques, we show that the underlying genetic differences between psoriasis subtypes can be used for individualized subtype risk assessment.
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Artritis Psoriásica/genética , Perfilación de la Expresión Génica , Medición de Riesgo , Biomarcadores/metabolismo , Estudios de Cohortes , Elementos de Facilitación Genéticos/genética , Sitios Genéticos , Humanos , Metaanálisis como AsuntoRESUMEN
BACKGROUND: Genomic approaches have revealed characteristic site specificities of skin bacterial community structures. In addition, in children with atopic dermatitis (AD), characteristic shifts were described at creases and, in particular, during flares, which have been postulated to mirror disturbed skin barrier function, cutaneous inflammation, or both. OBJECTIVE: We sought to comprehensively analyze microbial configurations in patients with AD across body sites and to explore the effect of distinct abnormalities of epidermal barrier function. METHODS: The skin microbiome was determined by using bacterial 16S rRNA sequencing at 4 nonlesional body sites, as well as acute and chronic lesions of 10 patients with AD and 10 healthy control subjects matched for age, sex, and filaggrin (FLG) mutation status. Nonlesional sampling sites were characterized for skin physiology parameters, including chromatography-based lipid profiling. RESULTS: Epidermal lipid composition, in particular levels of long-chain unsaturated free fatty acids, strongly correlated with bacterial composition, in particular Propionibacteria and Corynebacteria abundance. AD displayed a distinct community structure, with increased abundance and altered composition of staphylococcal species across body sites, the strongest loss of diversity and increase in Staphylococcus aureus seen on chronic lesions, and a progressive shift from nonlesional skin to acute and chronic lesions. FLG-deficient skin showed a distinct microbiome composition resembling in part the AD-related pattern. CONCLUSION: Epidermal barrier integrity and function affect the skin microbiome composition. AD shows an altered microbial configuration across diverse body sites, which is most pronounced at sites of predilection and AD. Eczematous affection appears to be a more important determinant than body site.
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Eccema/microbiología , Eccema/patología , Epidermis/microbiología , Epidermis/patología , Inflamación/microbiología , Inflamación/patología , Lípidos/fisiología , Adulto , Estudios de Casos y Controles , Dermatitis Atópica/genética , Dermatitis Atópica/microbiología , Dermatitis Atópica/patología , Eccema/genética , Femenino , Proteínas Filagrina , Humanos , Inflamación/genética , Proteínas de Filamentos Intermediarios/genética , Masculino , Microbiota/fisiología , Persona de Mediana Edad , ARN Ribosómico 16S/genética , Fenómenos Fisiológicos de la Piel/genética , Infecciones Estafilocócicas/genética , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/patología , Staphylococcus aureus/genética , Adulto JovenRESUMEN
Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 × 10-8, OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency < 0.01) via gene-wide aggregation testing (IFIH1: pburden = 2.53 × 10-7, OR = 0.707; TYK2: pburden = 6.17 × 10-4, OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.
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Psoriasis/genética , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Alelos , Estudios de Casos y Controles , Estudios de Cohortes , Exoma , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Helicasa Inducida por Interferón IFIH1/genética , Helicasa Inducida por Interferón IFIH1/metabolismo , Masculino , Polimorfismo de Nucleótido Simple/genética , Psoriasis/fisiopatología , Factores de Riesgo , TYK2 Quinasa/genética , TYK2 Quinasa/metabolismo , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Secuenciación del ExomaRESUMEN
Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size >39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFκB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8+ T-cells and CD4+ T-cells including TH0, TH1 and TH17). The identified loci explain â¼28% of the genetic heritability and generate a discriminatory genetic risk score (AUC=0.76 in our sample) that is significantly correlated with age at onset (p=2 × 10-89). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis.
Asunto(s)
Sitios Genéticos/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Psoriasis/genética , Población Blanca/genética , Edad de Inicio , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/inmunología , Humanos , Interferones/inmunología , Interferones/metabolismo , FN-kappa B/inmunología , FN-kappa B/metabolismo , Polimorfismo de Nucleótido Simple , Mapas de Interacción de Proteínas/genética , Mapas de Interacción de Proteínas/inmunología , Psoriasis/inmunología , Transducción de Señal/genética , Transducción de Señal/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Chronic venous disease (CVD) is a multifactorial condition representing one of the most common disorders among populations of Western countries. The heritability of about 17% suggests genetic risk factors in CVD etiology. However, so far the genetic causes are unknown. We undertook the hitherto first genome-wide association study (GWAS) for CVD, analyzing more than 1.93 M SNPs in 4,942 German individuals, followed by replication in two independent German data sets. The combined analysis of discovery and replication stages (2,269 cases and 7,765 controls) yielded robust associations within the two genes EFEMP1 and KCNH8 (rs17278665, rs727139 with P < 5 × 10-8), and suggestive association within gene SKAP2 (rs2030136 with P < 5 × 10-7). Association signals of rs17278665 and rs727139 reside in regions of low linkage disequilibrium containing no other genes. Data from the ENCODE and Roadmap Epigenomics projects show that tissue specific marks overlap with the variants. SNPs rs17278665 and rs2030136 are known eQTLs. Our study demonstrates that GWAS are a valuable tool to study the genetic component of CVD. With our approach, we identified two novel genome-wide significant susceptibility loci for this common disease. Particularly, the extracellular matrix glycoprotein EFEMP1 is promising for future functional studies due to its antagonistic role in vessel development and angiogenesis.