RESUMEN
Autoimmune thyroid disease is the most common autoimmune disease and is highly heritable1. Here, by using a genome-wide association study of 30,234 cases and 725,172 controls from Iceland and the UK Biobank, we find 99 sequence variants at 93 loci, of which 84 variants are previously unreported2-7. A low-frequency (1.36%) intronic variant in FLT3 (rs76428106-C) has the largest effect on risk of autoimmune thyroid disease (odds ratio (OR) = 1.46, P = 2.37 × 10-24). rs76428106-C is also associated with systemic lupus erythematosus (OR = 1.90, P = 6.46 × 10-4), rheumatoid factor and/or anti-CCP-positive rheumatoid arthritis (OR = 1.41, P = 4.31 × 10-4) and coeliac disease (OR = 1.62, P = 1.20 × 10-4). FLT3 encodes fms-related tyrosine kinase 3, a receptor that regulates haematopoietic progenitor and dendritic cells. RNA sequencing revealed that rs76428106-C generates a cryptic splice site, which introduces a stop codon in 30% of transcripts that are predicted to encode a truncated protein, which lacks its tyrosine kinase domains. Each copy of rs76428106-C doubles the plasma levels of the FTL3 ligand. Activating somatic mutations in FLT3 are associated with acute myeloid leukaemia8 with a poor prognosis and rs76428106-C also predisposes individuals to acute myeloid leukaemia (OR = 1.90, P = 5.40 × 10-3). Thus, a predicted loss-of-function germline mutation in FLT3 causes a reduction in full-length FLT3, with a compensatory increase in the levels of its ligand and an increased disease risk, similar to that of a gain-of-function mutation.
Asunto(s)
Codón sin Sentido/genética , Predisposición Genética a la Enfermedad/genética , Ligandos , Mutación , Tiroiditis Autoinmune/genética , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo , Alelos , Enfermedades Autoinmunes/genética , Bases de Datos Factuales , Estudio de Asociación del Genoma Completo , Mutación de Línea Germinal , Humanos , Islandia , Intrones/genética , Leucemia Mieloide Aguda , Mutación con Pérdida de Función , Sitios de Empalme de ARN/genética , Reino UnidoRESUMEN
OBJECTIVES: To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. METHODS: We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ~1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). RESULTS: We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1×10-9), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3×10-160). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6×10-11). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10-9-10-27) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. CONCLUSION: Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
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Artritis Reumatoide , Estudio de Asociación del Genoma Completo , Artritis Reumatoide/genética , Predisposición Genética a la Enfermedad/genética , Humanos , Interferón-alfa , Quinasas Janus/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 22/genética , Proteómica , Factores de Transcripción STAT/genética , Transducción de Señal/genéticaRESUMEN
Rheumatoid arthritis (RA) is a chronic multisystem disease with a complex immunopathology. Its inflammatory state is dominated by pro-inflammatory cytokines such as TNFα and activated Th1/Th17. Only proportion of patients achieve clinical remission despite potent biologics targeting these pathways. This study investigated the resolution of inflammation in RA patients (naïve for biologics) receiving TNFα inhibitors (TNFi) and evaluated the biological mechanisms behind treatment response and assessed them using clinical scoring systems. The majority showed a good clinical response after six months (6M) and a significant drop in DAS28-CRP (P ≤ .002), CDAI (P ≤ .0001) and RheumXpert (P ≤ .0001). Before treatment, the patients demonstrated a chronic innate and adaptive inflammatory state. The improved clinical condition was reflected with a decrease in Th17/Tc17 (P ≤ .05) and an increase in Tregs after 6M (P ≤ .05). Using a logistic regression model on serum data, IL-6, IL-18, IL-21, IL-22, IFNγ and TNFα were identified as the main contributing biomarkers in the chronic inflammatory state of RA. A specific test score (STS) was defined and converted to a single cytokine composite test score (CCTS), which showed the disease outcome on a scale 0-100, providing sensitivity and specificity of ≥90%. Thus, the immunological complexity in RA is driven by a complex interplay of pro-inflammatory cytokines and effector T-cell response dominated by Th17/Tc17. In addition, the resolution of inflammation could be linked to a partially Treg-driven homeostatic innate immune response. Therefore, a more complex therapeutic approach against the above markers might be of value to obtain full clinical remission in the future.
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Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Citocinas/sangre , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Artritis Reumatoide/inducido químicamente , Biomarcadores/sangre , Femenino , Humanos , Islandia , Inflamación/inmunología , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Células TH1/inmunología , Resultado del TratamientoRESUMEN
BACKGROUND: Although osteoporosis is an easily diagnosed and treatable condition, many individuals remain untreated. Clinical decision support systems might increase appropriate treatment of osteoporosis. We designed the Osteoporosis Advisor (OPAD), a computerized tool to support physicians managing osteoporosis at the point-of-care. The present study compares the treatment recommendations provided by OPAD, an expert physician and the National Osteoporosis Guideline Group (NOGG). METHODS: We performed a retrospective analysis of 259 patients attending the outpatient osteoporosis clinic at the University Hospital in Iceland. We entered each patient's data into the OPAD and recorded the OPAD diagnostic comments, 10-year risk of major osteoporotic fracture and treatment options. We compared OPAD recommendations to those given by the osteoporosis specialist, and to those of the NOGG. RESULTS: Risk estimates made by OPAD were highly correlated with those from FRAX (r = 0.99, 95% CI 0.99, 1.00 without femoral neck BMD; r = 0.98, 95% CI, 0.97, 0.99 with femoral neck BMD. Reassurance was recommended by the expert, NOGG and the OPAD in 68, 63 and 52% of cases, respectively. Likewise, intervention was recommended by the expert, NOGG, and the OPAD in 32, 37 and 48% of cases, respectively. The OPAD demonstrated moderate agreement with the physician (kappa 0.51, 95% CI 0.41, 0.61) and even higher agreement with NOGG (kappa 0.69, 95% CI 0.60, 0.77). CONCLUSION: Primary care physicians can use the OPAD to assess and treat patients' skeletal health. Recommendations given by OPAD are consistent with expert opinion and existing guidelines.
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Sistemas de Apoyo a Decisiones Clínicas/normas , Osteología/métodos , Osteoporosis/diagnóstico , Osteoporosis/terapia , Guías de Práctica Clínica como Asunto/normas , Medición de Riesgo/normas , Anciano , Femenino , Humanos , Persona de Mediana Edad , Médicos de Atención Primaria , Proyectos Piloto , Sistemas de Atención de Punto , Estudios RetrospectivosRESUMEN
PURPOSE: Primary immunodeficiencies (PID) are rare heterogeneous diseases. Little is known about the prevalence of PID in Iceland and no national registry exists. The aim of the study was to describe the epidemiology of PID in Iceland. METHODS: Using The European Society's for Immunodeficiencies (ESID) criteria for PID, information about individuals with a known PID between 1990 and 2010 in Iceland were collected from inpatient registries of the National University Hospital of Iceland, the Department of Immunology and from clinical immunologists. Selective IgA deficiency, mannan binding lectin deficiency and secondary immunodeficiencies were excluded RESULTS: Sixty six individuals met the study criteria, 35 of them (53%) were females. Four patients died during the study period from PID- or treatment related complications and two moved abroad. In the beginning of 2011 there were 60 individuals living in Iceland with a known PID diagnosis meeting ESID's criteria. Estimated prevalence for PID in the Icelandic population of 318.452 habitants was 18.8 for 100.000 inhabitants. Predominantly antibody disorders comprised the largest category of PID in Iceland. CONCLUSIONS: The prevalence of PID is high in Iceland compared to reports from other nations. Our patient data are easily accessible and a central laboratory measures the immune parameters. This high prevalence may indicate that PID is more common than generally recognized.
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Síndromes de Inmunodeficiencia/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Proteínas del Sistema Complemento/deficiencia , Síndrome de DiGeorge/epidemiología , Femenino , Humanos , Islandia/epidemiología , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/inmunología , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Fagocitos/inmunología , Prevalencia , Adulto JovenRESUMEN
BACKGROUND & AIMS: Antagonists of tumor necrosis factor (anti-TNF agents) can cause drug-induced liver injury (DILI), yet little is known about the level of risk. METHODS: We identified cases of DILI caused by anti-TNF agents in Iceland, from 2009 through 2013, at the National University Hospital of Iceland (n = 11). We collected data on the total use of the drugs by patients with DILI, and outcomes, compared with patients who received anti-TNF agents but who did not develop DILI (controls, n = 22). RESULTS: Of the 11 cases of DILI identified (8 women; mean age, 46 y), 9 cases were caused by infliximab. DILI developed in 1 of 120 patients who received infliximab, 1 in 270 patients who received adalimumab, and 1 in 430 patients who received etanercept. Most patients with infliximab-associated DILI developed this disorder after 4 infusions (n = 6). Four patients had jaundice at diagnosis of DILI, and 8 patients had hepatocellular liver injury. The mean peak level of alanine aminotransferase was 704 U/L, of aspartate aminotransferase was 503 U/L, of alkaline phosphatase was 261 U/L, and of bilirubin was 47 µmol/L. Seven patients with DILI were tested for antinuclear antibodies before therapy with an anti-TNF agent and 3 had positive test results, compared with 5 of the 14 controls tested. At DILI diagnosis, 8 of 11 patients tested positive for antinuclear antibodies. Of liver biopsy specimens collected from 5 patients with DILI, 3 showed signs of severe acute hepatitis. Only 9% of the patients who developed DILI received methotrexate during anti-TNF therapy, compared with 59% of controls (P = .009). DILI was treated with steroids in 5 patients, and in 4 cases steroid therapy was discontinued without relapse. Eight patients with DILI went on to receive treatment with different TNF antagonists without developing DILI. CONCLUSIONS: Of anti-TNF agents, infliximab is associated most frequently with DILI, developing in 1 of 120 patients who received this drug. Fifty percent of patients with anti-TNF-associated DILI required steroid therapy, but most did not need long-term treatment. The addition of methotrexate to anti-TNF therapy might reduce the risk of DILI.
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Anticuerpos Monoclonales/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Factores Inmunológicos/efectos adversos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto , Anticuerpos Monoclonales/administración & dosificación , Femenino , Hospitales Universitarios , Humanos , Islandia/epidemiología , Factores Inmunológicos/administración & dosificación , Infliximab , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Prevalencia , Estudios Prospectivos , Medición de RiesgoRESUMEN
Selective IgA deficiency (IgAD; serum IgA<0.07 g/l) is the most common form of human primary immune deficiency, affecting approximately 1â¶600 individuals in populations of Northern European ancestry. The polygenic nature of IgAD is underscored by the recent identification of several new risk genes in a genome-wide association study. Among the characterized susceptibility loci, the association with specific HLA haplotypes represents the major genetic risk factor for IgAD. Despite the robust association, the nature and location of the causal variants in the HLA region remains unknown. To better characterize the association signal in this region, we performed a high-density SNP mapping of the HLA locus and imputed the genotypes of common HLA-B, -DRB1, and -DQB1 alleles in a combined sample of 772 IgAD patients and 1,976 matched controls from 3 independent European populations. We confirmed the complex nature of the association with the HLA locus, which is the result of multiple effects spanning the entire HLA region. The primary association signal mapped to the HLA-DQB1*02 allele in the HLA Class II region (combined Pâ=â7.69×10(-57); ORâ=â2.80) resulting from the combined independent effects of the HLA-B*0801-DRB1*0301-DQB1*02 and -DRB1*0701-DQB1*02 haplotypes, while additional secondary signals were associated with the DRB1*0102 (combined Pâ=â5.86×10(-17); ORâ=â4.28) and the DRB1*1501 (combined Pâ=â2.24×10(-35); ORâ=â0.13) alleles. Despite the strong population-specific frequencies of HLA alleles, we found a remarkable conservation of these effects regardless of the ethnic background, which supports the use of large multi-ethnic populations to characterize shared genetic association signals in the HLA region. We also provide evidence for the location of association signals within the specific extended haplotypes, which will guide future sequencing studies aimed at characterizing the precise functional variants contributing to disease pathogenesis.
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Antígenos HLA-B/genética , Cadenas beta de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Deficiencia de IgA/genética , Alelos , Estudios de Casos y Controles , Mapeo Cromosómico , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple , Población Blanca/genéticaRESUMEN
Autoimmune thyroid disease (AITD) is a common autoimmune disease. In a GWAS meta-analysis of 110,945 cases and 1,084,290 controls, 290 sequence variants at 225 loci are associated with AITD. Of these variants, 115 are previously unreported. Multiomics analysis yields 235 candidate genes outside the MHC-region and the findings highlight the importance of genes involved in T-cell regulation. A rare 5'-UTR variant (rs781745126-T, MAF = 0.13% in Iceland) in LAG3 has the largest effect (OR = 3.42, P = 2.2 × 10-16) and generates a novel start codon for an open reading frame upstream of the canonical protein translation initiation site. rs781745126-T reduces mRNA and surface expression of the inhibitory immune checkpoint LAG-3 co-receptor on activated lymphocyte subsets and halves LAG-3 levels in plasma among heterozygotes. All three homozygous carriers of rs781745126-T have AITD, of whom one also has two other T-cell mediated diseases, that is vitiligo and type 1 diabetes. rs781745126-T associates nominally with vitiligo (OR = 5.1, P = 6.5 × 10-3) but not with type 1 diabetes. Thus, the effect of rs781745126-T is akin to drugs that inhibit LAG-3, which unleash immune responses and can have thyroid dysfunction and vitiligo as adverse events. This illustrates how a multiomics approach can reveal potential drug targets and safety concerns.
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Antígenos CD , Codón Iniciador , Predisposición Genética a la Enfermedad , Proteína del Gen 3 de Activación de Linfocitos , Humanos , Codón Iniciador/genética , Antígenos CD/genética , Antígenos CD/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Femenino , Polimorfismo de Nucleótido Simple , Vitíligo/genética , Masculino , Estudio de Asociación del Genoma Completo , Tiroiditis Autoinmune/genética , Regiones no Traducidas 5'/genética , Estudios de Casos y Controles , Islandia , AdultoRESUMEN
Urticaria is a skin disorder characterized by outbreaks of raised pruritic wheals. In order to identify sequence variants associated with urticaria, we performed a meta-analysis of genome-wide association studies for urticaria with a total of 40,694 cases and 1,230,001 controls from Iceland, the UK, Finland, and Japan. We also performed transcriptome- and proteome-wide analyses in Iceland and the UK. We found nine sequence variants at nine loci associating with urticaria. The variants are at genes participating in type 2 immune responses and/or mast cell biology (CBLB, FCER1A, GCSAML, STAT6, TPSD1, ZFPM1), the innate immunity (C4), and NF-κB signaling. The most significant association was observed for the splice-donor variant rs56043070[A] (hg38: chr1:247556467) in GCSAML (MAF = 6.6%, OR = 1.24 (95%CI: 1.20-1.28), P-value = 3.6 × 10-44). We assessed the effects of the variants on transcripts, and levels of proteins relevant to urticaria pathophysiology. Our results emphasize the role of type 2 immune response and mast cell activation in the pathogenesis of urticaria. Our findings may point to an IgE-independent urticaria pathway that could help address unmet clinical need.
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Estudio de Asociación del Genoma Completo , Urticaria , Humanos , Mastocitos , Urticaria/genética , Empalme del ARN , ProteomaRESUMEN
From the beginning of the COVID-19 pandemic, it has claimed over 6 million lives, and globally the pandemic rages with detrimental consequences, with the emergence of new more infectious and possibly virulent variants. A clinical obstacle in this battle has been to determine when an infected individual has reached a non-infectious state. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can be transmitted under diverse circumstances, and various rules and regulations, along with different testing methods, have been applied in an attempt to confine the transmission. However, that has proven to be a difficult task. In this review, we take together recently published data on infectivity and transmission of SARS-CoV-2 and have combined it with the clinical experience that physicians in Iceland have accumulated from the pandemic. In addition, we suggest guidelines for determining when patients with COVID-19 reach a non-infectious state based on a combination of clinical experience, scientific data, and proficient use of available tests. This review has addressed some of the questions regarding contagiousness and immunity against SARS-CoV-2.
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COVID-19 , Humanos , Pandemias , SARS-CoV-2RESUMEN
A detailed understanding of the antibody response against SARS-CoV-2 is of high importance, especially with the emergence of novel vaccines. A multiplex-based assay, analyzing IgG, IgM, and IgA antibodies against the receptor binding domain (RBD), spike 1 (S1), and nucleocapsid proteins of the SARS-CoV-2 virus was set up. The multiplex-based analysis was calibrated against the Elecsys® Anti-SARS-CoV-2 assay on a Roche Cobas® instrument, using positive and negative samples. The calibration of the multiplex based assay yielded a sensitivity of 100% and a specificity of 97.7%. SARS-CoV-2 specific antibody levels were analyzed by multiplex in 251 samples from 221 patients. A significant increase in all antibody types (IgM, IgG, and IgA) against RBD was observed between the first and the third weeks of disease. Additionally, the S1 IgG antibody response increased significantly between weeks 1, 2, and 3 of disease. Class switching appeared to occur earlier for IgA than for IgG. Patients requiring hospital admission and intensive care had higher levels of SARS-CoV-2 specific IgA levels than outpatients. These findings describe the initial antibody response during the first weeks of disease and demonstrate the importance of analyzing different antibody isotypes against multiple antigens and include IgA when examining the immunological response to COVID-19.
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Anticuerpos Antivirales/metabolismo , COVID-19/inmunología , Inmunoglobulina A/metabolismo , Inmunoglobulina G/metabolismo , Inmunoglobulina M/metabolismo , SARS-CoV-2/inmunología , Adulto , Anciano , Formación de Anticuerpos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dominios Proteicos/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunologíaRESUMEN
INTRODUCTION: Immunoglobulin A (IgA) is important for mucosal health. Selective IgA deficiency (IgAD) is the most common primary immunodeficiency but its effect on oral health is unclear. The aim of this study was to investigate dental, periodontal and oral mucosal health in IgAD individuals. MATERIAL AND METHODS: In total, 32 adult IgAD subjects were compared with 63 randomly selected individuals. Participants answered questionnaires regarding general and oral health and underwent oral examination, including examination using the periodontal screening and recording (PSR) system and dental examination using the DMF system. RESULTS: The IgAD individuals had significantly more often undergone tonsillectomy (44%versus 24%, p=0.046) and adenoidectomy (31%versus 8%, p=0.003) compared with the controls. Furthermore, the IgAD subjects reported having pharyngitis, stomatitis and herpes labialis significantly more often. There was no significant difference in periodontal health (mean PSR index; 1.87 versus 1.77) or dental health (mean DMFS; 51.3 versus 53.7) between the two cohorts. A positive correlation between Helicobacter pylori infection and severity of periodontitis was found (p=0.036). CONCLUSION: IgAD predisposes to oral mucosal infections but does not influence periodontal or dental health. This is the first controlled study to include detailed clinical history and investigations, together with full oral and dental examination, in adults with IgAD.
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Deficiencia de IgA/complicaciones , Enfermedades de la Boca/complicaciones , Enfermedades Periodontales/complicaciones , Enfermedades Dentales/complicaciones , Adenoidectomía , Adulto , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Índice CPO , Femenino , Reflujo Gastroesofágico/complicaciones , Gingivitis/complicaciones , Estado de Salud , Helicobacter/aislamiento & purificación , Infecciones por Helicobacter/complicaciones , Herpes Labial/complicaciones , Humanos , Deficiencia de IgA/sangre , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Masculino , Persona de Mediana Edad , Salud Bucal , Índice Periodontal , Periodontitis/complicaciones , Faringitis/complicaciones , Estomatitis/complicaciones , Tonsilectomía , Xerostomía/complicacionesRESUMEN
Asthma is one of the most common chronic diseases affecting both children and adults. We report a genome-wide association meta-analysis of 69,189 cases and 702,199 controls from Iceland and UK biobank. We find 88 asthma risk variants at 56 loci, 19 previously unreported, and evaluate their effect on other asthma and allergic phenotypes. Of special interest are two low frequency variants associated with protection against asthma; a missense variant in TNFRSF8 and 3' UTR variant in TGFBR1. Functional studies show that the TNFRSF8 variant reduces TNFRSF8 expression both on cell surface and in soluble form, acting as loss of function. eQTL analysis suggests that the TGFBR1 variant acts through gain of function and together with an intronic variant in a downstream gene, SMAD3, points to defective TGFßR1 signaling as one of the biological perturbations increasing asthma risk. Our results increase the number of asthma variants and implicate genes with known role in T cell regulation, inflammation and airway remodeling in asthma pathogenesis.
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Remodelación de las Vías Aéreas (Respiratorias)/genética , Asma/genética , Antígeno Ki-1/genética , Receptor Tipo I de Factor de Crecimiento Transformador beta/genética , Linfocitos T/inmunología , Regiones no Traducidas 3'/genética , Remodelación de las Vías Aéreas (Respiratorias)/inmunología , Asma/inmunología , Eosinófilos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Islandia , Antígeno Ki-1/inmunología , Antígeno Ki-1/metabolismo , Recuento de Leucocitos , MicroARNs/metabolismo , Polimorfismo de Nucleótido Simple/inmunología , Sitios de Carácter Cuantitativo/inmunología , Receptor Tipo I de Factor de Crecimiento Transformador beta/inmunología , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Reino UnidoRESUMEN
BACKGROUND: The prevalence of autoimmunity is thought to be increased among IgA deficient (IgAD) individuals. However, it is currently unclear if the two conditions coincide within families. OBJECTIVE: To evaluate the prevalence of autoimmunity among IgAD individuals and their 1 degrees relatives. MATERIAL AND METHODS: A total of 43 IgAD individuals (32 adults and 11 children) and all available 1 degrees relatives were evaluated by a physician. A family history of autoimmunity was obtained, together with physical examination and a structured questionnaire that focused on symptoms and signs suggestive of autoimmunity. RESULTS: Eight of the 32 (25%) adult IgAD, were found to have definite autoimmunity, with organ specific- and systemic autoimmune diseases equally distributed. None of the IgAD children had autoimmunity. Among the 1 degrees relatives, 27/269 (10%) had autoimmunity, compared to an estimate of 5% in the general population (p<0.05). CONCLUSION: Autoimmune diseases are highly prevalent in individuals with IgAD and more common in their 1 degrees relatives than expected, thus, suggesting a possible common genetic component.
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Autoinmunidad/genética , Predisposición Genética a la Enfermedad , Deficiencia de IgA/genética , Inmunoglobulina A/genética , Encuestas y Cuestionarios , Adolescente , Adulto , Edad de Inicio , Anciano , Niño , Preescolar , Femenino , Humanos , Inmunoglobulina A/inmunología , Masculino , Persona de Mediana Edad , LinajeRESUMEN
Objectives: It has recently been shown that individuals with selective IgA deficiency (sIgAD) have defective B cell responses both to T cell dependent and independent mimicking stimulations. The complex intracellular signaling pathways from different stimuli leading to IgA isotype switching have not been fully elucidated. Thus, the main objective of this study was to delineate these pathways and their potential role in the immunopathology linked to sIgAD. Materials and Methods: PBMCs from 10 individuals with sIgAD and 10 healthy controls (HC) were activated in vitro via either a T cell dependent or independent mimicking stimulation. Intracellular phosphorylation of pSTAT3, pSTAT5, pSTAT6, and as pERK1/2 was evaluated in T and B cells using phosphoflow cytometry. Results: By evaluating T cell dependent cytokine driven pathways linked to IgA isotype induction we identified a defect involving an IL-21 driven STAT3 activation isolated to B cells in sIgAD individuals. However, all other signaling pathways studied were found to be normal compared to HC. In T cell dependent cytokine driven stimulations linked to IgA isotype induction the following patterns emerged: (i) IL-10 led to significant STAT3 activation in both T- and B cells; (ii) IL-4 stimulation was predominantly confined to STAT6 activation in both T- and B cells, with some effects on STAT3 activation in T-cells; (iii) as expected, of tested stimuli, IL-2 alone activated STAT5 and some STAT3 activation though in both cases only in T-cells; (iv) IL-21 induced significant activation of STAT3 in both T- and B cells, with some effects on STAT5 activation in T-cells; and finally (v) synergistic effects were noted of IL-4+IL-10 on STAT5 activation in T-cells, and possibly STAT6 in both T- and B cells. On the other hand, CPG induced T cell independent activation was confined to ERK1/2 activation in B cells. Conclusion: Our results indicate a diminished STAT3 phosphorylation following IL-21 stimulation solely in B cells from sIgAD individuals. This can represent aberrant germinal center reactions or developmental halt. Thus, our work provides further insight into the unraveling of the previously hypothesized role of IL-21 to reconstitute immunoglobulin production in primary antibody deficiencies.
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Linfocitos B/inmunología , Deficiencia de IgA/inmunología , Interleucinas/inmunología , Activación de Linfocitos/inmunología , Factor de Transcripción STAT3/inmunología , Linfocitos B/metabolismo , Humanos , Deficiencia de IgA/metabolismo , Fosforilación , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Nasal polyps (NP) are lesions on the nasal and paranasal sinus mucosa and are a risk factor for chronic rhinosinusitis (CRS). We performed genome-wide association studies on NP and CRS in Iceland and the UK (using UK Biobank data) with 4,366 NP cases, 5,608 CRS cases, and >700,000 controls. We found 10 markers associated with NP and 2 with CRS. We also tested 210 markers reported to associate with eosinophil count, yielding 17 additional NP associations. Of the 27 NP signals, 7 associate with CRS and 13 with asthma. Most notably, a missense variant in ALOX15 that causes a p.Thr560Met alteration in arachidonate 15-lipoxygenase (15-LO) confers large genome-wide significant protection against NP (P = 8.0 × 10-27, odds ratio = 0.32; 95% confidence interval = 0.26, 0.39) and CRS (P = 1.1 × 10-8, odds ratio = 0.64; 95% confidence interval = 0.55, 0.75). p.Thr560Met, carried by around 1 in 20 Europeans, was previously shown to cause near total loss of 15-LO enzymatic activity. Our findings identify 15-LO as a potential target for therapeutic intervention in NP and CRS.
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Araquidonato 15-Lipooxigenasa/genética , Variación Genética/genética , Pólipos Nasales/genética , Sinusitis/genética , Adulto , Asma/genética , Enfermedad Crónica , Eosinófilos/patología , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Islandia , Recuento de Leucocitos/métodos , Masculino , Pólipos Nasales/patología , Sinusitis/patologíaRESUMEN
Selective IgA deficiency (IgAD) is the most common primary antibody deficiency in the western world with affected individuals suffering from an increased burden of autoimmunity, atopic diseases and infections. It has been shown that IgAD B cells can be induced with germinal center mimicking reactions to produce IgA. However, IgA is the most prevalent antibody in mucosal sites, where antigen-independent responses are important. Much interest has recently focused on the role of TLR9 in both naïve and mature B cell differentiation into IgA secreting plasma cells. Here, we analyze the phenotype and function of T and B cells in individuals with IgAD following IgA-inducing CpG-TLR9 stimulations. The IgAD individuals had significantly lower numbers of transitional B cells (CD19+CD24hiCD38hi) and class-switched memory B cells (CD20+CD27+IgD-) ex vivo. However, proportions of T cell populations ex vivo as well as in vitro induced T effector cells and T regulatory cells were comparable to healthy controls. After CpG stimulation, the transitional B cell defect was further enhanced, especially within its B regulatory subset expressing IL-10. Finally, CpG stimulation failed to induce IgA production in IgAD individuals. Collectively, our results demonstrate a defect of the TLR9 responses in IgAD that leads to B cell dysregulation and decreased IgA production.
Asunto(s)
Linfocitos B/patología , Deficiencia de IgA/inmunología , Inmunoglobulina A/biosíntesis , Activación de Linfocitos , Receptor Toll-Like 9/inmunología , Adulto , Anciano , Diferenciación Celular , Femenino , Humanos , Cambio de Clase de Inmunoglobulina , Interleucina-10/genética , Masculino , Persona de Mediana Edad , Oligodesoxirribonucleótidos , Células Precursoras de Linfocitos B/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacosRESUMEN
Immunoglobulins are the effector molecules of the adaptive humoral immune system. In a genome-wide association study of 19,219 individuals, we found 38 new variants and replicated 5 known variants associating with IgA, IgG or IgM levels or with composite immunoglobulin traits, accounted for by 32 loci. Variants at these loci also affect the risk of autoimmune diseases and blood malignancies and influence blood cell development. Notable associations include a rare variant at RUNX3 decreasing IgA levels by shifting isoform proportions (rs188468174[C>T]: P = 8.3 × 10-55, ß = -0.90 s.d.), a rare in-frame deletion in FCGR2B abolishing IgG binding to the encoded receptor (p.Asn106del: P = 4.2 × 10-8, ß = 1.03 s.d.), four IGH locus variants influencing class switching, and ten new associations with the HLA region. Our results provide new insight into the regulation of humoral immunity.
Asunto(s)
Variación Genética , Inmunoglobulinas/genética , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Hematopoyesis/genética , Humanos , Islandia , Inmunidad Humoral/genética , Cambio de Clase de Inmunoglobulina/genética , Isotipos de Inmunoglobulinas/genética , Masculino , Polimorfismo de Nucleótido Simple , SueciaRESUMEN
BACKGROUND AND AIMS: Very few population-based studies exist on the epidemiology of primary biliary cirrhosis (PBC), and none have been conducted in the last decade. We aimed to determine the epidemiology and prognosis of PBC over the past two decades. METHODS: Patients were identified by multiple case finding strategies, covering the total population of Iceland. A search was conducted in the centralized database of antimitochondrial antibody (AMA) measurements and computerized diagnosis and pathological registries. All AMA measurements taken in Iceland between 1991 and 2010 were analyzed. Relevant clinical information was gathered from medical records, pathology reports, and death certificates. Incidence was compared between two periods, 1991-2000 versus 2001-2010. RESULTS: A total of 168 patients were identified, of which 138 were female (82%), with a median age 62 years (range 13-92). Prevalence at the end of the study period was 38.3 cases per 100 000 person-years. Age-standardized incidence for female patients during the first period was 3.4 versus 4.1 during the second (NS) and that for male patients was 0.6 during the first period versus 1.0 per 100 000 during the second (NS). Overall incidence in the first period was 2.0 and that in the second was 2.5 per 100 000 (NS). Stage III-IV liver fibrosis was present in 28% of patients at diagnosis with no significant differences between the two decades. Median survival after diagnosis was 15 years. Five patients underwent liver transplantation. CONCLUSION: The incidence and prevalence figures of PBC in Iceland are among the highest reported and have been stable over the last two decades. The prognosis of patients in this population-based cohort is better than that previously reported.
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Cirrosis Hepática Biliar/epidemiología , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Colagogos y Coleréticos/uso terapéutico , Femenino , Humanos , Islandia/epidemiología , Incidencia , Cirrosis Hepática Biliar/diagnóstico , Cirrosis Hepática Biliar/terapia , Trasplante de Hígado , Masculino , Persona de Mediana Edad , Prevalencia , Pronóstico , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Ácido Ursodesoxicólico/uso terapéutico , Adulto JovenRESUMEN
Immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency, with suggested association with various types of autoimmunity, including Graves' disease. This study investigated the association of IgAD with elevated thyrotropin-receptor autoantibodies (TRAb). IgA was measured in TRAb-seropositive individuals from both Iceland (N = 299] and Sweden (N = 841]. In addition, TRAb levels were evaluated in 43 Icelandic and 50 Swedish IgAD individuals using Medizym TRA immunoassay, and positive samples were re-evaluated using BRAHMS TRAK human RIA. The IgAD individuals were HLA-genotyped to determine the HLA-B, DR, and DQ alleles. None of the 299 Icelandic TRAb-seropositive individuals had IgAD, whereas, a high prevalence of IgAD (14/841 (1:60)) was observed in the Swedish cohort (p = 0.027). The prevalence of TRAb-seropositivity in IgAD individuals was, however, increased in both cohorts. The HLA-DQ6 allele was associated with TRAb-seronegativity within the Icelandic IgAD cohort (p = 0.037). The prevalence of IgAD in TRAb-seropositive individuals in Sweden is 10 times higher than expected in the general population. Furthermore, TRAb seropositivity is common among IgAD individuals, both in Iceland and Sweden, suggesting a predisposition toward Graves' disease. These findings underline the significant association of IgAD with autoimmunity and its possible association with certain HLA-DQ alleles.