RESUMO
BACKGROUND: Immune regulation by gut microbiota is affected by dysbiosis and may precede food allergy onset. Prior studies lacked comparisons stratified by age and clinical phenotype. OBJECTIVE: To assess the microbiome of children with food allergy (<3 years, 3-18 years) compared with similar aged children without food allergy. METHODS: A real-world prospective cross-sectional study performed from 2014 to 2019 recruited children highly likely to have milk, egg, or peanut allergy defined by history and serum IgE or confirmed by food challenge. 16S ribosomal RNA sequencing identified stool microbial DNA. Alpha and beta diversity was compared between groups with food allergy and healthy controls stratified by age. Differential abundance for non a priori taxa was accepted at absolute fold-change greater than 2 and q value less than 0.05. RESULTS: A total of 70 patients were included (56 with food allergy and 14 healthy controls). Groups were not significantly different in age, gender at birth, race, mode of delivery, breastfeeding duration, or antibiotic exposure. Younger children with food allergy had similar alpha diversity compared with controls. Beta diversity was significantly different by age (P = .001). There was differential abundance of several a priori (P < .05) taxa (including Clostridia) only in younger children. Both a priori (including Coprococcus and Clostridia) and non a priori (q < 0.05) Acidobacteria_Gp15, Aestuariispira, Tindallia, and Desulfitispora were significant in older children with food allergy, especially with peanut allergy. CONCLUSION: Dysbiosis associates with food allergy, most prominent in older children with peanut allergy. Younger children with and without food allergy have fewer differences in gut microbiota. This correlates with clinical observations of persistence of peanut allergy and improved efficacy and safety of oral immunotherapy in younger children. Age younger than 3 years should be considered when initiating therapeutic interventions.
Assuntos
Hipersensibilidade a Ovo , Microbioma Gastrointestinal , Hipersensibilidade a Leite , Hipersensibilidade a Amendoim , Humanos , Feminino , Pré-Escolar , Criança , Masculino , Hipersensibilidade a Amendoim/imunologia , Hipersensibilidade a Amendoim/microbiologia , Microbioma Gastrointestinal/imunologia , Estudos Transversais , Adolescente , Hipersensibilidade a Leite/imunologia , Hipersensibilidade a Leite/microbiologia , Hipersensibilidade a Ovo/imunologia , Estudos Prospectivos , Disbiose/imunologia , Disbiose/microbiologia , Fatores Etários , Lactente , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Fezes/microbiologia , Alérgenos/imunologia , RNA Ribossômico 16S/genéticaRESUMO
BACKGROUND: Immune-mediated inflammatory diseases (IMIDs) are associated with an abnormal immune response, resulting in a disturbed homeostasis and chronic inflammation. Most canine dermatological IMIDs (cDIMIDs), such as allergies, autoimmune and immune-mediated diseases, require long-term treatment with immunosuppressive drugs with potential adverse effects. In general, nutraceuticals are thought to be safe. As a result, there is a tendency for the more frequent use of nutraceuticals in veterinary medicine. OBJECTIVES: The aim of this review was to present evidence-based proof for the use of various nutraceuticals in the treatment of cDIMIDs and, where possible, to provide conclusions to guide their use in veterinary dermatological practice. METHODS: A comprehensive literature search on common cDIMIDs and nutraceuticals was performed. Only peer-reviewed articles published in English and related to the study topic were included. A total of 64 eligible publications were classified in five categories based on study design and substantively assessed on additional criteria such as standardisation of diets and number of included animals. For final appraisal, classification of major, minor or no evidence was used whereby efficacy was based on clinical outcome measurements. CONCLUSIONS: Minor evidence for the beneficial use of several nutraceuticals, including essential fatty acids, niacinamide and probiotics, was found for treatment of specific cDIMIDs. These nutraceuticals may improve clinical signs or reduce the required dose of concurrent medication (e.g. drug-sparing effect) in some dogs. Some nutraceuticals also may be used for long-term maintenance therapy. Despite some promising findings, major evidence for the use of nutraceuticals in cDIMIDs is lacking, warranting further research.
Assuntos
Doenças do Cão , Agentes de Imunomodulação , Cães , Animais , Suplementos Nutricionais , Dieta , Inflamação/veterinária , Imunossupressores , Doenças do Cão/tratamento farmacológicoRESUMO
BACKGROUND: Allergen-specific immunotherapy (ASIT) is an effective therapy for canine atopic dermatitis (cAD). Intralymphatic immunotherapy (ILIT) is potentially beneficial in decreasing time to clinical effectiveness. OBJECTIVE: To compare clinical efficacy of six monthly ILIT injections combined with three monthly injections of lokivetmab (LVM) with monthly LVM monotherapy at Day (D)168. To monitor dogs treated with ILIT for an additional six months of subcutaneous immunotherapy (SCIT). ANIMALS: Thirty-six client-owned dogs with cAD. MATERIALS AND METHODS: In this double-blinded, randomised study, dogs received either six monthly injections of ILIT combined with three monthly LVM injections (ILIT group) or six monthly LVM injections (LVM group). Monthly evaluations with pruritus Visual Analogue Scale (pVAS), Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-04) and medication scores (MS) were undertaken. Owners completed a Quality of Life (QoL) questionnaire. Treatment success was predefined as ≥50% reduction in pVAS and CADESI-04 score ≤ 10. After D168, the ILIT group continued with SCIT until subjective assessment at 12 months. RESULTS: The treatment benchmark at D168 was achieved by 11.1% of the ILIT group and 11.8% of LVM group. A significant decrease in mean pVAS and CADESI scores was observed in both groups (p < 0.001). The ILIT group had a trend towards higher MS compared to LVM. QoL was better in LVM (p = 0.01). At 12 months subjective good-to-excellent response in 77.8% of dogs in the ILIT/SCIT group was seen. CONCLUSION AND CLINICAL RELEVANCE: The efficacy of this ILIT protocol was comparable with LVM monotherapy at six months. When ILIT was continued with SCIT, a favourable response was seen.
Assuntos
Dermatite Atópica , Doenças do Cão , Cães , Animais , Dermatite Atópica/veterinária , Dermatite Atópica/tratamento farmacológico , Qualidade de Vida , Anticorpos Monoclonais/uso terapêutico , Prurido/veterinária , Dessensibilização Imunológica/veterinária , Dessensibilização Imunológica/métodos , Doenças do Cão/tratamento farmacológicoRESUMO
BACKGROUND: Endometriosis is a common, complex disorder which is underrecognized and subject to prolonged delays in diagnosis. It is accompanied by significant changes in the eutopic endometrial lining. METHODS: We have undertaken the first single-cell RNA-sequencing (scRNA-Seq) comparison of endometrial tissues in freshly collected menstrual effluent (ME) from 33 subjects, including confirmed endometriosis patients (cases) and controls as well as symptomatic subjects (who have chronic symptoms suggestive of endometriosis but have not been diagnosed). RESULTS: We identify a unique subcluster of proliferating uterine natural killer (uNK) cells in ME-tissues from controls that is almost absent from endometriosis cases, along with a striking reduction of total uNK cells in the ME of cases (p < 10-16). In addition, an IGFBP1+ decidualized subset of endometrial stromal cells are abundant in the shed endometrium of controls when compared to cases (p < 10-16) confirming findings of compromised decidualization of cultured stromal cells from cases. By contrast, endometrial stromal cells from cases are enriched in cells expressing pro-inflammatory and senescent phenotypes. An enrichment of B cells in the cases (p = 5.8 × 10-6) raises the possibility that some may have chronic endometritis, a disorder which predisposes to endometriosis. CONCLUSIONS: We propose that characterization of endometrial tissues in ME will provide an effective screening tool for identifying endometriosis in patients with chronic symptoms suggestive of this disorder. This constitutes a major advance, since delayed diagnosis for many years is a major clinical problem in the evaluation of these patients. Comprehensive analysis of ME is expected to lead to new diagnostic and therapeutic approaches to endometriosis and other associated reproductive disorders such as female infertility.
Assuntos
Endometriose , Endometriose/diagnóstico , Endométrio , Feminino , Humanos , Células Matadoras Naturais , Fenótipo , Análise de Célula ÚnicaRESUMO
RESEARCH QUESTIONS: Can a previously defined relationship between sperm capacitation and the probability of a man generating pregnancy within three cycles, prospectively predict male fertility in diverse clinical settings? A second study asked, what is the prevalence of impaired sperm fertilizing ability in men questioning their fertility (MQF), and does this relate to traditional semen analysis metrics? DESIGN: In the multicentric, prospective observational study, data (n = 128; six clinics) were analysed to test a published relationship between the percentage of fertilization-competent, capacitated spermatozoa (Cap-Score) and probability of generating pregnancy (PGP) within three cycles of intrauterine insemination. Logistic regression of total pregnancy outcomes (n = 252) assessed fit. In the cohort comparison, Cap-Scores of MQF (n = 2155; 22 clinics) were compared with those of 76 fertile men. RESULTS: New outcomes (n = 128) were rank-ordered by Cap-Score and divided into quintiles (25-26 per group); chi-squared testing revealed no difference between predicted and observed pregnancies (P = 0.809). Total outcomes (n = 252; 128 new + 124 previous) were pooled and the model recalculated, yielding an improved fit (P < 0.001). Applying the Akaike information criterion found that the optimal model used Cap-Score alone. Cap-Scores were performed on 2155 men (with semen analysis data available for 1948). To compare fertilizing ability, men were binned by PGP (≤19%, 20-29%, 30-39%, 40-49%, 50-59%, ≥60%). Distributions of PGP and the corresponding Cap-Scores were significantly lower in MQF versus fertile men (P < 0.001). Notably, 64% of MQF with normal volume, concentration and motility (757/1183) had PGP of 39% or less (Cap-Scores ≤31), versus 25% of fertile men. CONCLUSIONS: Sperm capacitation prospectively predicted male fertility. Impaired capacitation affects many MQF with normal semen analysis results, informing diagnosis versus idiopathic infertility.
Assuntos
Fertilidade/fisiologia , Fertilização/fisiologia , Infertilidade Masculina/fisiopatologia , Capacitação Espermática/fisiologia , Espermatozoides/fisiologia , Feminino , Humanos , Masculino , Gravidez , Taxa de Gravidez , Estudos Prospectivos , Análise do Sêmen , Motilidade dos Espermatozoides/fisiologiaRESUMO
Single-cell sequencing (SCS) is a powerful new tool that applies Next Generation Sequencing at the cellular level. SCS has revolutionized our understanding of tumor heterogeneity and the tumor microenvironment, immune infiltration, cancer stem cells (CSCs), circulating tumor cells (CTCs), and clonal evolution. The following chapter highlights the current literature on SCS in genitourinary (GU) malignancies and discusses future applications of SCS technology. The renal cell carcinoma (RCC) section highlights the use of SCS in characterizing the initial cells driving tumorigenesis, the intercellular mutational landscape of RCC, intratumoral heterogeneity (ITH) between primary and metastatic lesions, and genes driving RCC cancer stem cells (CSCs). The bladder cancer section will also illustrate molecular drivers of bladder cancer stem cells (BCSCs), SCS use in reconstructing tumor developmental history and underlying subclones, and understanding the effect of cisplatin on intratumoral heterogeneity in vitro and potential mechanisms behind platinum resistance. The final section featuring prostate cancer will discuss how SCS can be used to identify the cellular origins of benign prostatic hyperplasia and prostate cancer, the plasticity and heterogeneity of prostate cancer cells with regard to androgen dependence, and the use of SCS in CTCs to understand chemotherapy resistance and gene expression changes after androgen deprivation therapy (ADT). The studies listed in this chapter illustrate many translational applications of SCS in GU malignancies, including diagnostic, prognostic, and treatment-related approaches. The ability of SCS to resolve intratumor heterogeneity and better define the genomic landscape of tumors and CTCs will be fundamental in the new era of precision-based care.
Assuntos
Neoplasias Renais/genética , Neoplasias da Próstata/genética , Análise de Sequência , Análise de Célula Única , Androgênios , Humanos , Neoplasias Renais/patologia , Masculino , Neoplasias da Próstata/patologiaRESUMO
BRCA1 and BRCA2 (BRCA1/2) pathogenic sequence variants (PSVs) confer elevated risks of multiple cancers. However, most BRCA1/2 PSVs reports focus on European ancestry individuals. Knowledge of the PSV distribution in African descent individuals is poorly understood. We undertook a systematic review of the published literature and publicly available databases reporting BRCA1/2 PSVs also accessed the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) database to identify African or African descent individuals. Using these data, we inferred which of the BRCA PSVs were likely to be of African continental origin. Of the 43,817 BRCA1/2 PSV carriers in the CIMBA database, 469 (1%) were of African descent. Additional African descent individuals were identified in public databases (n = 291) and the literature (n = 601). We identified 164 unique BRCA1 and 173 unique BRCA2 PSVs in individuals of African ancestry. Of these, 83 BRCA1 and 91 BRCA2 PSVs are of likely or possible African origin. We observed numerous differences in the distribution of PSV type and function in African origin versus non-African origin PSVs. Research in populations of African ancestry with BRCA1/2 PSVs is needed to provide the information needed for clinical management and decision-making in African descent individuals worldwide.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , População Negra/genética , Predisposição Genética para Doença , Variação Genética , Alelos , Feminino , Estudos de Associação Genética , Humanos , Mutação , Vigilância da PopulaçãoRESUMO
OBJECTIVES: Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies. METHODS: We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups. RESULTS: We report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10-5. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10-53 and HLA-DRB1*03:01, p=3.25×10-9), anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10-26) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10-11). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10-13) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10-6). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10-64) and position 9 of HLA-B (p=7.03×10-11). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies. CONCLUSIONS: These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research.
Assuntos
Autoanticorpos/genética , Cadeias HLA-DRB1/genética , Miosite/genética , Miosite/imunologia , População Branca/genética , Adulto , Alelos , Autoanticorpos/imunologia , Feminino , Genótipo , Cadeias HLA-DRB1/imunologia , Haplótipos , Humanos , Complexo Principal de Histocompatibilidade/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo GenéticoRESUMO
BACKGROUND: Endometriosis is a chronic and underdiagnosed disease which affects 5-10% of women of childbearing age and is characterized by growth of endometrial tissue outside of the uterus, most often in the peritoneal cavity. Delay in diagnosis is a major problem for management of this disorder, and treatment is often not initiated until the disease has progressed for many years. Although the exact etiology of endometriosis remains unknown, retrograde menstruation is recognized as a common underlying factor leading to the deposit of menstrual effluent (ME) into the peritoneal cavity. Differences in the cellular biology and genetics of the cells within ME are therefore likely to explain why endometriosis develops in only a subset of women. METHODS: Patients with and without endometriosis were consented to provide ME. ME was analyzed by flow cytometry for CD45- and CD45+ cell populations or used to isolate stromal fibroblast cells. ME-derived stromal fibroblast cells were assessed using decidualization assays following the addition of cAMP and IGFBP-1 concentrations in the culture supernatants were measured by ELISA. In addition, RNA was collected and analyzed by RNA-Seq and qPCR for markers of decidualization and to identify differentially expressed genes in ME-derived stromal fibroblast cells obtained from controls and subjects with endometriosis (±cAMP). RESULTS: Flow cytometry analysis of cell subsets within the CD45+ fraction of ME revealed a significant decrease in the number of uterine NK cells in endometriosis patients compared with controls (p < 0.01). No other significant differences within either the CD45+ or CD45- cell populations were observed. Most strikingly, ME-derived stromal fibroblast cells cultured from endometriosis subjects showed impaired decidualization potential compared with controls. Highly significant differences in decidualization response were detected by measuring IGFBP-1 production at multiple time points after cAMP stimulation (p = 0.0025 at 6 h; p = 0.0045 at 24 h; p = 0.0125 at 48 h). RNA-Seq and qPCR analyses were used to identify genes differentially expressed by ME-derived stromal fibroblast cells obtained from endometriosis and control subjects. CONCLUSIONS: Menstrual effluent can be useful for investigating the pathobiology of endometriosis and for developing a non-invasive diagnostic for endometriosis which may lead to earlier and more effective treatments for this common disorder.
Assuntos
Endometriose/diagnóstico , Menstruação , Adulto , Decídua , Endometriose/genética , Feminino , Fibroblastos/metabolismo , Expressão Gênica , Humanos , Pessoa de Meia-Idade , Fenótipo , Adulto JovemRESUMO
In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.
Assuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 3/genética , Loci Gênicos , Predisposição Genética para Doença , Escleroderma Sistêmico/genética , Alelos , Proteína 5 Relacionada à Autofagia , Proteínas de Transporte/genética , Estudos de Casos e Controles , RNA Helicases DEAD-box/genética , Endodesoxirribonucleases/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Antígenos HLA/genética , Humanos , Subunidade p35 da Interleucina-12/genética , Desequilíbrio de Ligação , Modelos Logísticos , Masculino , Procedimentos Analíticos em Microchip , Proteínas Associadas aos Microtúbulos/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Fatores de Risco , População Branca/genéticaRESUMO
Over 100 risk loci for rheumatoid arthritis (RA) have been identified in individuals of European and Asian descent, but the genetic basis for RA in African Americans is less well understood. We genotyped 610 African Americans with autoantibody positive RA and 933 African American controls on the ImmunoChip (iChip) array. Using multivariable regression we evaluated the association between iChip markers and the risk of RA and radiographic severity. The single nucleotide polymorphism (SNP) rs1964995 (OR = 1.97, p = 1.28 × 10-15) near HLA-DRB1 was the most strongly associated risk SNP for RA susceptibility; SNPs in AFF3, TNFSF11, and TNFSF18 loci were suggestively associated (10-4 < p < 3.1 × 10-6). Trans-ethnic fine mapping of AFF3 identified a 90% credible set containing previously studied variants including rs9653442, rs7608424, and rs6712515 as well as the novel candidate variant rs11681966; several of these likely influence AFF3 gene expression level. Variants in TNFRSF9, CTLA4, IL2RA, C5/TRAF1, and ETS1 - but no variants within the major histocompatibility complex - were associated with RA radiographic severity. Conditional regression and pairwise linkage disequilibrium (LD) analyses suggest that additional pathogenic variants may be found in ETS1 and IL2RA beyond those found in other ethnicities. In summary, we use the dense genotyping of the iChip array and unique LD structure of African Americans to validate known risk loci for RA susceptibility and radiographic severity, and to better characterize the associations of AFF3, ETS1, and IL2RA.
Assuntos
Artrite Reumatoide/genética , Negro ou Afro-Americano/genética , Subunidade alfa de Receptor de Interleucina-2/genética , Adulto , Idoso , Artrite Reumatoide/diagnóstico por imagem , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Proteína Proto-Oncogênica c-ets-1/genética , Risco , Índice de Gravidade de DoençaRESUMO
Patients that dialyze in the nursing home setting are known to be an especially at-risk vulnerable population compared to the overall ESRD population. This is likely due to the nursing home dialysis patients' advanced age, multiple co-morbidities, and frailty, requiring skilled nursing support. These challenges often result in worse outcomes compared to the overall end-stage renal disease (ESRD) population but few studies have investigated interventions to improve health outcomes in this population. Previously, we reported results from a study using a large epidemiological database of patients from an independent nursing home dialysis provider, showing that patients treated with daily home hemodialysis had improved outcomes compared to patients treated with conventional dialysis. One limitation of the previous study was that the timeframe for the two comparison groups was different; therefore, the results could have been due to over-all improvements in care over time unrelated to the modality of dialysis: To address this as well as expand on the previous analysis, the objective of the present study was to compare outcomes in ESRD patients in the nursing home setting treated with daily home hemodialysis versus con- ventional three-day-a-week (TIW) hemodialysis using an updated database, specifically assessing patients treated during a concurrent time: frame. Health status was evaluated for 6,314 patients (n=4,778 conventional, n=1,902 daily home hemodialysis; 2006 to November 2015 for conventional; 2011 to November 2015 for daily home hemodialysis). Analyses included monthly mortality rates, Kaplan-Meier survival analysis, and laboratory values. In the "Compared to the conventional dialysis population, daily HHD patients had similar or lower incident mortality rates." analysis of patients treated during the concurrent timeframe, median overall survival was 36 months with daily home hemodialysis versus 21 months with conventional dialysis (P=0.0025). These results were similar to the analysis of all patients regardless of timeframe. Compared to the conventional dialysis population, daily home hemodialysis patients had similar or lower incident mortality rates. Survival rates were higher at 3 months (89% vs 82%), 6 months (84% vs 73%), and 12 months (74% vs 62%) in the daily home hemodialy- sis population compared to conventional dialysis population. Monthly mean albumin was consistent over time in the daily home hemodialysis population but gradually increased in the conventional dialysis population. Hemoglobin values were consistently lower over the follow-up period in the daily home hemodialysis population and ferritin values were similar in both populations. These results confirm and extend previous findings that daily home hemodialysis is associated with improved patient outcomes compared to conventional hemodialysis. Although difficult to conduct practically, a prospective randomized outcomes study evaluating daily home hemodialysis versus conventional TIW dialysis would be valuable in informing the standard of dialysis care in this population.
Assuntos
Hemodiálise no Domicílio/métodos , Instituição de Longa Permanência para Idosos/estatística & dados numéricos , Falência Renal Crônica/mortalidade , Falência Renal Crônica/terapia , Casas de Saúde/estatística & dados numéricos , Diálise Renal/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Estudos Prospectivos , Taxa de SobrevidaRESUMO
To investigate the genetics of late-onset myasthenia gravis (LOMG), we conducted a genome-wide association study imputation of>6 million single nucleotide polymorphisms (SNPs) in 532 LOMG cases (anti-acetylcholine receptor [AChR] antibody positive; onset age≥50 years) and 2,128 controls matched for sex and population substructure. The data confirm reported TNFRSF11A associations (rs4574025, P = 3.9 × 10-7, odds ratio [OR] 1.42) and identify a novel candidate gene, ZBTB10, achieving genome-wide significance (rs6998967, P = 8.9 × 10-10, OR 0.53). Several other SNPs showed suggestive significance including rs2476601 (P = 6.5 × 10-6, OR 1.62) encoding the PTPN22 R620W variant noted in early-onset myasthenia gravis (EOMG) and other autoimmune diseases. In contrast, EOMG-associated SNPs in TNIP1 showed no association in LOMG, nor did other loci suggested for EOMG. Many SNPs within the major histocompatibility complex (MHC) region showed strong associations in LOMG, but with smaller effect sizes than in EOMG (highest OR ~2 versus ~6 in EOMG). Moreover, the strongest associations were in opposite directions from EOMG, including an OR of 0.54 for DQA1*05:01 in LOMG (P = 5.9 × 10-12) versus 2.82 in EOMG (P = 3.86 × 10-45). Association and conditioning studies for the MHC region showed three distinct and largely independent association peaks for LOMG corresponding to (a) MHC class II (highest attenuation when conditioning on DQA1), (b) HLA-A and (c) MHC class III SNPs. Conditioning studies of human leukocyte antigen (HLA) amino acid residues also suggest potential functional correlates. Together, these findings emphasize the value of subgrouping myasthenia gravis patients for clinical and basic investigations and imply distinct predisposing mechanisms in LOMG.
RESUMO
OBJECTIVES: The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and extramuscular manifestations such as skin rashes and interstitial lung disease. We genotyped 2566 IIM cases of Caucasian descent using the Immunochip; a custom array covering 186 established autoimmune susceptibility loci. The cohort was predominantly comprised of patients with dermatomyositis (DM, n=879), juvenile DM (JDM, n=481), polymyositis (PM, n=931) and inclusion body myositis (n=252) collected from 14 countries through the Myositis Genetics Consortium. RESULTS: The human leucocyte antigen (HLA) and PTPN22 regions reached genome-wide significance (p<5×10(-8)). Nine regions were associated at a significance level of p<2.25×10(-5), including UBE2L3, CD28 and TRAF6, with evidence of independent effects within STAT4. Analysis of clinical subgroups revealed distinct differences between PM, and DM and JDM. PTPN22 was associated at genome-wide significance with PM, but not DM and JDM, suggesting this effect is driven by PM. Additional suggestive associations including IL18R1 and RGS1 in PM and GSDMB in DM were identified. HLA imputation confirmed that alleles HLA-DRB1*03:01 and HLA-B*08:01 of the 8.1 ancestral haplotype (8.1AH) are most strongly associated with IIM, and provides evidence that amino acids within the HLA, such as HLA-DQB1 position 57 in DM, may explain part of the risk in this locus. Associations with alleles outside the 8.1AH reveal differences between PM, DM and JDM. CONCLUSIONS: This work represents the largest IIM genetic study to date, reveals new insights into the genetic architecture of these rare diseases and suggests different predominating pathophysiology in different clinical subgroups.
Assuntos
Antígenos HLA/genética , Miosite/genética , Alelos , Autoimunidade/genética , Estudos de Casos e Controles , Dermatomiosite/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Miosite/imunologia , Polimorfismo de Nucleotídeo Único , Polimiosite/genética , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Locos de Características Quantitativas , Fatores de RiscoRESUMO
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 Assuntos
Imunidade Adaptativa/genética
, Alopecia em Áreas/genética
, Doenças Autoimunes/genética
, Predisposição Genética para Doença
, Estudo de Associação Genômica Ampla
, Imunidade Inata/genética
, Imunidade Adaptativa/imunologia
, Adulto
, Idoso
, Alelos
, Alopecia em Áreas/imunologia
, Antígenos CD/genética
, Doenças Autoimunes/imunologia
, Antígeno CTLA-4
, Estudos de Casos e Controles
, Feminino
, Proteínas Ligadas por GPI
, Folículo Piloso/citologia
, Folículo Piloso/imunologia
, Folículo Piloso/metabolismo
, Humanos
, Fator de Transcrição Ikaros/genética
, Imunidade Inata/imunologia
, Peptídeos e Proteínas de Sinalização Intercelular/genética
, Peptídeos e Proteínas de Sinalização Intercelular/metabolismo
, Subunidade alfa de Receptor de Interleucina-2/genética
, Masculino
, Pessoa de Meia-Idade
, Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia
, Peroxirredoxinas/genética
, Polimorfismo de Nucleotídeo Único/genética
, Proteínas Qa-SNARE/genética
, Linfócitos T Reguladores/citologia
, Linfócitos T Reguladores/imunologia
RESUMO
Sialic acid acetylesterase (SIAE) is an enzyme that negatively regulates B lymphocyte antigen receptor signalling and is required for the maintenance of immunological tolerance in mice. Heterozygous loss-of-function germline rare variants and a homozygous defective polymorphic variant of SIAE were identified in 24/923 subjects of European origin with relatively common autoimmune disorders and in 2/648 controls of European origin. All heterozygous loss-of-function SIAE mutations tested were capable of functioning in a dominant negative manner. A homozygous secretion-defective polymorphic variant of SIAE was catalytically active, lacked the ability to function in a dominant negative manner, and was seen in eight autoimmune subjects but in no control subjects. The odds ratio for inheriting defective SIAE alleles was 8.6 in all autoimmune subjects, 8.3 in subjects with rheumatoid arthritis, and 7.9 in subjects with type I diabetes. Functionally defective SIAE rare and polymorphic variants represent a strong genetic link to susceptibility in relatively common human autoimmune disorders.
Assuntos
Acetilesterase/genética , Doenças Autoimunes/enzimologia , Doenças Autoimunes/genética , Autoimunidade/genética , Hidrolases de Éster Carboxílico/genética , Predisposição Genética para Doença/genética , Mutação em Linhagem Germinativa/genética , Ácido N-Acetilneuramínico/metabolismo , Acetilação , Acetilesterase/metabolismo , Alelos , Animais , Anticorpos Antinucleares/sangue , Artrite Reumatoide/enzimologia , Artrite Reumatoide/genética , Linfócitos B/metabolismo , Biocatálise , Hidrolases de Éster Carboxílico/metabolismo , Estudos de Casos e Controles , Linhagem Celular , Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 1/genética , Europa (Continente)/etnologia , Éxons/genética , Humanos , Camundongos , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Tamanho da Amostra , Análise de Sequência de DNARESUMO
Absolute pitch (AP) and synesthesia are two uncommon cognitive traits that reflect increased neuronal connectivity and have been anecdotally reported to occur together in an individual. Here we systematically evaluate the occurrence of synesthesia in a population of 768 subjects with documented AP. Out of these 768 subjects, 151 (20.1%) reported synesthesia, most commonly with color. These self-reports of synesthesia were validated in a subset of 21 study subjects, using an established methodology. We further carried out combined linkage analysis of 53 multiplex families with AP and 36 multiplex families with synesthesia. We observed a peak NPL LOD = 4.68 on chromosome 6q, as well as evidence of linkage on chromosome 2, using a dominant model. These data establish the close phenotypic and genetic relationship between AP and synesthesia. The chromosome 6 linkage region contains 73 genes; several leading candidate genes involved in neurodevelopment were investigated by exon resequencing. However, further studies will be required to definitively establish the identity of the causative gene(s) in the region.
Assuntos
Cromossomos Humanos Par 6/genética , Escore Lod , Linhagem , Transtornos da Percepção/genética , Percepção da Altura Sonora , Característica Quantitativa Herdável , Mapeamento Cromossômico/métodos , Família , Feminino , Humanos , Masculino , SinestesiaRESUMO
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.
Assuntos
Antígenos HLA-B/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Deficiência de IgA/genética , Alelos , Estudos de Casos e Controles , Mapeamento Cromossômico , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Haplótipos , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , População Branca/genéticaRESUMO
The gene B lymphocyte kinase (BLK) is associated with rheumatoid arthritis, systemic lupus erythematosus and several other autoimmune disorders. The disease risk haplotype is known to be associated with reduced expression of BLK mRNA transcript in human B cell lines; however, little is known about cis-regulation of BLK message or protein levels in native cell types. Here, we show that in primary human B lymphocytes, cis-regulatory effects of disease-associated single nucleotide polymorphisms in BLK are restricted to naïve and transitional B cells. Cis-regulatory effects are not observed in adult B cells in later stages of differentiation. Allelic expression bias was also identified in primary human T cells from adult peripheral and umbilical cord blood (UCB), thymus and tonsil, although mRNA levels were reduced compared with B cells. Allelic regulation of Blk expression at the protein level was confirmed in UCB B cell subsets by intracellular staining and flow cytometry. Blk protein expression in CD4(+) and CD8(+) T cells was documented by western blot analysis; however, differences in protein expression levels by BLK genotype were not observed in any T cell subset. Blk allele expression differences at the protein level are thus restricted to early B cells, indicating that the involvement of Blk in the risk for autoimmune disease likely acts during the very early stages of B cell development.