RESUMO
Adult-onset Still disease (AOSD) is a rare autoinflammatory syndrome characterized by recurring fevers, arthralgia, and consistent laboratory abnormalities that include leukocytosis and hyperferritinemia. Skin findings accompany the disease in nearly 90% of the cases. Early reports described evanescent, pruritic, salmon-pink or urticarial lesions, referred to as the typical eruption of AOSD. Histopathologic findings consist of superficial perivascular dermatitis with varying number of interstitial neutrophils. Later reports described a more persistent rash that tended to be photodistributed, hyperpigmented, often in a linear configuration, sometimes in a rippled pattern, referred to as the atypical eruption of AOSD. The presence of individual necrotic keratinocytes in the upper spinous layer has been the consistent histopathologic finding. The persistent rash may not represent an atypical presentation of AOSD as recent reports indicate a high prevalence of the rash. Emerging data also suggest that patients with persistent eruption have a worse prognosis. The recognition of the clinical and histopathological findings of skin eruptions of AOSD may facilitate an earlier diagnosis, potentially improving disease outcome. Herein, clinical and histopathological features of cutaneous manifestation of AOSD in 2 Asian women are highlighted accompanied by a relevant review of the disease.
Assuntos
Dermatite , Infiltração de Neutrófilos , Neutrófilos , Pele , Doença de Still de Início Tardio , Adulto , Dermatite/metabolismo , Dermatite/patologia , Feminino , Humanos , Neutrófilos/metabolismo , Neutrófilos/patologia , Pele/metabolismo , Pele/patologia , Doença de Still de Início Tardio/metabolismo , Doença de Still de Início Tardio/patologiaRESUMO
BACKGROUND: Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown. METHODS: We carried out a genomewide association study involving children with asthma. The sample included 793 North American children of European ancestry with persistent asthma who required daily inhaled glucocorticoid therapy and 1988 matched controls (the discovery set). We also tested for genomewide association in an independent cohort of 917 persons of European ancestry who had asthma and 1546 matched controls (the replication set). Finally, we tested for an association between 20 single-nucleotide polymorphisms (SNPs) at chromosome 1q31 and asthma in 1667 North American children of African ancestry who had asthma and 2045 ancestrally matched controls. RESULTS: In our meta-analysis of all samples from persons of European ancestry, we observed an association, with genomewide significance, between asthma and SNPs at the previously reported locus on 17q21 and an additional eight SNPs at a novel locus on 1q31. The SNP most strongly associated with asthma was rs2786098 (P=8.55x10(-9)). We observed replication of the association of asthma with SNP rs2786098 in the independent series of persons of European ancestry (combined P=9.3x10(-11)). The alternative allele of each of the eight SNPs on chromosome 1q31 was strongly associated with asthma in the children of African ancestry (P=1.6x10(-13) for the comparison across all samples). The 1q31 locus contains the 1q31 locus contains DENND1B, a gene expressed by natural killer cells and dendritic cells. DENND1B protein is predicted to interact with the tumor necrosis factor α receptor [corrected]. CONCLUSIONS: We have identified a locus containing DENND1B on chromosome 1q31.3 that is associated with susceptibility to asthma.
Assuntos
Asma/genética , Cromossomos Humanos Par 1 , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Fatores de Troca do Nucleotídeo Guanina/genética , Polimorfismo de Nucleotídeo Único , População Branca/genética , População Negra/genética , Estudos de Casos e Controles , Criança , Cromossomos Humanos Par 17 , Feminino , Humanos , Masculino , Metanálise como Assunto , América do Norte , Razão de Chances , Receptores do Fator de Necrose Tumoral/metabolismoRESUMO
We present a database of copy number variations (CNVs) detected in 2026 disease-free individuals, using high-density, SNP-based oligonucleotide microarrays. This large cohort, comprised mainly of Caucasians (65.2%) and African-Americans (34.2%), was analyzed for CNVs in a single study using a uniform array platform and computational process. We have catalogued and characterized 54,462 individual CNVs, 77.8% of which were identified in multiple unrelated individuals. These nonunique CNVs mapped to 3272 distinct regions of genomic variation spanning 5.9% of the genome; 51.5% of these were previously unreported, and >85% are rare. Our annotation and analysis confirmed and extended previously reported correlations between CNVs and several genomic features such as repetitive DNA elements, segmental duplications, and genes. We demonstrate the utility of this data set in distinguishing CNVs with pathologic significance from normal variants. Together, this analysis and annotation provides a useful resource to assist with the assessment of CNVs in the contexts of human variation, disease susceptibility, and clinical molecular diagnostics.
Assuntos
Mapeamento Cromossômico/métodos , Bases de Dados Genéticas , Dosagem de Genes/genética , Variação Genética , Genoma Humano/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , População Negra/genética , Criança , Duplicação Gênica , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Projetos de Pesquisa , População Branca/genéticaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/efeitos adversos , Carcinossarcoma/tratamento farmacológico , Toxidermias/etiologia , Eczema/induzido quimicamente , Exantema/induzido quimicamente , Paclitaxel/efeitos adversos , Pele/efeitos dos fármacos , Neoplasias Uterinas/tratamento farmacológico , Biópsia , Toxidermias/diagnóstico , Eczema/diagnóstico , Exantema/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , Pele/patologiaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/efeitos adversos , Carcinossarcoma/tratamento farmacológico , Toxidermias/etiologia , Eczema/induzido quimicamente , Exantema/induzido quimicamente , Paclitaxel/efeitos adversos , Pele/efeitos dos fármacos , Neoplasias Uterinas/tratamento farmacológico , Biópsia , Toxidermias/diagnóstico , Eczema/diagnóstico , Exantema/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , Pele/patologiaAssuntos
Asma/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Asma/epidemiologia , Asma/metabolismo , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/metabolismo , Estudos de Coortes , Feminino , Humanos , Masculino , Proteínas de Membrana/biossíntese , Locos de Características Quantitativas/genética , Estados Unidos/epidemiologia , População BrancaAssuntos
Toxinas Botulínicas Tipo A/efeitos adversos , Transtornos de Deglutição/induzido quimicamente , Fármacos Neuromusculares/efeitos adversos , Adulto , Dor de Orelha/induzido quimicamente , Face , Feminino , Cefaleia/induzido quimicamente , Rouquidão/induzido quimicamente , Humanos , Envelhecimento da PeleRESUMO
Recently an association was demonstrated between the single nucleotide polymorphism (SNP), rs10516487, within the B-cell gene BANK1 and systemic lupus erythematosus (SLE) as a consequence of a genome wide association study of this disease in European and Argentinean populations. In a bid for replication, we examined the effects of the R61H non-synonymous variant with respect to SLE in our genotyped American cohorts of European and African ancestry. Utilizing data from our ongoing genome-wide association study in our cohort of 178 Caucasian SLE cases and 1808 Caucasian population-based controls plus 148 African American (AA) SLE cases and 1894 AA population-based controls we investigated the association of the previously described non-synonymous SNP at the BANK1 locus with the disease in the two ethnicities separately. Using a Fisher's exact test, the minor allele frequency (MAF) of rs10516487 in the Caucasian cases was 22.6% while it was 31.2% in Caucasian controls, yielding a protective odds ratio (OR) of 0.64 (95% CI 0.49-0.85; one-sided p = 7.07 × 10(-4)). Furthermore, the MAF of rs10516487 in the AA cases was 18.7% while it was 23.3% in AA controls, yielding a protective OR of 0.75 (95% CI 0.55-1.034; one-sided p = 0.039). The OR of the BANK1 variant in our study cohorts is highly comparable with that reported previously in a South American/European SLE case-control cohort (OR = 0.72). As such, R61H in the BANK1 gene confers a similar magnitude of SLE protection, not only in European Americans, but also in African Americans.
RESUMO
Recently a modest, but consistently, replicated association was demonstrated between obesity and the single-nucleotide polymorphism (SNP), rs17782313, 3' of the MC4R locus as a consequence of a meta-analysis of genome-wide association (GWA) studies of the disease in white populations. We investigated the association in the context of the childhood form of the disease utilizing data from our ongoing GWA study in a cohort of 728 European-American (EA) obese children (BMI > or =95th percentile) and 3,960 EA controls (BMI <95th percentile), as well as 1,008 African-American (AA) obese children and 2,715 AA controls. rs571312, rs10871777, and rs476828 (perfect surrogates for rs17782313) yielded odds ratios in the EA cohort of 1.142 (P = 0.045), 1.137 (P = 0.054), and 1.145 (P = 0.042); however, there was no significant association with these SNPs in the AA cohort. When investigating all 30 SNPs present on the Illumina BeadChip at this locus, again there was no evidence for association in AA cases when correcting for the number of tests employed. As such, variants 3' to the MC4R locus present on the genotyping platform utilized confer a similar magnitude of risk of obesity in white children as to their adult white counterparts but this observation did not extend to AAs.
Assuntos
Negro ou Afro-Americano/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único/genética , Receptor Tipo 4 de Melanocortina/genética , População Branca/genética , Adolescente , Negro ou Afro-Americano/etnologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Genótipo , Humanos , Obesidade/etnologia , População Branca/etnologiaRESUMO
OBJECTIVE: Two recent genome-wide association (GWA) studies have revealed novel loci for type 1 diabetes, a common multifactorial disease with a strong genetic component. To fully utilize the GWA data that we had obtained by genotyping 563 type 1 diabetes probands and 1,146 control subjects, as well as 483 case subject-parent trios, using the Illumina HumanHap550 BeadChip, we designed a full stage 2 study to capture other possible association signals. RESEARCH DESIGN AND METHODS: From our existing datasets, we selected 982 markers with P < 0.05 in both GWA cohorts. Genotyping these in an independent set of 636 nuclear families with 974 affected offspring revealed 75 markers that also had P < 0.05 in this third cohort. Among these, six single nucleotide polymorphisms in five novel loci also had P < 0.05 in the Wellcome Trust Case-Control Consortium dataset and were further tested in 1,303 type 1 diabetes probands from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) plus 1,673 control subjects. RESULTS: Two markers (rs9976767 and rs3757247) remained significant after adjusting for the number of tests in this last cohort; they reside in UBASH3A (OR 1.16; combined P = 2.33 x 10(-8)) and BACH2 (1.13; combined P = 1.25 x 10(-6)). CONCLUSIONS: Evaluation of a large number of statistical GWA candidates in several independent cohorts has revealed additional loci that are associated with type 1 diabetes. The two genes at these respective loci, UBASH3A and BACH2, are both biologically relevant to autoimmunity.
Assuntos
Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Canadá , Criança , Pré-Escolar , Estudos de Coortes , Genótipo , Humanos , Lactente , Metanálise como Assunto , Estados Unidos , Adulto JovemRESUMO
Recently an association was demonstrated between the single nucleotide polymorphism (SNP), rs9939609, within the FTO locus and obesity as a consequence of a genome wide association (GWA) study of type 2 diabetes in adults. We examined the effects of two perfect surrogates for this SNP plus 11 other SNPs at this locus with respect to our childhood obesity cohort, consisting of both Caucasians and African Americans (AA). Utilizing data from our ongoing GWA study in our cohort of 418 Caucasian obese children (BMI>or=95th percentile), 2,270 Caucasian controls (BMI<95th percentile), 578 AA obese children and 1,424 AA controls, we investigated the association of the previously reported variation at the FTO locus with the childhood form of this disease in both ethnicities. The minor allele frequencies (MAF) of rs8050136 and rs3751812 (perfect surrogates for rs9939609 i.e. both r(2) = 1) in the Caucasian cases were 0.448 and 0.443 respectively while they were 0.391 and 0.386 in Caucasian controls respectively, yielding for both an odds ratio (OR) of 1.27 (95% CI 1.08-1.47; P = 0.0022). Furthermore, the MAFs of rs8050136 and rs3751812 in the AA cases were 0.449 and 0.115 respectively while they were 0.436 and 0.090 in AA controls respectively, yielding an OR of 1.05 (95% CI 0.91-1.21; P = 0.49) and of 1.31 (95% CI 1.050-1.643; P = 0.017) respectively. Investigating all 13 SNPs present on the Illumina HumanHap550 BeadChip in this region of linkage disequilibrium, rs3751812 was the only SNP conferring significant risk in AA. We have therefore replicated and refined the association in an AA cohort and distilled a tag-SNP, rs3751812, which captures the ancestral origin of the actual mutation. As such, variants in the FTO gene confer a similar magnitude of risk of obesity to children as to their adult counterparts and appear to have a global impact.
Assuntos
População Negra , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , População Branca , Alelos , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Estudos de Casos e Controles , Criança , Frequência do Gene , Humanos , Desequilíbrio de Ligação , Obesidade/epidemiologia , Obesidade/etnologia , PrevalênciaRESUMO
OBJECTIVE: In stage 1 of our genome-wide association (GWA) study for type 1 diabetes, one locus at 16p13 was detected (P = 1.03 x 10(-10)) and confirmed in two additional cohorts. Here we describe the results of testing, in these additional cohorts, 23 loci that were next in rank of statistical significance. RESEARCH DESIGN AND METHODS: Two independent cohorts were studied. The Type 1 Diabetes Genetics Consortium replication cohort consisted of 549 families with at least one child diagnosed with diabetes (946 total affected) and DNA from both parents. The Canadian replication cohort consisted of 364 nuclear family trios with one type 1 diabetes-affected offspring and two parents (1,092 individuals). RESULTS: One locus at 12q13, with the highest statistical significance among the 23, was confirmed. It involves type 1 diabetes association with the minor allele of rs1701704 (P = 9.13 x 10(-10), OR 1.25 [95% CI 1.12-1.40]). CONCLUSIONS: We have discovered a type 1 diabetes locus at 12q13 that is replicated in an independent cohort of type 1 diabetic patients and confers a type 1 diabetes risk comparable with that of the 16p13 locus we recently reported. These two loci are identical to two loci identified by the whole-genome association study of the Wellcome Trust Case-Control Consortium, a parallel independent discovery that adds further support to the validity of the GWA approach.
Assuntos
Cromossomos Humanos Par 12 , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Genoma Humano , Mapeamento Cromossômico , Cromossomos Humanos Par 6 , Estudos de Coortes , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/imunologia , Antígenos HLA-D/genética , Humanos , Medição de RiscoRESUMO
Inflammatory bowel disease (IBD) is a common inflammatory disorder with complex etiology that involves both genetic and environmental triggers, including but not limited to defects in bacterial clearance, defective mucosal barrier and persistent dysregulation of the immune response to commensal intestinal bacteria. IBD is characterized by two distinct phenotypes: Crohn's disease (CD) and ulcerative colitis (UC). Previously reported GWA studies have identified genetic variation accounting for a small portion of the overall genetic susceptibility to CD and an even smaller contribution to UC pathogenesis. We hypothesized that stratification of IBD by age of onset might identify additional genes associated with IBD. To that end, we carried out a GWA analysis in a cohort of 1,011 individuals with pediatric-onset IBD and 4,250 matched controls. We identified and replicated significantly associated, previously unreported loci on chromosomes 20q13 (rs2315008[T] and rs4809330[A]; P = 6.30 x 10(-8) and 6.95 x 10(-8), respectively; odds ratio (OR) = 0.74 for both) and 21q22 (rs2836878[A]; P = 6.01 x 10(-8); OR = 0.73), located close to the TNFRSF6B and PSMG1 genes, respectively.