RESUMO
Pulmonary involvement occurs in up to 95% of sarcoidosis cases. In this pilot study, we examine lung compartment-specific protein expression to identify pathways linked to development and progression of pulmonary sarcoidosis. We characterized bronchoalveolar lavage (BAL) cells and fluid (BALF) proteins in recently diagnosed sarcoidosis cases. We identified 4,306 proteins in BAL cells, of which 272 proteins were differentially expressed in sarcoidosis compared to controls. These proteins map to novel pathways such as integrin-linked kinase and IL-8 signaling and previously implicated pathways in sarcoidosis, including phagosome maturation, clathrin-mediated endocytic signaling and redox balance. In the BALF, the differentially expressed proteins map to several pathways identified in the BAL cells. The differentially expressed BALF proteins also map to aryl hydrocarbon signaling, communication between innate and adaptive immune response, integrin, PTEN and phospholipase C signaling, serotonin and tryptophan metabolism, autophagy, and B cell receptor signaling. Additional pathways that were different between progressive and non-progressive sarcoidosis in the BALF included CD28 signaling and PFKFB4 signaling. Our studies demonstrate the power of contemporary proteomics to reveal novel mechanisms operational in sarcoidosis. Application of our workflows in well-phenotyped large cohorts maybe beneficial to identify biomarkers for diagnosis and prognosis and therapeutically tenable molecular mechanisms.
Assuntos
Progressão da Doença , Proteínas/metabolismo , Sarcoidose Pulmonar/metabolismo , Adulto , Líquido da Lavagem Broncoalveolar/química , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Projetos Piloto , Sarcoidose Pulmonar/patologiaRESUMO
AIMS: To identify gestational diabetes mellitus exposure-associated DNA methylation changes and assess whether such changes are also associated with adiposity-related outcomes. METHODS: We performed an epigenome-wide association analysis, using Illumina 450k methylation arrays, on whole blood collected, on average, at 10.5 years of age from 81 gestational diabetes-exposed and 81 unexposed offspring enrolled in the EPOCH (Exploring Perinatal Outcomes in Children) study, and on the cord blood of 31 gestational diabetes-exposed and 64 unexposed offspring enrolled in the Colorado Healthy Start cohort. Validation was performed by pyrosequencing. RESULTS: We identified 98 differentially methylated positions associated with gestational diabetes exposure at a false discovery rate of <10% in peripheral blood, with 51 loci remaining significant (plus additional 40 loci) after adjustment for cell proportions. We also identified 2195 differentially methylation regions at a false discovery rate of <5% after adjustment for cell proportions. We prioritized loci for pyrosequencing validation and association analysis with adiposity-related outcomes based on strengths of association and effect size, network and pathway analysis, analysis of cord blood, and previous publications. Methylation in six out of nine (67%) gestational diabetes-associated genes was validated and we also showed that methylation of SH3PXD2A was significantly (P<0.05) associated with multiple adiposity-related outcomes. CONCLUSIONS: Our findings suggest that epigenetic marks may provide an important link between in utero exposure to gestational diabetes and obesity in childhood, and add to the growing body of evidence that DNA methylation is affected by gestational diabetes exposure.
Assuntos
Metilação de DNA/genética , Diabetes Gestacional/genética , Epigênese Genética , Obesidade Infantil/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Adiposidade/genética , Estudos de Casos e Controles , Criança , Estudos de Coortes , Epigenômica , Feminino , Sangue Fetal , Humanos , Masculino , GravidezRESUMO
AIM: To examine the extent to which offspring obesity-associated genetic risk explains the association between gestational diabetes mellitus and childhood adiposity. METHODS: We studied 282 children aged 7-12 years who were enrolled in the Exploring Perinatal Outcomes in Children Study. A genetic risk score for BMI was calculated as the count of 91 established BMI-raising risk alleles. Multivariable linear and logistic regression models were used to estimate associations between the offspring genetic risk score and exposure to gestational diabetes and childhood adiposity (BMI and waist circumference), adjusting for clinical and demographic covariates. The contribution of offspring genetic risk to associations between maternal gestational diabetes and childhood outcomes was estimated by comparing the regression coefficients for the gestational diabetes variable in models with and without the genetic risk score. RESULTS: The offspring BMI genetic risk score was associated with childhood BMI (P = 0.006) and waist circumference (P = 0.02), and marginally with gestational diabetes (P = 0.05). Offspring BMI genetic risk did not contribute significantly to associations between gestational diabetes and childhood BMI [7.7% (95% CI -3.3, 18.8)] or waist circumference [5.8% (95% CI -3.1, 14.8); P = 0.2 for both]. CONCLUSIONS: Offspring obesity genetic risk does not explain a significant proportion of the association between gestational diabetes exposure and childhood adiposity. The association between gestational diabetes and childhood adiposity is probably explained through alternative pathways, including direct intrauterine effects or a shared postnatal environment.
Assuntos
Adiposidade/genética , Diabetes Gestacional/epidemiologia , Obesidade Infantil/epidemiologia , Obesidade Infantil/genética , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adulto , Peso ao Nascer/fisiologia , Criança , Estudos de Coortes , Diabetes Gestacional/genética , Feminino , Predisposição Genética para Doença , Humanos , Recém-Nascido , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Fatores de RiscoRESUMO
In this study, we explored potential associations among self-injurious behaviors (SIB) and a diverse group of protective and risk factors in children with autism spectrum disorder from two databases: Autism and Developmental Disabilities Monitoring (ADDM) Network and the Autism Speaks-Autism Treatment Network (AS-ATN). The presence of SIB was determined from children's records in ADDM and a parent questionnaire in AS-ATN. We used multiple imputation to account for missing data and a non-linear mixed model with site as a random effect to test for associations. Despite differences between the two databases, similar associations were found; SIB were associated with developmental, behavioral, and somatic factors. Implications of these findings are discussed in relation to possible etiology, future longitudinal studies, and clinical practice.
Assuntos
Transtorno do Espectro Autista/epidemiologia , Comportamento Autodestrutivo/epidemiologia , Criança , Comorbidade , Estudos Transversais , Bases de Dados Factuais , Feminino , Humanos , Masculino , Fatores de Proteção , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
Targeted knockout of genes in primary human cells using CRISPR-Cas9-mediated genome-editing represents a powerful approach to study gene function and to discern molecular mechanisms underlying complex human diseases. We used lentiviral delivery of CRISPR-Cas9 machinery and conditional reprogramming culture methods to knockout the MUC18 gene in human primary nasal airway epithelial cells (AECs). Massively parallel sequencing technology was used to confirm that the genome of essentially all cells in the edited AEC populations contained coding region insertions and deletions (indels). Correspondingly, we found mRNA expression of MUC18 was greatly reduced and protein expression was absent. Characterization of MUC18 knockout cell populations stimulated with TLR2, 3 and 4 agonists revealed that IL-8 (a proinflammatory chemokine) responses of AECs were greatly reduced in the absence of functional MUC18 protein. Our results show the feasibility of CRISPR-Cas9-mediated gene knockouts in AEC culture (both submerged and polarized), and suggest a proinflammatory role for MUC18 in airway epithelial response to bacterial and viral stimuli.
Assuntos
Vetores Genéticos , Lentivirus , Mucosa Respiratória/metabolismo , Antígeno CD146/genética , Antígeno CD146/imunologia , Antígeno CD146/metabolismo , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Inflamação/genética , Cultura Primária de Células , Mucosa Respiratória/imunologiaRESUMO
The present study investigated the association between variants in the vitamin D receptor gene (VDR) and protein tyrosine phosphatase, non-receptor type 2 gene (PTPN2), as well as an interaction between VDR and PTPN2 and the risk of islet autoimmunity (IA) and progression to type 1 diabetes (T1D). The Diabetes Autoimmunity Study in the Young (DAISY) has followed children at increased risk of T1D since 1993. Of the 1692 DAISY children genotyped for VDR rs1544410, VDR rs2228570, VDR rs11568820, PTPN2 rs1893217, and PTPN2 rs478582, 111 developed IA, defined as positivity for GAD, insulin or IA-2 autoantibodies on 2 or more consecutive visits, and 38 IA positive children progressed to T1D. Proportional hazards regression analyses were conducted. There was no association between IA development and any of the gene variants, nor was there evidence of a VDR*PTPN2 interaction. Progression to T1D in IA positive children was associated with the VDR rs2228570 GG genotype (HR: 0.49, 95% CI: 0.26-0.92) and there was an interaction between VDR rs1544410 and PTPN2 rs1893217 (p(interaction)=0.02). In children with the PTPN2 rs1893217 AA genotype, the VDR rs1544410 AA/AG genotype was associated with a decreased risk of T1D (HR: 0.24, 95% CI: 0.11-0.53, p=0.0004), while in children with the PTPN2 rs1893217 GG/GA genotype, the VDR rs1544410 AA/AG genotype was not associated with T1D (HR: 1.32, 95% CI: 0.43-4.06, p=0.62). These findings should be replicated in larger cohorts for confirmation. The interaction between VDR and PTPN2 polymorphisms in the risk of progression to T1D offers insight concerning the role of vitamin D in the etiology of T1D.
Assuntos
Diabetes Mellitus Tipo 1/genética , Ilhotas Pancreáticas/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Receptores de Calcitriol/genética , Autoanticorpos/sangue , Autoimunidade/genética , Criança , Pré-Escolar , Estudos de Coortes , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/imunologia , Progressão da Doença , Feminino , Glutamato Descarboxilase/imunologia , Humanos , Lactente , Anticorpos Anti-Insulina/sangue , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de RiscoRESUMO
AIMS/HYPOTHESIS: The majority of type 2 diabetes genome-wide association studies (GWAS) to date have been performed in European-derived populations and have identified few variants that mediate their effect through insulin resistance. The aim of this study was to evaluate two quantitative, directly assessed measures of insulin resistance, namely insulin sensitivity index (S(I)) and insulin disposition index (DI), in Hispanic-American participants using an agnostic, high-density single nucleotide polymorphism (SNP) scan, and to validate these findings in additional samples. METHODS: A two-stage GWAS was performed in Hispanic-American samples from the Insulin Resistance Atherosclerosis Family Study. In Stage 1, 317,000 SNPs were assessed using 229 DNA samples. SNPs with evidence of association with glucose homeostasis and adiposity traits were then genotyped on the entire set of Hispanic-American samples (n = 1,190). This report focuses on the glucose homeostasis traits: S(I) and DI. RESULTS: Although evidence of association did not reach genome-wide significance (p = 5 x 10(-7)), in the combined analysis SNPs had admixture-adjusted p values of p (ADD) = 0.00010-0.0020 with 8 to 41% differences in genotypic means for S(I) and DI. CONCLUSIONS/INTERPRETATION: Several candidate loci were identified that are nominally associated with S(I) and/or DI in Hispanic-American participants. Replication of these findings in independent cohorts and additional focused analysis of these loci is warranted.
Assuntos
Aterosclerose/genética , Estudo de Associação Genômica Ampla , Hispânico ou Latino/genética , Resistência à Insulina/genética , Polimorfismo de Nucleotídeo Único , Adulto , Mapeamento Cromossômico/métodos , DNA/genética , Diabetes Mellitus Tipo 2/genética , Família , Jejum , Feminino , Genótipo , Glucose/metabolismo , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Grupos Minoritários/estatística & dados numéricos , Reprodutibilidade dos Testes , Estados Unidos , População Branca/genéticaRESUMO
AIMS/HYPOTHESIS: Larger childhood body size and rapid growth have been associated with increased type 1 diabetes risk. We analysed height, weight, BMI and velocities of growth in height, weight and BMI, for association with development of islet autoimmunity (IA) and type 1 diabetes. METHODS: Since 1993, the Diabetes Autoimmunity Study in the Young (DAISY) has followed children at increased type 1 diabetes risk, based on HLA-DR, -DQ genotype or family history, for the development of IA and type 1 diabetes. IA was defined as the presence of autoantibodies to insulin, GAD or protein tyrosine phosphatase islet antigen 2 twice in succession, or autoantibody-positive on one visit and diabetic at the next consecutive visit within 1 year. Type 1 diabetes was diagnosed by a physician. Height and weight were collected starting at age 2 years. Of 1,714 DAISY children <11.5 years of age, 143 developed IA and 21 progressed to type 1 diabetes. We conducted Cox proportional hazards analysis to explore growth velocities and size measures for association with IA and type 1 diabetes development. RESULTS: Greater height growth velocity was associated with IA development (HR 1.63, 95% CI 1.31-2.05) and type 1 diabetes development (HR 3.34, 95% CI 1.73-6.42) for a 1 SD difference in velocity. CONCLUSIONS/INTERPRETATION: Our study suggests that greater height growth velocity may be involved in the progression from genetic susceptibility to autoimmunity and then to type 1 diabetes in pre-pubertal children.
Assuntos
Autoimunidade/imunologia , Estatura/imunologia , Estatura/fisiologia , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/imunologia , Ilhotas Pancreáticas/imunologia , Fatores Etários , Autoanticorpos/imunologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Genótipo , Antígenos HLA-DR/genética , Humanos , Insulina/imunologia , Masculino , Modelos de Riscos Proporcionais , Fatores SexuaisRESUMO
Apoptosis may perpetuate some forms of inflammation. Of the apoptotic pathway proteins, Fas is particularly overexpressed in sarcoidosis. We hypothesized that Fas promoter single nucleotide polymorphisms (SNPs) contribute to the development and severity of sarcoidosis. Associations of known Fas promoter SNPs (-670, -690 and -1377) and deduced haplotypes with sarcoidosis and sarcoidosis severity were evaluated using matched case-control (n = 656 pairs) and case-comparison (n = 656) studies, respectively, using conditional logistic regression. Hardy-Weinberg equilibrium was confirmed for all three polymorphisms in African-Americans (AA), and for the -670 and -1377 in whites. Genotype and allele frequencies were significantly different between whites and AA. Race-stratified analysis revealed that a common haplotype, -1377G/-690T/-670G, was associated with sarcoidosis [odds ratio (OR) = 1.78, P = 0.05] only in AA. The haplotype -1377G/-690C/-670A was negatively associated with sarcoidosis (OR = 0.39, P = 0.03) only in AA. In conclusion, the consistency of these findings suggests that Fas promoter genetic variants may be related to sarcoidosis disease risk in AA.
Assuntos
Negro ou Afro-Americano/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Sarcoidose/genética , Receptor fas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Sarcoidose/epidemiologia , Índice de Gravidade de Doença , População Branca/genéticaRESUMO
The objective of the study was to test for an association between type 2 diabetes mellitus (T2DM) and body mass index (BMI) and three single nucleotide polymorphisms (SNP)s in the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha) gene. We were also interested in whether these associations differed by tertiles of diet, physical activity or presence of polymorphisms in the peroxisome proliferator-activated receptor gamma (PPAR-gamma) gene among Hispanics and Non-Hispanic Whites (NHW) from Colorado. We studied 216 Hispanic pedigrees (1850 nuclear families) and 236 NHW pedigrees (1240 families) from the San Luis Valley and Denver. We genotyped the Gly482Ser, Thr528Thr and Thr612Met polymorphisms in the PGC-1alpha gene and the Pro12Ala polymorphism of the PPAR-gamma gene. Historical physical activity (average METS/week) as well as average dietary intake over the past year was assessed by self-report. Data were analyzed using the Family Based Association Test (FBAT) as well as generalized estimating equations (GEE). We did not find any significant association between three SNPs in the PGC-1alpha gene and T2DM in Hispanics or NHW; however, using FBAT, we found the common Thr612Thr allele of the PGC-1alpha gene to be associated with T2DM among Hispanic subjects carrying the rare Pro12Ala allele of the PPAR-gamma gene (p=.003). We found similar associations when we considered a haplotype containing that allele (p=.002). However, the results of the GEE analysis did not confirm these findings: odds ratio (OR)=1.68, 95% CI (0.5, 5.2) suggesting these results may due to chance. BMI also did not show any consistent associations with the PGC-1alpha gene. In conclusion, we did not find an association between the PGC-1alpha gene and T2DM or BMI and there were no consistent interactions with diet, physical activity or the Pro12Ala polymorphism of the PPAR-gamma gene.
Assuntos
Diabetes Mellitus Tipo 2/sangue , Proteínas de Choque Térmico/genética , Fatores de Transcrição/genética , Adulto , Idoso , Substituição de Aminoácidos , Índice de Massa Corporal , Colorado , Primers do DNA , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Genótipo , Hispânico ou Latino , Humanos , Masculino , Pessoa de Meia-Idade , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Polimorfismo Genético , População BrancaRESUMO
BACKGROUND: Better understanding of factors influencing the quality of life (QOL) of cardiac patients can guide treatment decisions. OBJECTIVES: To describe the impact of clinical and psychosocial factors on the QOL of older women with heart disease. RESEARCH DESIGN: Baseline and 12-month data from women participating in an intervention study. SUBJECTS: Eligible participants, identified from medical records, were female, > or = 60 years of age, and diagnosed with cardiac disease. A volunteer sample of 570 women (87% white) completed baseline interviews, with 485 women completing the 12-month assessment. MEASURES: Utilizing Wilson and Cleary's conceptual framework (1995), measures of clinical, psychosocial, and functional status were examined for their associations with QOL. RESULTS: At baseline, General Health Perceptions and Symptom Status accounted for 38% and 26%, respectively, of the variation in the QOL rating. Using logistic regression models, seven measures were significant predictors (P < 0.05) of maintenance/improvement versus decline in QOL over 12 months: baseline QOL rating; baseline value and change in satisfaction with social activities over 12 months; change in satisfaction with physical activities; change in satisfaction with mental activities; and baseline value and change in perceived stress. For women who maintained or improved their satisfaction with social activities, the odds for also maintaining or improving QOL were 4.5 times the odds for women whose satisfaction with social activities deteriorated. CONCLUSIONS: Satisfaction with social activities and perceived stress are important predictors of subsequent QOL. Consideration of the impact of treatments on these factors may help to prevent deterioration of QOL among older female cardiac patients.
Assuntos
Cardiopatias/fisiopatologia , Cardiopatias/psicologia , Qualidade de Vida , Saúde da Mulher , Idoso , Estudos Transversais , Feminino , Pesquisa sobre Serviços de Saúde , Cardiopatias/terapia , Humanos , Entrevistas como Assunto , Modelos Logísticos , Estudos Longitudinais , Pessoa de Meia-Idade , Satisfação Pessoal , Autocuidado , Autoavaliação (Psicologia) , Estados UnidosRESUMO
Type 2 diabetes mellitus is a complex disorder encompassing multiple metabolic defects. We report results from an autosomal genome scan for type 2 diabetes-related quantitative traits in 580 Finnish families ascertained for an affected sibling pair and analyzed by the variance components-based quantitative-trait locus (QTL) linkage approach. We analyzed diabetic and nondiabetic subjects separately, because of the possible impact of disease on the traits of interest. In diabetic individuals, our strongest results were observed on chromosomes 3 (fasting C-peptide/glucose: maximum LOD score [MLS] = 3.13 at 53.0 cM) and 13 (body-mass index: MLS = 3.28 at 5.0 cM). In nondiabetic individuals, the strongest results were observed on chromosomes 10 (acute insulin response: MLS = 3.11 at 21.0 cM), 13 (2-h insulin: MLS = 2.86 at 65.5 cM), and 17 (fasting insulin/glucose ratio: MLS = 3.20 at 9.0 cM). In several cases, there was evidence for overlapping signals between diabetic and nondiabetic individuals; therefore we performed joint analyses. In these joint analyses, we observed strong signals for chromosomes 3 (body-mass index: MLS = 3.43 at 59.5 cM), 17 (empirical insulin-resistance index: MLS = 3.61 at 0.0 cM), and 19 (empirical insulin-resistance index: MLS = 2.80 at 74.5 cM). Integrating genome-scan results from the companion article by Ghosh et al., we identify several regions that may harbor susceptibility genes for type 2 diabetes in the Finnish population.
Assuntos
Diabetes Mellitus Tipo 2/genética , Testes Genéticos , Genoma Humano , Característica Quantitativa Herdável , Fatores Etários , Glicemia/metabolismo , Índice de Massa Corporal , Cromossomos Humanos/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Jejum , Feminino , Finlândia , Ligação Genética/genética , Predisposição Genética para Doença/genética , Humanos , Insulina/sangue , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Núcleo Familiar , Fatores Sexuais , Estados UnidosRESUMO
OBJECTIVES: This study involving 570 women aged 60 years or older with heart disease, assessed the effects of a disease management program on physical functioning, symptom experience, and psychosocial status. METHODS: Women were randomly assigned to control or program groups. Six to eight women met weekly with a health educator and peer leader over 4 weeks to learn self-regulation skills with physical activity as the focus. Evaluative data were collected through telephone interviews, physical assessments, and medical records at baseline and 4 and 12 months post baseline. RESULTS: At 12 months, compared with controls, program women were less symptomatic (p < .01), scored better on the physical dimension of the Sickness Impact Profile (SIP; p < 0.05), had improved ambulation as measured by the 6-minute walk (p < 0.01), and lost more body weight (p < .001). No differences related to psychosocial factors as measured by the SIP were noted. CONCLUSION: A self-regulation-based program that was provided to older women with heart disease and that focused on physical activity and disease management problems salient to them, improved their physical functioning and symptom experience. Psychosocial benefit was not evident and may be a result of measurement error or due to insufficient program time spent on psychosocial aspects of functioning.
Assuntos
Nível de Saúde , Cardiopatias/diagnóstico , Controles Informais da Sociedade , Idoso , Depressão/diagnóstico , Depressão/psicologia , Feminino , Humanos , Avaliação de Programas e Projetos de Saúde , Ajustamento SocialRESUMO
This study describes the symptom experience of 570 older women with heart disease and evaluates a disease-management program's impact on symptoms over time. Women were randomly assigned to either usual care or a 4-week program ("Women take PRIDE") designed to improve self-regulation skills by focusing on increasing physical activity. At 4 months follow-up, program women, compared to controls, reported fewer total symptoms (p = 0.01) and decreased symptom frequency (p = 0.02) and bothersomeness (p = 0.02). By 12 months, positive intervention effects emerged within the common cardiac and sleep and rest symptom categories. Program group women reported more improvements in symptoms likely to be affected by increasing physical activity at both follow-ups (p < 0.05).