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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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (SI) 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. 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: SI and DI. Although evidence of association did not reach genome-wide significance ( p = 5 × 10−7), in the combined analysis SNPs had admixture-adjusted p values of pADD = 0.00010–0.0020 with 8 to 41% differences in genotypic means for SI and DI. Several candidate loci were identified that are nominally associated with SI and/or DI in Hispanic-American participants. Replication of these findings in independent cohorts and additional focused analysis of these loci is warranted. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]