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Background: Household endotoxin levels have been variably associated with risk for asthma and atopy. Methods: We studied participants from the 2005‐2006 National Health and Nutrition Examination Survey (NHANES, n = 6963), a large cohort representative of the US population (aged 1‐84 years). We built logistic regression models to test for associations between house dust endotoxin and sensitization to specific foods (milk, egg, and peanut). To experimentally explore the detected epidemiologic associations, peripheral blood mononuclear cells (PBMCs) were collected from 21 children (aged 1‐19 years) mono‐food allergic (ie, sensitized and clinically reactive) to milk, egg, or peanut and nonallergic controls for stimulation with endotoxin and secreted cytokine measurement. For each food allergy, linear mixed‐effects models were built to test the association between endotoxin stimulation and cytokine level. Results: Among NHANES subjects, the geometric mean household endotoxin level was 15.5 EU/mg (GSE 0.5). Prevalence of food allergen sensitization (sIgE ≥ 0.35 kUA/L) varied by food: milk 5.7%, egg 4.0%, and peanut 7.9%. In models adjusted for potential confounders (age, race, country of birth, total people per household, US region, and history of wheezing in the past year), household endotoxin level was associated with sensitization to milk (OR 1.7, 95% CI 1.2‐2.1) and egg (OR 1.4, 95% CI 1.01‐1.9), but not peanut (OR 0.98, 95% CI 0.8‐1.2). Interferon‐γ levels of endotoxin‐stimulated PBMCs from children allergic to milk or egg, but not peanut, were significantly lower compared to controls in linear mixed‐effects models adjusted for repeated measures, experimental variables, age, and inter‐individual variability (P‐values.007,.018, and.058, respectively). Conclusion: Higher household endotoxin is associated with increased odds of milk and egg sensitization. Altered cytokine responsiveness to endotoxin is also observed in PBMCs from individuals with milk and egg allergy. [ABSTRACT FROM AUTHOR]

Background: Animal model studies reported robust associations between fructose intake, a known determinant of metabolic health across species, and DNA methylation/gene expression patterns. To date, these associations have not been comprehensively investigated in humans. Methods: Using DNA methylation data on ~470,000 cytosine-phosphate-guanine (CpG) sites in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n=991) quantified in CD4+ T-cells, we have interrogated the cross-sectional relationships between fructose intake (ascertained using a validated food frequency questionnaire) and epigenome-wide methylation. We fit linear mixed models adjusted for age, sex, study site, technical covariates (fixed effects) and family relatedness (random effect). We have supplemented the methylation analyses with a transcriptome-wide scan on 98 unrelated GOLDN participants with available RNASeq data in whole blood. For the RNASeq data analysis, we used negative binomial models of read counts as a function of fructose intake, adjusted for age, sex, study site, technical covariates (including differential white blood cell counts). Results and Conclusions: The top loci differentially methylated with respect to fructose intake mapped to SNED1 (regression coefficient +/- SE= 0.002 +/- 0.0005, P=5x10-6) and FARSB (regression coefficient +/- SE= 0.002 +/- 0.0004, P=5x10-6) on chromosome 2. SNED1 is an insulin responsive transcription factor that has previously been shown to be downregulated in the setting of metabolic syndrome. FARSB encodes an aminoacyl-tRNA synethetase implicated in cell growth. Additionally, two genes reached transcriptome-wide significance in the RNASeq analysis: MTATP8P1 (P=1x10-7) and PDXDC1 (P=6x10-7). Sequence variation in PDXDC1 (pyridoxal-dependent decarboxylase isoform) has previously been linked to lipid metabolism, while MTATP8P1 is a pseudogene for a mitochondrially encoded ATP synthase. Upon future replication and functional validation, our preliminary findings offer promising insights into the link between fructose intake and metabolic health. [ABSTRACT FROM AUTHOR]

In Alzheimer's disease (AD), the most common cause of dementia, females have higher prevalence and faster progression, but sex-specific molecular findings in AD are limited. Here, we comprehensively examined and validated 7,006 aptamers targeting 6,162 proteins in cerebral spinal fluid (CSF) from 2,077 amyloid/tau positive cases and controls to identify sex-specific proteomic signatures of AD. In discovery (N=1,766), we identified 330 male-specific and 121 female-specific proteomic alternations in CSF (FDR <0.05). These sex-specific proteins strongly predicted amyloid/tau positivity (AUC=0.98 in males; 0.99 in females), significantly higher than those with age, sex, and APOE-ε4 (AUC=0.85). The identified sex-specific proteins were well validated (r≥0.5) in the Stanford study (N=108) and Emory study (N=148). Biological follow-up of these proteins led to sex differences in cell-type specificity, pathways, interaction networks, and drug targets. Male-specific proteins, enriched in astrocytes and oligodendrocytes, were involved in postsynaptic and axon-genesis. The male network exhibited direct connections among 152 proteins and highlighted PTEN, NOTCH1, FYN, and MAPK8 as hubs. Drug target suggested melatonin (used for sleep-wake cycle regulation), nabumetone (used for pain), daunorubicin, and verteporfin for treating AD males. In contrast, female-specific proteins, enriched in neurons, were involved in phosphoserine residue binding including cytokine activities. The female network exhibits strong connections among 51 proteins and highlighted JUN and 14-3-3 proteins (YWHAG and YWHAZ) as hubs. Drug target suggested biperiden (for muscle control of Parkinson's disease), nimodipine (for cerebral vasospasm), quinostatin and ethaverine for treating AD females. Together, our findings provide mechanistic understanding of sex differences for AD risk and insights into clinically translatable interventions., Competing Interests: Conflict of interest CC has received research support from: GSK and EISAI. AR and MB have received research support from Grifols, Roche, Araclon and Janssen. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. CC is a member of the advisory board of Circular Genomics and owns stocks.