Influence of Maternal Lifestyle and Diet on Perinatal DNA Methylation Signatures Associated With Childhood Arterial Stiffness at 8 to 9 Years

Increases in aortic pulse wave velocity, a measure of arterial stiffness, can lead to elevated systolic blood pressure and increased cardiac afterload in adulthood. These changes are detectable in childhood and potentially originate in utero, where an adverse early life environment can alter DNA methylation patterns detectable at birth. Here, analysis of epigenome-wide methylation patterns using umbilical cord blood DNA from 470 participants in the Southampton’s Women’s Survey identified differential methylation patterns associated with systolic blood pressure, pulse pressure, arterial distensibility, and descending aorta pulse wave velocity measured by magnetic resonance imaging at 8 to 9 years. Perinatal methylation levels at 16 CpG loci were associated with descending aorta pulse wave velocity, with identified CpG sites enriched in pathways involved in DNA repair (P=9.03×10−11). The most significant association was with cg20793626 methylation (within protein phosphatase, Mg2+/Mn2+ dependent 1D; β=−0.05 m/s/1% methylation change, [95% CI, −0.09 to −0.02]). Genetic variation was also examined but had a minor influence on these observations. Eight pulse wave velocity-linked dmCpGs were associated with prenatal modifiable risk factors, with cg08509237 methylation (within palmitoyl-protein thioesterase-2) associated with maternal oily fish consumption in early and late pregnancy. Lower oily fish consumption in early pregnancy modified the relationship between methylation and pulse wave velocity, with lower consumption strengthening the association between cg08509237 methylation and increased pulse wave velocity. In conclusion, measurement of perinatal DNA methylation signatures has utility in identifying infants who might benefit from preventive interventions to reduce risk of later cardiovascular disease, and modifiable maternal factors can reduce this risk in the child

Altered H19/miR‐675 expression in skeletal muscle is associated with low muscle mass in community‐dwelling older adults

Background: Despite increasing knowledge of the pathogenesis of muscle ageing, the molecular mechanisms are poorly understood. Based on an expression analysis of muscle biopsies from older Caucasian men, we undertook an in-depth analysis of the expression of the long non-coding RNA, H19, to identify molecular mechanisms that may contribute to the loss of muscle mass with age. Methods: We carried out transcriptome analysis of vastus lateralis muscle biopsies from 40 healthy Caucasian men aged 68–76 years from the Hertfordshire Sarcopenia Study (HSS) with respect to appendicular lean mass adjusted for height (ALMi). Validation and replication was carried out using qRT-PCR in 130 independent male and female participants aged 73–83 years recruited into an extension of the HSS (HSSe). DNA methylation was assessed using pyrosequencing. Results: Lower ALMi was associated with higher muscle H19 expression (r2 = 0.177, P < 0.001). The microRNAs, miR-675-5p/3p encoded by exon 1 of H19, were positively correlated with H19 expression (Pearson r = 0.192 and 0.182, respectively, P < 0.03), and miR-675-5p expression negatively associated with ALMi (r2 = 0.629, P = 0.005). The methylation of CpGs within the H19 imprinting control region (ICR) were negatively correlated with H19 expression (Pearson r = −0.211 to −0.245, P ≤ 0.05). Moreover, RNA and protein levels of SMAD1 and 5, targets of miR-675-3p, were negatively associated with miR-675-3p (r2 = 0.792 and 0.760, respectively) and miR-675-5p (r2 = 0.584 and 0.723, respectively) expression, and SMAD1 and 5 RNA levels positively associated with greater type II fibre size (r2 = 0.184 and 0.246, respectively, P < 0.05). Conclusions: Increased expression profiles of H19/miR-675-5p/3p and lower expression of the anabolic SMAD1/5 effectors of bone morphogenetic protein (BMP) signalling are associated with low muscle mass in older individuals

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.</p

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities

Nucleation and Growth of Atmospheric Particles

New particle formation (NPF) in the atmospheric is a two-step process: Nucleation leads to the birth of stable nuclei that subsequently grow to sizes that can be detected and affect the atmosphere’s radiative properties. Our group is studying both of these processes. Our nucleation research is largely supported by NSF and involves measurements of neutral molecular clusters formed by nucleation with a new custom-designed mass spectrometer (the Cluster-CIMS) and measurements of nanoparticle size distributions as small as 1 nm with a new aerosol spectrometer (the DEG SMPS). These measurements are providing new insights into aspects of cluster behavior that affect nucleation rates. The U.S. DOE supports our research on nanoparticle growth rates. This research couples physical and chemical measurements of aerosol properties and behavior. The TDCIMS, which enables real-time measurements of composition for freshly nucleated particles as small as 8 nm and was developed with support from DOE, is the most important tool in this work. Our most important discoveries about processes that affect growth rates are summarized in a recent PNAS article (doi:10.1073/pnas.0912127107). In short, this work has shown that alkylammonium-carboxylate salts, formed, for example, by reactions between amines and carboxylic acids, account for 20–50% of the mass of freshly nucleated particles in locations that include Atlanta, Mexico City, Boulder, and Hyytiälä, while sulfates account for only about 10%. These newly discovered compounds help to explain the high growth rates of freshly nucleated particles that have been observed around the globe and help to explain why nucleation is an important atmospheric process, not just a scientific curiosity. Our poster will provide an overview of this work

Neuropsychological Predictors of Trauma Centrality in OIF/OEF Veterans

This study examined whether reduced performance on two neuropsychological tasks, cognitive flexibility and working memory, were associated with higher levels of trauma centrality. A growing body of research has shown that trauma centrality, the extent to which a person believes a potentially traumatic event has become central to their self-identity and life story, is associated with post-traumatic stress disorder (PTSD). Furthermore, PTSD is often associated with alterations in neuropsychological functioning. The relationship between neuropsychological processes and trauma centrality, however, has yet to be explored. OEF/OIF combat veterans (N = 41) completed the Post-traumatic Diagnostic Scale (PDS), the Beck Depression Inventory-II (BDI-II), the Centrality of Event Scale (CES), and on-line measures of cognitive flexibility and working memory assessed via WebNeuro. Bivariate Pearson correlations showed that CES scores were positively correlated with PDS and BDI scores, and negatively correlated with cognitive flexibility and working memory. Linear regressions revealed that working memory significantly predicted CES when controlling for depression and PTSD severity while cognitive flexibility approached significance when controlling for these same variables. This study employed a cross-sectional design, precluding causality. The small sample size, entirely male sample, and use of an online neuropsychological assessment warrant follow-up research. Although numerous studies have found an association between CES and PTSD, this is the first to suggest that neuropsychological processes underlie the construct of trauma centrality. Given the importance of maladaptive cognitive processes underlying the pathogenesis of PTSD, these data suggest that future studies aimed at examining the link between neuropsychological processes and maladaptive cognitive processes, such as trauma centrality, may help to characterize and treat PTSD

DNA METHYLATION AND ITS RELATIONSHIP WITH MUSCULOSKELETAL HEALTH IN OLDER ADULTS FROM THE HERTFORDSHIRE COHORT STUDY: FINDINGS FROM AN EPIGENOME-WIDE ASSOCIATION STUDY

Abstract 090 from British Society for Rheumatology Annual Conference 201