Genome-Wide Association with Select Biomarker Traits in the Framingham Heart Study

BACKGROUND: Systemic biomarkers provide insights into disease pathogenesis, diagnosis, and risk stratification. Many systemic biomarker concentrations are heritable phenotypes. Genome-wide association studies (GWAS) provide mechanisms to investigate the genetic contributions to biomarker variability unconstrained by current knowledge of physiological relations. METHODS: We examined the association of Affymetrix 100K GeneChip single nucleotide polymorphisms (SNPs) to 22 systemic biomarker concentrations in 4 biological domains: inflammation/oxidative stress; natriuretic peptides; liver function; and vitamins. Related members of the Framingham Offspring cohort (n = 1012; mean age 59 ± 10 years, 51% women) had both phenotype and genotype data (minimum-maximum per phenotype n = 507–1008). We used Generalized Estimating Equations (GEE), Family Based Association Tests (FBAT) and variance components linkage to relate SNPs to multivariable-adjusted biomarker residuals. Autosomal SNPs (n = 70,987) meeting the following criteria were studied: minor allele frequency ≥ 10%, call rate ≥ 80% and Hardy-Weinberg equilibrium p ≥ 0.001. RESULTS: With GEE, 58 SNPs had p < 10-6: the top SNPs were rs2494250 (p = 1.00*10-14) and rs4128725 (p = 3.68*10-12) for monocyte chemoattractant protein-1 (MCP1), and rs2794520 (p = 2.83*10-8) and rs2808629 (p = 3.19*10-8) for C-reactive protein (CRP) averaged from 3 examinations (over about 20 years). With FBAT, 11 SNPs had p < 10-6: the top SNPs were the same for MCP1 (rs4128725, p = 3.28*10-8, and rs2494250, p = 3.55*10-8), and also included B-type natriuretic peptide (rs437021, p = 1.01*10-6) and Vitamin K percent undercarboxylated osteocalcin (rs2052028, p = 1.07*10-6). The peak LOD (logarithm of the odds) scores were for MCP1 (4.38, chromosome 1) and CRP (3.28, chromosome 1; previously described) concentrations; of note the 1.5 support interval included the MCP1 and CRP SNPs reported above (GEE model). Previous candidate SNP associations with circulating CRP concentrations were replicated at p < 0.05; the SNPs rs2794520 and rs2808629 are in linkage disequilibrium with previously reported SNPs. GEE, FBAT and linkage results are posted at . CONCLUSION: The Framingham GWAS represents a resource to describe potentially novel genetic influences on systemic biomarker variability. The newly described associations will need to be replicated in other studies.National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC25195); National Institutes of Health National Center for Research Resources Shared Instrumentation grant (1S10RR163736-01A1); National Institutes of Health (HL064753, HL076784, AG028321, HL71039, 2 K24HL04334, 1K23 HL083102); Doris Duke Charitable Foundation; American Diabetes Association Career Developement Award; National Center for Research Resources (GCRC M01-RR01066); US Department of Agriculture Agricultural Research Service (58-1950-001, 58-1950-401); National Institute of Aging (AG14759

Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017.

This is a report on the CNS barrier congress held in London, UK, March 22-23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consisted of invited academic researchers studying the brain barriers in relation to neurological diseases and industry researchers studying new methods to deliver therapeutics to treat neurological diseases. We include here brief reports from the speakers

Great art for everyone? Engagement and participation policy in the arts

New Labour began its administration with a commitment to bring democracy to culture. However, a decade later the Arts Council England (ACE)'s mission statement of "Great art for everyone" suggested a continued emphasis on access to mainstream culture rather than on cultural democracy. The argument in this paper is that Labour's vision has resulted in little change to the basis upon which arts institutions receive regular funding, or the social composition of those who participate in the arts in Britain today - who remain predominantly white and middle class. Public consultation through The arts debate provides evidence that the arts are still perceived as elitist, and policy too insular and self-reflective. The report clearly identified the public's desire for not only greater transparency in decisionmaking processes but also involvement in the decisions themselves, in order to democratise the arts. This paper draws on research investigating the extent to which participatory decisionmaking schemes affect cultural democracy and the subsequent impact on artistic policy and practice. In addition to documentary analysis, this study involved interviews with policymakers, practitioners and the public, focusing on two projects using participatory decision-making in England. © 2011 Copyright Taylor and Francis Group, LLC

No Evidence for Association of Autism with Rare Heterozygous Point Mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contactin-Associated Proteins or Contactins

Contactins and Contactin-Associated Proteins, and Contactin-Associated Protein-Like 2 (CNTNAP2) in particular, have been widely cited as autism risk genes based on findings from homozygosity mapping, molecular cytogenetics, copy number variation analyses, and both common and rare single nucleotide association studies. However, data specifically with regard to the contribution of heterozygous single nucleotide variants (SNVs) have been inconsistent. In an effort to clarify the role of rare point mutations in CNTNAP2 and related gene families, we have conducted targeted next-generation sequencing and evaluated existing sequence data in cohorts totaling 2704 cases and 2747 controls. We find no evidence for statistically significant association of rare heterozygous mutations in any of the CNTN or CNTNAP genes, including CNTNAP2, placing marked limits on the scale of their plausible contribution to risk

A psychosocial exploration of bereaved children’s experiences of exclusion from school: what understanding can be gained from a psychoanalytic perspective?

According to the Childhood Bereavement network, a parent dies every 22 minutes in the U.K. Despite this, there is little research into the impact of parental death on children and young people. This psychosocial study explores the experiences of children and young people who have been bereaved of a parent and who are subsequently excluded from school. Three participants of school age were interviewed about their experiences of these two events and the data obtained from the interviews was analysed using an individual, psychoanalytically informed case study approach, allowing for an in-depth exploration of the affect generated by the existence of dynamic, intersubjective, unconscious processes during the interviews. The data emerging from the transference and counter transference was explored and it was found that the ongoing presence of an attachment figure might mitigate some of the risk factors associated with the experience of parental death. It also seems possible that this population of children and young people are likely to be under identified in schools and when they are known to have experienced parental bereavement, school professionals struggle to understand and respond to their emotional needs. Consideration is given to the implications for the role of the Educational Psychologist in working with this vulnerable population of children and young people. The wider potential of psychoanalytically informed approaches to working with pupils and staff in schools is also considered

The participation myth

Policy rhetoric around strategies to and the value of increasing participation in the arts has been well documented internationally over more than a decade. But in the UK, which is the focus for this article, targets to increase participation have been consistently missed and there remains a direct correlation between those taking part in cultural activity and their socio-economic status. The starting point for this article is to examine the barriers to increasing participation in the arts and question the way that such policy has been implemented within the English context, which may have relevance for policy making in other countries. What is demonstrated is that policy implementation is influenced by vested interest of those in receipt of funding and that a narrow range of voices, from a powerful cultural elite, are involved in the decision making in the arts. The article makes a case for widening the range of voices heard in decision making in order to support both artistic practice and public engagement

Effects of tobacco cigarettes, e-cigarettes, and waterpipe smoking on endothelial function and clinical outcomes

Tobacco smoking is a leading cause of non-communicable disease globally and is a major risk factor for cardiovascular disease (CVD) and lung disease. Importantly, recent data by the World Health Organizations (WHO) indicate that in the last two decades global tobacco use has significantly dropped, which was largely driven by decreased numbers of female smokers. Despite such advances, the use of e-cigarettes and waterpipes (shisha, hookah, narghile) is an emerging trend, especially among younger generations. There is growing body of evidence that e-cigarettes are not a harm-free alternative to tobacco cigarettes and there is considerable debate as to whether e-cigarettes are saving smokers or generating new addicts. Here, we provide an updated overview of the impact of tobacco/waterpipe (shisha) smoking and e-cigarette vaping on endothelial function, a biomarker for early, subclinical, atherosclerosis from human and animal studies. Also their emerging adverse effects on the proteome, transcriptome, epigenome, microbiome, and the circadian clock are summarized. We briefly discuss heat-not-burn tobacco products and their cardiovascular health effects. We discuss the impact of the toxic constituents of these products on endothelial function and subsequent CVD and we also provide an update on current recommendations, regulation and advertising with focus on the USA and Europe. As outlined by the WHO, tobacco cigarette, waterpipe, and e-cigarette smoking/vaping may contribute to an increased burden of symptoms due to coronavirus disease 2019 (COVID-19) and to severe health consequences