197 research outputs found

    The Cardiovascular Epidemiology and Genome-Wide Associations of Biomarkers of Innate and Adaptive Immunity: sCD163 and sIL2RA

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    Cardiovascular disease (CVD) is a major cause of morbidity and mortality in the U.S. and worldwide. Atherosclerosis, the buildup of plaque in the arteries, is a common cause of CVD. For many years, research in atherosclerosis was focused on lipid metabolism and the accumulation of low-density lipoprotein in the arteries. While this research set public health guidelines for lipid management, lipid concentration was not the only factor influencing atherosclerosis and CVD events. Many scientists, as far back as the 1850’s recognized the role of inflammation in the progression of atherosclerotic disease. The continuous low levels of immune activation in the body contribute to atherosclerosis. Research in animal models and epidemiologic studies have shown the involvement of both the innate and the adaptive immune systems in plaque development and to elucidate the roles of monocytes and T cells. In addition to animal studies and epidemiologic research, CVD and atherosclerotic research has extended to genetic analysis in the search for associations with risk factors and outcomes. The first chapter is a review of the literature studying the immune system’s involvement in atherosclerosis. Beginning with an examination of the impact of CVD and atherosclerosis, the basic pathophysiology, and the involvement of the innate and adaptive immune systems through animal models and epidemiology. Some of the significant cohort studies in CVD and genome wide association studies are also discussed. Chapter 2 examines the associations of soluble interleukin 2 receptor alpha (sIL-2Rα) with clinical events in the Cardiovascular Health Study and genetic variants. Interleukin 2 (IL-2) and its receptor regulate both tolerance and immunity, IL-2 induces the proliferation and differentiation of T cells, part of the adaptive immune system. The results showed an association between sIL-2Rα and CVD events. The genome-wide association study found 52 variants to be significantly associated with sIL-2Rα in European Americans. Chapter 3 assesses the involvement of the innate immune system in atherosclerosis through the associations of soluble CD163 (sCD163). CD163 is a marker of macrophage activation, specifically associated with M2 macrophages. In CHS, sCD163 levels were analyzed for associations with cardiovascular events and genetic variants. sCD163 was found to be associated with CVD risk factors and with cardiovascular events. In a genome-wide association study six variants in European Americans and three variants in African Americans were found to be significant. Chapter 4 summarizes the results and discusses some bench to bedside translational science already seen in atherosclerosis treatment and prevention. Continued investigation of markers of T-cell and monocyte differentiation in animal models and cohort studies may lead to opportunities for the prevention of atherosclerosis and/or treatment through an increased understanding of the biology and genetics of the innate and adaptive immune

    Epigenome-Wide Association Study of Kidney Function Identifies Trans-Ethnic and Ethnic-Specific Loci

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    BACKGROUND: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. METHODS: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses. RESULTS: We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development. CONCLUSIONS: We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context

    The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature

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    Although both growth hormone (GH) and insulin-like growth factor 1 (IGF-1) signaling were shown to regulate life span in lower organisms, the role of GH signaling in human longevity remains unclear. Because a GH receptor exon 3 deletion (d3-GHR) appears to modulate GH sensitivity in humans, we hypothesized that this polymorphism could play a role in human longevity. We report a linear increased prevalence of d3-GHR homozygosity with age in four independent cohorts of long-lived individuals: 841 participants [567 of the Longevity Genes Project (LGP) (8% increase; P = 0.01), 152 of the Old Order Amish (16% increase; P = 0.02), 61 of the Cardiovascular Health Study (14.2% increase; P = 0.14), and 61 of the French Long-Lived Study (23.5% increase; P = 0.02)]. In addition, mega analysis of males in all cohorts resulted in a significant positive trend with age (26% increase; P = 0.007), suggesting sexual dimorphism for GH action in longevity. Further, on average, LGP d3/d3 homozygotes were 1 inch taller than the wild-type (WT) allele carriers (P = 0.05) and also showed lower serum IGF-1 levels (P = 0.003). Multivariate regression analysis indicated that the presence of d3/d3 genotype adds approximately 10 years to life span. The LGP d3/d3-GHR transformed lymphocytes exhibited superior growth and extracellular signal–regulated kinase activation, to GH treatment relative to WT GHR lymphocytes (P < 0.01), indicating a GH dose response. The d3-GHR variant is a common genetic polymorphism that modulates GH responsiveness throughout the life span and positively affects male longevity

    A methylation risk score for chronic kidney disease: a HyperGEN study

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    Chronic kidney disease (CKD) impacts about 1 in 7 adults in the United States, but African Americans (AAs) carry a disproportionately higher burden of disease. Epigenetic modifications, such as DNA methylation at cytosine-phosphate-guanine (CpG) sites, have been linked to kidney function and may have clinical utility in predicting the risk of CKD. Given the dynamic relationship between the epigenome, environment, and disease, AAs may be especially sensitive to environment-driven methylation alterations. Moreover, risk models incorporating CpG methylation have been shown to predict disease across multiple racial groups. In this study, we developed a methylation risk score (MRS) for CKD in cohorts of AAs. We selected nine CpG sites that were previously reported to be associated with estimated glomerular filtration rate (eGFR) in epigenome-wide association studies to construct a MRS in the Hypertension Genetic Epidemiology Network (HyperGEN). In logistic mixed models, the MRS was significantly associated with prevalent CKD and was robust to multiple sensitivity analyses, including CKD risk factors. There was modest replication in validation cohorts. In summary, we demonstrated that an eGFR-based CpG score is an independent predictor of prevalent CKD, suggesting that MRS should be further investigated for clinical utility in evaluating CKD risk and progression

    A methylation risk score for chronic kidney disease: a HyperGEN study

    Get PDF
    Chronic kidney disease (CKD) impacts about 1 in 7 adults in the United States, but African Americans (AAs) carry a disproportionately higher burden of disease. Epigenetic modifications, such as DNA methylation at cytosine-phosphate-guanine (CpG) sites, have been linked to kidney function and may have clinical utility in predicting the risk of CKD. Given the dynamic relationship between the epigenome, environment, and disease, AAs may be especially sensitive to environment-driven methylation alterations. Moreover, risk models incorporating CpG methylation have been shown to predict disease across multiple racial groups. In this study, we developed a methylation risk score (MRS) for CKD in cohorts of AAs. We selected nine CpG sites that were previously reported to be associated with estimated glomerular filtration rate (eGFR) in epigenome-wide association studies to construct a MRS in the Hypertension Genetic Epidemiology Network (HyperGEN). In logistic mixed models, the MRS was significantly associated with prevalent CKD and was robust to multiple sensitivity analyses, including CKD risk factors. There was modest replication in validation cohorts. In summary, we demonstrated that an eGFR-based CpG score is an independent predictor of prevalent CKD, suggesting that MRS should be further investigated for clinical utility in evaluating CKD risk and progression

    A new facility for airborne solar astronomy: NASA's WB-57 at the 2017 total solar eclipse

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    NASA's WB-57 High Altitude Research Program provides a deployable, mobile, stratospheric platform for scientific research. Airborne platforms are of particular value for making coronal observations during total solar eclipses because of their ability both to follow the Moon's shadow and to get above most of the atmospheric airmass that can interfere with astronomical observations. We used the 2017 Aug 21 eclipse as a pathfinding mission for high-altitude airborne solar astronomy, using the existing high-speed visible-light and near-/mid-wave infrared imaging suite mounted in the WB-57 nose cone. In this paper, we describe the aircraft, the instrument, and the 2017 mission; operations and data acquisition; and preliminary analysis of data quality from the existing instrument suite. We describe benefits and technical limitations of this platform for solar and other astronomical observations. We present a preliminary analysis of the visible-light data quality and discuss the limiting factors that must be overcome with future instrumentation. We conclude with a discussion of lessons learned from this pathfinding mission and prospects for future research at upcoming eclipses, as well as an evaluation of the capabilities of the WB-57 platform for future solar astronomy and general astronomical observation.Comment: 17 pages, 10 figures; accepted for publication by the Astrophysical Journa
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