scholarly journals Systems epidemiology of metabolomics measures reveals new relationships between lipoproteins and other small molecules

Metabolomics ◽  
2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Fotios Drenos

Abstract Introduction The study of lipoprotein metabolism at the population level can provide valuable information for the organisation of lipoprotein related processes in the body. To use this information towards interventional hypotheses generation and testing, we need to be able to identify the mechanistic connections among the large number of observed correlations between the measured components of the system. Objectives To use population level metabolomics information to gain insight on their biochemical networks and metabolism. Methods Genetic and metabolomics information for 230 metabolic measures, predominately lipoprotein related, from a targeted nuclear magnetic resonance approach, in two samples of an established European cohort, totalling more than 9400 individuals analysed using phenotypic and genetic correlations, as well as Mendelian Randomisation. Results More than 20,500 phenotypic correlations were identified in the data, with almost 2000 also showing evidence of strong genetic correlation. Mendelian randomisation, provided evidence for a causal effect between 9496 pairs of metabolic measures, mainly between lipoprotein traits. The results provide insights on the organisation of lipoproteins in three distinct classes, the heterogeneity between HDL particles, and the association, or lack of, between CLA, glycolysis markers, such as glucose and citrate, and glycoproteins with lipids subfractions. Two examples for the use of the approach in systems biology of lipoproteins are presented. Conclusions Genetic variation can be used to infer the underlying mechanisms for the associations between lipoproteins for hypothesis generation and confirmation, and, together with biological information, to map complex biological processes.

Author(s):  
Kevin M Bakker ◽  
Marisa C Eisenberg ◽  
Robert Woods ◽  
Micaela E Martinez

Abstract Varicella zoster virus (VZV) is a herpesvirus that causes chickenpox and shingles. The biological mechanisms underpinning the multi-decadal latency of VZV in the body and subsequent viral reactivation—which occurs in approximately 30% of individuals—are largely unknown. Because chickenpox and shingles are endemic worldwide, understanding the relationship between VZV transmission and reactivation is important for informing disease treatment and control. While chickenpox is a vaccine-preventable childhood disease with a rich legacy of research, shingles is not a notifiable disease in most countries. To date, population-level studies of shingles have had to rely on small-scale hospital or community-level datasets. Here, we examined chickenpox and shingles notifications from Thailand and found strong seasonal incidence in both diseases, with a 3-month lag between peak chickenpox transmission season and peak shingles reactivation. We tested and fit 14 mathematical models examining the biological driversof chickenpox and shingles over an 8-year period to estimate rates of VZV transmission, reactivation, and immunity boosting, wherein re-exposure to VZV boosts VZV-specific immunity to reinforce protection against shingles. The models suggested the seasonal cycles of chickenpox and shingles have different underlying mechanisms, with ultraviolet radiation (UV) being correlated with shingles reactivation.


2019 ◽  
Vol 59 (5) ◽  
pp. 1275-1280 ◽  
Author(s):  
H Frederik Nijhout ◽  
Kenneth Z McKenna

Abstract Until recently, the study of allometry has been mostly descriptive, and consisted of a diversity of methods for fitting regressions to bivariate or multivariate morphometric data. During the past decade, researchers have been developing methods to extract biological information from allometric data that could be used to deduce the underlying mechanisms that gave rise to the allometry. In addition, an increasing effort has gone into understanding the kinetics of growth and the regulatory mechanisms that control growth of the body and its component parts. The study of allometry and scaling has now become an exceptionally diverse field, with different investigators applying state of the art methods and concepts in evolution, developmental biology, cell biology, and genetics. Diversity has caused divergence, and we felt that although there is general agreement about the new goals for the study of allometry (understanding underlying mechanisms and how those evolve to produce different morphologies), progress is hindered by lack of coordination among the different approaches. We felt the time was right to bring these diverse practitioners together in a symposium to discuss their most recent work in the hope of forging new functional, conceptual, and collaborative connections among established and novice practitioners.


Author(s):  
Richard Culliford ◽  
Alex J. Cornish ◽  
Philip J. Law ◽  
Susan M. Farrington ◽  
Kimmo Palin ◽  
...  

Abstract Background Epidemiological studies of the relationship between gallstone disease and circulating levels of bilirubin with risk of developing colorectal cancer (CRC) have been inconsistent. To address possible confounding and reverse causation, we examine the relationship between these potential risk factors and CRC using Mendelian randomisation (MR). Methods We used two-sample MR to examine the relationship between genetic liability to gallstone disease and circulating levels of bilirubin with CRC in 26,397 patients and 41,481 controls. We calculated the odds ratio per genetically predicted SD unit increase in log bilirubin levels (ORSD) for CRC and tested for a non-zero causal effect of gallstones on CRC. Sensitivity analysis was applied to identify violations of estimator assumptions. Results No association between either gallstone disease (P value = 0.60) or circulating levels of bilirubin (ORSD = 1.00, 95% confidence interval (CI) = 0.96–1.03, P value = 0.90) with CRC was shown. Conclusions Despite the large scale of this study, we found no evidence for a causal relationship between either circulating levels of bilirubin or gallstone disease with risk of developing CRC. While the magnitude of effect suggested by some observational studies can confidently be excluded, we cannot exclude the possibility of smaller effect sizes and non-linear relationships.


2021 ◽  
Vol 19 (2) ◽  
pp. 115-122
Author(s):  
A. Hartley ◽  
C. L. Gregson ◽  
L. Paternoster ◽  
J. H. Tobias

Abstract Purpose of Review This paper reviews how bone genetics has contributed to our understanding of the pathogenesis of osteoarthritis. As well as identifying specific genetic mechanisms involved in osteoporosis which also contribute to osteoarthritis, we review whether bone mineral density (BMD) plays a causal role in OA development. Recent Findings We examined whether those genetically predisposed to elevated BMD are at increased risk of developing OA, using our high bone mass (HBM) cohort. HBM individuals were found to have a greater prevalence of OA compared with family controls and greater development of radiographic features of OA over 8 years, with predominantly osteophytic OA. Initial Mendelian randomisation analysis provided additional support for a causal effect of increased BMD on increased OA risk. In contrast, more recent investigation estimates this relationship to be bi-directional. However, both these findings could be explained instead by shared biological pathways. Summary Pathways which contribute to BMD appear to play an important role in OA development, likely reflecting shared common mechanisms as opposed to a causal effect of raised BMD on OA. Studies in HBM individuals suggest this reflects an important role of mechanisms involved in bone formation in OA development; however further work is required to establish whether the same applies to more common forms of OA within the general population.


2021 ◽  
pp. bmjnph-2020-000151
Author(s):  
Hasnat A Amin ◽  
Fotios Drenos

BackgroundUpper respiratory tract infections are reportedly more frequent and more severe in individuals with lower vitamin D levels. Based on these findings, it has been suggested that vitamin D can prevent or reduce the severity of COVID-19.MethodsWe used two-sample Mendelian randomisation (MR) to assess the causal effect of vitamin D levels on SARS-CoV-2 infection risk and COVID-19 severity using publicly available data. We also carried out a genome-wide association analysis (GWA) of vitamin D deficiency in the UK Biobank (UKB) and used these results and two-sample MR to assess the causal effect of vitamin D deficiency on SARS-CoV-2 infection risk and COVID-19 severity.ResultsWe found no evidence that vitamin D levels causally affect the risk of SARS-CoV-2 infection (ln(OR)=0.17 (95% CI −0.22 to 0.57, p=0.39)) nor did we find evidence that vitamin D levels causally affect COVID-19 severity (ln(OR)=0.36 (95% CI −0.89 to 1.61, p=0.57)). Based on our GWA analysis, we found that 17 independent variants are associated with vitamin D deficiency in the UKB. Using these variants as instruments for our two-sample MR analyses, we found no evidence that vitamin D deficiency causally affects the risk of SARS-CoV-2 infection (ln(OR)=−0.04 (95% CI −0.1 to 0.03, p=0.25)) nor did we find evidence that vitamin D deficiency causally affects COVID-19 severity (ln(OR)=−0.24 (95% CI −0.55 to 0.08, p=0.14)).ConclusionsIn conclusion, we found no evidence that vitamin D is protective against SARS-CoV-2 infection or COVID-19 severity. Our data support the recent statement by the National Institute for Health and Care Excellence that the use of vitamin D supplementation to mitigate COVID-19 is not supported by the available data.


2018 ◽  
Vol 115 (48) ◽  
pp. 12313-12318 ◽  
Author(s):  
Gang Wu ◽  
Marc D. Ruben ◽  
Robert E. Schmidt ◽  
Lauren J. Francey ◽  
David F. Smith ◽  
...  

Skin is the largest organ in the body and serves important barrier, regulatory, and sensory functions. The epidermal layer shows rhythmic physiological responses to daily environmental variation (e.g., DNA repair). We investigated the role of the circadian clock in the transcriptional regulation of epidermis using a hybrid experimental design, in which a limited set of human subjects (n = 20) were sampled throughout the 24-h cycle and a larger population (n = 219) were sampled once. We found a robust circadian oscillator in human epidermis at the population level using pairwise correlations of clock and clock-associated genes in 298 epidermis samples. We then used CYCLOPS to reconstruct the temporal order of all samples, and identified hundreds of rhythmically expressed genes at the population level in human epidermis. We compared these results with published time-series skin data from mice and found a strong concordance in circadian phase across species for both transcripts and pathways. Furthermore, like blood, epidermis is readily accessible and a potential source of biomarkers. Using ZeitZeiger, we identified a biomarker set for human epidermis that is capable of reporting circadian phase to within 3 hours from a single sample. In summary, we show rhythms in human epidermis that persist at the population scale and describe a path to develop robust single-sample circadian biomarkers.


2020 ◽  
Author(s):  
Tom C. Russ ◽  
Sarah E. Harris ◽  
G. David Batty

ABSTRACTDementia is a major global public health concern and in addition to recognised risk factors there is emerging evidence that poorer pulmonary function is linked with subsequent dementia risk. However, it is unclear if this observed association is causal or whether it might result from confounding. Therefore, we present the first two-sample Mendelian randomisation study of the association between pulmonary function and Alzheimer dementia using the most recent genome-wide association studies to produce instrumental variables for both. We found no evidence of a causal effect of reduced Forced Expiratory Volume in 1 second (FEV1) or Forced Vital Capacity (FVC) on Alzheimer dementia risk (both P>0.35). However, the FEV1/FVC ratio was associated with Alzheimer dementia risk with, in fact, superior function predicting an increased dementia risk (OR 1.12, 95%CI 1.02-1.23; P=0.016) which may result from survivor bias. While we can conclude that there is no causal link between impaired pulmonary function and Alzheimer dementia, our study sheds less light on potential links with other types of dementia.


2007 ◽  
Vol 13 ◽  
pp. 45-48 ◽  
Author(s):  
Mark T. Hutchison ◽  
Louise Josefine Nielsen ◽  
Stefan Bernstein

Exploration for diamonds in West Greenland has experienced a major boost within the last decade following the establishment of world-class diamond mines within the nearby Slave Province of the Canadian Arctic. Numerous companies have active programmes of diamond exploration and increasingly larger diamonds have been discovered, notably a 2.392 carat dodecahedral stone recovered by the Canadian exploration company Hudson Resources Inc. in January 2007. The Geological Survey of Denmark and Greenland (GEUS) is currently carrying out several studies aimed at understanding the petrogenesis of diamondiferous kimberlites in Greenland and the physical and chemical properties of their associated mantle source regions (e.g. Hutchison 2005; Nielsen & Jensen 2005). Constraint of the mantle geotherm, i.e. the variation of temperature with depth for a particular mantle volume, is an important initial step in assessing the likelihood of such a volume to grow diamonds and hence the diamond potential of associated deep-sourced magmatic rocks occurring at surface. Cool geotherms are often present within old cratonic blocks such as West Greenland (Garde et al. 2000) and provide a good environment for the formation of diamonds (Haggerty 1986). This study aims to constrain the mantle geotherm for the southern extent of the North Atlantic Craton in Greenland by applying three-phase geothermobarometry calculations using chemical compositions of clinopyroxene, orthopyroxene and garnet from four-phase kimberlite-hosted lherzolite xenoliths. Xenoliths have been sampled from kimberlites from two areas in South-West Greenland: Midternæs and Pyramide- fjeld (Fig. 1). Kimberlites in the Pyramidefjeld area principally occur as sheeted sills hosted in the Pyramidefjeld granite complex of Palaeoproterozoic Ketilidian age. In contrast, Midternæs kimberlites occur as outcrops within a single, extensive and undulating sill hosted within pre-Ketilidian granodioritic gneiss and Ketilidian supracrustal rocks. Pyramidefjeld kimberlites have been shown to be Mesozoic (Andrews & Emeleus 1971), and work is currently being carried out to further constrain the ages of these and the Midternæs kimberlites and also xenoliths using modern methods. No attempt is made herein to provide a correct petrological classification of the rocks hosting the xenoliths; however, the abundance of clinopyroxene reported by Andrews & Emeleus (1971) suggests that further work may more correctly conclude a classification as ‘orangeite’ after Mitchell (1995). Notwithstanding this, the term ‘kimberlite’ is employed throughout in order to be consistent with that adopted by previous authors. The Precambrian Pyramide fjeld granite complex and adjacent Archaean granod ioritic gneisses are host to several kimberlite sheets located at various levels between 400 and 900 m elevation (Fig. 1A; Andrews & Emeleus 1971, 1975). Kimberlites are mainly found as loose blocks in scree; however, these are almost always sourced locally from in situ bodies. Sheets can often be found deep within overhanging clefts, particularly in granitic walls. The kimberlite bodies are gently dipping, typically 20 degrees, and with a range of strikes. The maximum thickness of sills is approximately 2 m but thickness varies significantly over short distances. In many instances, the occurrence of kimberlite is seen to be controlled locally by structures in the country rocks. Field observations of the range of orientations of intrusive bodies do not appear to suggest a particular focal point which could be a likely location for an intrusive centre such as a pipe. This observation is in line with what is seen throughout West Greenland where kimberlite emplacement appears as dykes and sills (Larsen & Rex 1992) rather than the pipes and blows which are common in other world-wide settings. The occurrence of xenoliths amongst Pyramidefjeld kimberlites is highly variable with the most xenolith-rich localities being in the vicinity of Safirsø (Fig. 1A). The majority of xenoliths are dunites with occasional wehrlites and lherzolites (Emeleus & Andrews 1975). Of particular interest from the point of view of thermobarometry is the occurrence of garnet. This is rarely found, even in clinopyroxene-bearing samples, and the two samples chosen for thermobarometry (Fig. 1A) represent the majority of the garnet-bearing xenoliths identified within an estimated total population of 75 xenoliths collected. The Midternæs kimberlites are hosted in Archaean gneisses and Proterozoic supracrustal rocks (Fig. 1B; Andrews & Emeleus 1971, 1975). The style of kimberlite emplacement and occurrence of garnet-bearing xenoliths are closely similar to those of Pyramidefjeld. Contours of elevation between outcrops suggest that the kimberlites form parts of a largely contiguous single body dipping at approximately 30 degrees to the west-south-west. Individual outcrops as in Pyramidefjeld indicate that the body varies in thickness and undulates in response to local structure. The south-western portion of the body which outcrops near the glacier Sioralik Bræ, is considerably thicker than elsewhere (Fig. 2) and in some places is seen to have a true thickness in excess of 4 m. Xenoliths are less abundant on average than in Pyramidefjeld kimberlites, but a similar variety and proportion of rock types and infrequent occurrence of garnet is observed. The kimberlites from both areas were intruded along zones of platy jointing which likely were caused by degassing of the magma and formed just prior to the kimberlite intrusion. In contrast to some kimberlites in other cratons, very few xenoliths of local, lower crustal rock types have been recognised in the kimberlites from Pyramidefjeld and Mid ternæs. The intrusions are therefore believed to have been of a non-explosive nature, perhaps because of host-rock rheol - ogy or due to emplacement at relatively deep crustal levels. Here we report on calculations of equilibrium pressure and temperature using compositions of three-phase assemblages of garnet, orthopyroxene and clinopyroxene from Midternæs and Pyramidefjeld mantle xenoliths.


Author(s):  
I.J. Ohagenyi ◽  
F.C. Iregbu ◽  
V.C. Udeh

Background: This study was conducted to estimate the genetic parameters of body weight and some colour traits in seventh generation (G7) index selected Nigerian Heavy Local Chicken Ecotype (NHLCE) progenies at point of lay to 12 weeks. Methods: 5 sires and 12 hens were used to generate the progenies used for the experiment. Traits measured included weekly body weight, egg colour, beak colour and feather colour. Data collected were subjected to one way analysis of variance in a Paternal half sib analysis using Animal model of SAS (2003). Four weeks body weight measurements, egg colour, beak colour and feather colour for 5 sires ranged from 1.29±0.05 1.54±0.07; 2.55±0.02 to 4.00±0.02; 2.45±0.02 to 4.83±0.02 and 1.73±0.02 to 4.58±0.04 respectively. Result: The new Duncan’s multiple range test shows that sire families are similar (p greater than 0.05) in the body weight and beak colour, but significantly differed (p greater than 0.05) in the egg colour and feather colour. The heritability estimates of mature body weight for week 3 was medium, while estimates of heritability for weekly mature body weight for weeks 1, 2 and 4, egg colour, beak colour and feather colour of NHLCE were low heritability. Low h2 of traits suggest that progeny and pedigree selection could be employed for improvement of the egg colour, beak colour and feather colour of NHLCE. The study showed positive genetic correlations between beak colour and egg colour, negative genetic correlations between beak and feather colour. This means that no decision can be taken in isolation as the selection of one trait will have consequences on other traits.


2021 ◽  
Vol 28 ◽  
Author(s):  
Syed Mohammad Zakariya ◽  
Aiman Zehr ◽  
Rizwan Hasan Khan

: The failure of protein to correctly fold into its functional and unique three dimensional form leads to misfolded or partially folded protein. When these rogue proteins and polypeptides escape the quality control mechanism within the body, they result in aberrant aggregation of proteins into characteristic amyloid fibrils. This is the main cause for the number of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s and Huntington’s diseases. This review aims to summarise the underlying mechanisms of protein folding, misfolding and aggregation. It also highlights the recent technologies for the structural characterisation and detection of amyloid fibrils in addition to the various factors responsible for the aggregate formation and the strategies to combat the aggregation process. Besides, the journey from origin to the current scenario of protein aggregation is also concisely discussed.


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