Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase

Background Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized. Objectives This study sought to determine the molecular effects of statin therapy on multiple metabolic pathways. Methods Metabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts. Results Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R2 = 0.94, slope 1.00 ± 0.03). Conclusions Statin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug targets can inform indications, pleiotropic effects, and pharmacological mechanisms

Arctic air pollution: Challenges and opportunities for the next decade

The Arctic is a sentinel of global change. This region is influenced by multiple physical and socio-economic drivers and feedbacks, impacting both the natural and human environment. Air pollution is one such driver that impacts Arctic climate change, ecosystems and health but significant uncertainties still surround quantification of these effects. Arctic air pollution includes harmful trace gases (e.g. tropospheric ozone) and particles (e.g. black carbon, sulphate) and toxic substances (e.g. polycyclic aromatic hydrocarbons) that can be transported to the Arctic from emission sources located far outside the region, or emitted within the Arctic from activities including shipping, power production, and other industrial activities. This paper qualitatively summarizes the complex science issues motivating the creation of a new international initiative, PACES (air Pollution in the Arctic: Climate, Environment and Societies). Approaches for coordinated, international and interdisciplinary research on this topic are described with the goal to improve predictive capability via new understanding about sources, processes, feedbacks and impacts of Arctic air pollution. Overarching research actions are outlined, in which we describe our recommendations for 1) the development of trans-disciplinary approaches combining social and economic research with investigation of the chemical and physical aspects of Arctic air pollution; 2) increasing the quality and quantity of observations in the Arctic using long-term monitoring and intensive field studies, both at the surface and throughout the troposphere; and 3) developing improved predictive capability across a range of spatial and temporal scales

Association of branched-chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimer's disease: A prospective study in eight cohorts

Introduction: Metabolite, lipid, and lipoprotein lipid profiling can provide novel insights into mechanisms underlying incident dementia and Alzheimer's disease. Methods: We studied eight prospective cohorts with 22,623 participants profiled by n

Sphingomyelin is associated with kidney disease in type 1 diabetes (The FinnDiane Study)

Diabetic kidney disease, diagnosed by urinary albumin excretion rate (AER), is a critical symptom of chronic vascular injury in diabetes, and is associated with dyslipidemia and increased mortality. We investigated serum lipids in 326 subjects with type 1 diabetes: 56% of patients had normal AER, 17% had microalbuminuria (20 ≤ AER < 200 μg/min or 30 ≤ AER < 300 mg/24 h) and 26% had overt kidney disease (macroalbuminuria AER ≥ 200 μg/min or AER ≥ 300 mg/24 h). Lipoprotein subclass lipids and low-molecular-weight metabolites were quantified from native serum, and individual lipid species from the lipid extract of the native sample, using a proton NMR metabonomics platform. Sphingomyelin (odds ratio 2.53, P < 10−7), large VLDL cholesterol (odds ratio 2.36, P < 10−10), total triglycerides (odds ratio 1.88, P < 10−6), omega-9 and saturated fatty acids (odds ratio 1.82, P < 10−5), glucose disposal rate (odds ratio 0.44, P < 10−9), large HDL cholesterol (odds ratio 0.39, P < 10−9) and glomerular filtration rate (odds ratio 0.19, P < 10−10) were associated with kidney disease. No associations were found for polyunsaturated fatty acids or phospholipids. Sphingomyelin was a significant regressor of urinary albumin (P < 0.0001) in multivariate analysis with kidney function, glycemic control, body mass, blood pressure, triglycerides and HDL cholesterol. Kidney injury, sphingolipids and excess fatty acids have been linked in animal models—our exploratory approach provides independent support for this relationship in human patients with diabetes

Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA

Genome-wide association studies have identified numerous loci linked with complex diseases, for which the molecular mechanisms remain largely unclear. Comprehensive molecular profiling of circulating metabolites captures highly heritable traits, which can help to uncover metabolic pathophysiology underlying established disease variants. We conduct an extended genome-wide association study of genetic influences on 123 circulating metabolic traits quantified by nuclear magnetic resonance metabolomics from up to 24,925 individuals and identify eight novel loci for amino acids, pyruvate and fatty acids. The LPA locus link with cardiovascular risk exemplifies how detailed metabolic profiling may inform underlying aetiology via extensive associations with very-low-density lipoprotein and triglyceride metabolism. Genetic fine mapping and Mendelian randomization uncover wide-spread causal effects of lipoprotein(a) on overall lipoprotein metabolism and we assess potential pleiotropic consequences of genetically elevated lipoprotein(a) on diverse morbidities via electronic health-care records. Our findings strengthen the argument for safe LPA-targeted intervention to reduce cardiovascular risk

Overview: Recent advances in the understanding of the northern Eurasian environments and of the urban air quality in China – a Pan-Eurasian Experiment (PEEX) programme perspective

The Pan-Eurasian Experiment (PEEX) Science Plan, released in 2015, addressed a need for a holistic system understanding and outlined the most urgent research needs for the rapidly changing Arctic-boreal region. Air quality in China, together with the long-range transport of atmospheric pollutants, was also indicated as one of the most crucial topics of the research agenda. These two geographical regions, the northern Eurasian Arctic-boreal region and China, especially the megacities in China, were identified as a “PEEX region”. It is also important to recognize that the PEEX geographical region is an area where science-based policy actions would have significant impacts on the global climate. This paper summarizes results obtained during the last 5 years in the northern Eurasian region, together with recent observations of the air quality in the urban environments in China, in the context of the PEEX programme. The main regions of interest are the Russian Arctic, northern Eurasian boreal forests (Siberia) and peatlands, and the megacities in China. We frame our analysis against research themes introduced in the PEEX Science Plan in 2015. We summarize recent progress towards an enhanced holistic understanding of the land–atmosphere–ocean systems feedbacks. We conclude that although the scientific knowledge in these regions has increased, the new results are in many cases insufficient, and there are still gaps in our understanding of large-scale climate–Earth surface interactions and feedbacks. This arises from limitations in research infrastructures, especially the lack of coordinated, continuous and comprehensive in situ observations of the study region as well as integrative data analyses, hindering a comprehensive system analysis. The fast-changing environment and ecosystem changes driven by climate change, socio-economic activities like the China Silk Road Initiative, and the global trends like urbanization further complicate such analyses. We recognize new topics with an increasing importance in the near future, especially “the enhancing biological sequestration capacity of greenhouse gases into forests and soils to mitigate climate change” and the “socio-economic development to tackle air quality issues”

Pan-Eurasian Experiment (PEEX): Towards a holistic understanding of the feedbacks and interactions in the land-Atmosphere-ocean-society continuum in the northern Eurasian region

The northern Eurasian regions and Arctic Ocean will very likely undergo substantial changes during the next decades. The Arctic-boreal natural environments play a crucial role in the global climate via albedo change, carbon sources and sinks as well as atmospheric aerosol production from biogenic volatile organic compounds. Furthermore, it is expected that global trade activities, demographic movement, and use of natural resources will be increasing in the Arctic regions. There is a need for a novel research approach, which not only identifies and tackles the relevant multi-disciplinary research questions, but also is able to make a holistic system analysis of the expected feedbacks. In this paper, we introduce the research agenda of the Pan-Eurasian Experiment (PEEX), a multi-scale, multi-disciplinary and international program started in 2012 (https://www.atm.helsinki.fi/peex/). PEEX sets a research approach by which large-scale research topics are investigated from a system perspective and which aims to fill the key gaps in our understanding of the feedbacks and interactions between the land-Atmosphere-Aquatic-society continuum in the northern Eurasian region. We introduce here the state of the art for the key topics in the PEEX research agenda and present the future prospects of the research, which we see relevant in this context

Adaptative Potential of the Lactococcus Lactis IL594 Strain Encoded in Its 7 Plasmids

The extrachromosomal gene pool plays a significant role both in evolution and in the environmental adaptation of bacteria. The L. lactis subsp. lactis IL594 strain contains seven plasmids, named pIL1 to pIL7, and is the parental strain of the plasmid-free L. lactis IL1403, which is one of the best characterized lactococcal strains of LAB. Complete nucleotide sequences of pIL1 (6,382 bp), pIL2 (8,277 bp), pIL3 (19,244 bp), pIL4 (48,979), pIL5 (23,395), pIL6 (28,435 bp) and pIL7 (28,546) were established and deposited in the generally accessible database (GeneBank). Nine highly homologous repB-containing replicons, belonging to the lactococcal theta-type replicons, have been identified on the seven plasmids. Moreover, a putative region involved in conjugative plasmid mobilization was found on four plasmids, through identification of the presence of mob genes and/or oriT sequences. Detailed bioinformatic analysis of the plasmid nucleotide sequences provided new insight into the repertoire of plasmid-encoded functions in L. lactis, and indicated that plasmid genes from IL594 strain can be important for L. lactis adaptation to specific environmental conditions (e.g. genes coding for proteins involved in DNA repair or cold shock response) as well as for technological processes (e.g. genes encoding citrate and lactose utilization, oligopeptide transport, restriction-modification system). Moreover, global gene analysis indicated cooperation between plasmid- and chromosome-encoded metabolic pathways

Arctic air pollution : Challenges and opportunities for the next decade

Peer reviewe

Introgression and rapid species turnover in sympatric damselflies

<p>Abstract</p> <p>Background</p> <p>Studying contemporary hybridization increases our understanding of introgression, adaptation and, ultimately, speciation. The sister species <it>Ischnura elegans </it>and <it>I. graellsii </it>(Odonata: Coenagrionidae) are ecologically, morphologically and genetically similar and hybridize. Recently, <it>I. elegans </it>has colonized northern Spain, creating a broad sympatric region with <it>I. graellsii</it>. Here, we review the distribution of both species in Iberia and evaluate the degree of introgression of <it>I. graellsii </it>into <it>I. elegans </it>using six microsatellite markers (442 individuals from 26 populations) and five mitochondrial genes in sympatric and allopatric localities. Furthermore, we quantify the effect of hybridization on the frequencies of the genetically controlled colour polymorphism in females of both species.</p> <p>Results</p> <p>In a principal component analysis of the microsatellite data, the first two principal components summarised almost half (41%) of the total genetic variation. The first axis revealed a clear separation of <it>I. graellsii </it>and <it>I</it>. <it>elegans </it>populations, while the second axis separated <it>I. elegans </it>populations. Admixture analyses showed extensive hybridization and introgression in <it>I. elegans </it>populations, consistent with <it>I. elegans </it>backcrosses and occasional F₁-hybrids, suggesting hybridization is on-going. More specifically, approximately 58% of the 166 Spanish <it>I. elegans </it>individuals were assigned to the <it>I. elegans </it>backcross category, whereas not a single of those individuals was assigned to the backcross with <it>I. graellsii</it>. The mitochondrial genes held little genetic variation, and the most common haplotype was shared by the two species.</p> <p>Conclusions</p> <p>The results suggest rapid species turnover in sympatric regions in favour of <it>I. elegans</it>, corroborating previous findings that <it>I. graellsii </it>suffers a mating disadvantage in sympatry with <it>I. elegans</it>. Examination of morph frequency dynamics indicates that hybridization is likely to have important implications for the maintenance of multiple female morphs, in particular during the initial period of hybridization.</p