Polygenic and clinical risk scores and their impact on age at onset and prediction of cardiometabolic diseases and common cancers

Polygenic risk scores (PRSs) have shown promise in predicting susceptibility to common diseases1,2,3. We estimated their added value in clinical risk prediction of five common diseases, using large-scale biobank data (FinnGen; n = 135,300) and the FINRISK study with clinical risk factors to test genome-wide PRSs for coronary heart disease, type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer. We evaluated the lifetime risk at different PRS levels, and the impact on disease onset and on prediction together with clinical risk scores. Compared to having an average PRS, having a high PRS contributed 21% to 38% higher lifetime risk, and 4 to 9 years earlier disease onset. PRSs improved model discrimination over age and sex in type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer, and over clinical risk in type 2 diabetes, breast cancer and prostate cancer. In all diseases, PRSs improved reclassification over clinical thresholds, with the largest net reclassification improvements for early-onset coronary heart disease, atrial fibrillation and prostate cancer. This study provides evidence for the additional value of PRSs in clinical disease prediction. The practical applications of polygenic risk information for stratified screening or for guiding lifestyle and medical interventions in the clinical setting remain to be defined in further studies.Peer reviewe

Patients with type 1 diabetes show signs of vascular dysfunction in response to multiple high-fat meals

Peer reviewe

The interplay between inflammatory cytokines and cardiometabolic disease: bi-directional mendelian randomisation study

Objective To leverage large scale genetic association data to investigate the interplay between circulating cytokines and cardiometabolic traits, and thus identifying potential therapeutic targets. Design Bi-directional Mendelian randomisation study. Setting Genome-wide association studies from three Finnish cohorts (Northern Finland Birth Cohort 1966, Young Finns Study, or FINRISK study), and genetic association summary statistics pooled from observational studies for expression quantitative trait loci and cardiometabolic traits. Participants Data for 47 circulating cytokines in 13 365 individuals from genome-wide association studies, summary statistic data for up to 21 735 individuals on circulating cytokines, summary statistic gene expression data across 49 tissues in 838 individuals, and summary statistic data for up to 1 320 016 individuals on cardiometabolic traits. Interventions Relations between circulating cytokines and cardiovascular, anthropometric, lipid, or glycaemic traits (coronary artery disease, stroke, type 2 diabetes mellitus, body mass index, waist circumference, waist to hip ratio, systolic blood pressure, glycated haemoglobin, high density lipoprotein cholesterol, low density lipoprotein cholesterol, total cholesterol, triglycerides, C reactive protein, glucose, fasting insulin, and lifetime smoking). Main outcome methods Genetic instrumental variables that are biologically plausible for the circulating cytokines were generated. The effects of cardiometabolic risk factors on concentrations of circulating cytokines, circulating cytokines on other circulating cytokines, and circulating cytokines on cardiometabolic outcomes were investigated. Results Genetic evidence (mendelian randomisation P0.5) suggested that coronary artery disease risk is increased by higher concentrations of circulating tumour necrosis factor related apoptosis-inducing ligand (TRAIL), interleukin-1 receptor antagonist (IL1RA), and macrophage colony-stimulating factor (MCSF). Conclusion This study offers insight into inflammatory mediators of cardiometabolic risk factors, cytokine signalling cascades, and effects of circulating cytokines on different cardiometabolic outcomes

Adaptive responses of animals to climate change are most likely insufficient

Biological responses to climate change have been widely documented across taxa and regions, but it remains unclear whether species are maintaining a good match between phenotype and environment, i.e. whether observed trait changes are adaptive. Here we reviewed 10,090 abstracts and extracted data from 71 studies reported in 58 relevant publications, to assess quantitatively whether phenotypic trait changes associated with climate change are adaptive in animals. A meta-analysis focussing on birds, the taxon best represented in our dataset, suggests that global warming has not systematically affected morphological traits, but has advanced phenological traits. We demonstrate that these advances are adaptive for some species, but imperfect as evidenced by the observed consistent selection for earlier timing. Application of a theoretical model indicates that the evolutionary load imposed by incomplete adaptive responses to ongoing climate change may already be threatening the persistence of species. © 2019, The Author(s)

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Adaptive responses of animals to climate change are most likely insufficient

Biological responses to climate change have been widely documented across taxa and regions, but it remains unclear whether species are maintaining a good match between phenotype and environment, i.e. whether observed trait changes are adaptive. Here we reviewed 10,090 abstracts and extracted data from 71 studies reported in 58 relevant publications, to assess quantitatively whether phenotypic trait changes associated with climate change are adaptive in animals. A meta-analysis focussing on birds, the taxon best represented in our dataset, suggests that global warming has not systematically affected morphological traits, but has advanced phenological traits. We demonstrate that these advances are adaptive for some species, but imperfect as evidenced by the observed consistent selection for earlier timing. Application of a theoretical model indicates that the evolutionary load imposed by incomplete adaptive responses to ongoing climate change may already be threatening the persistence of species.Peer reviewe

Reaction kinetics and reactor modelling in the design of catalytic reactors for automotive exhaust gas abatement

Abstract The tightening environmental legislation and technological development in automotive engineering form a challenge in reactor design of catalytic reactors for automotive exhaust gas abatement. The catalytic reactor is the heart of the exhaust aftertreatment processes, but it can be seen also just as one subsidiary part of vehicles. The aim of this work is to reveal applicable kinetic models to predict behaviour of the particular catalysts and to establish guidelines for modelling procedures and experimentation facilitating catalytic reactor design, especially in the field of automotive exhaust gas abatement. The studies in this thesis include catalyst kinetics with synthetic exhaust gas composition in stoichiometric and net oxidative conditions, DRIFT measurements, and the warm-up of three-way catalysts in real conditions. Knowledge on surface concentrations facilitates kinetic model construction and discrimination. For example, identification of even semi-quantitative surface concentrations may lead to a successful falsification of incorrect kinetic model candidates. Especially, that is clearly seen in cases where models predict the same kind of gas phase behaviour but different kinds of surface concentration profiles. The transient kinetic experiments could give a hint on predominant reaction mechanism, support quantifying of the adsorption capacity and reveal the impact of surface phenomena on reactor dynamics. The level of model complexity should be adapted depending on the purpose of the model. For example, it is mostly convenient for reactor design purposes to perceive only one type of active sites even in a case of mechanical mixture of different catalytic materials; whereas the optimisation of catalyst content demands the management of every prominent site type separately. Or, when a catalytic material has been selected, the stationary kinetic model is, in most cases, adequate for the catalytic converter design and structural optimization for warm-up conditions

Production of levulinic acid from glucose in sulfolane/water mixtures

Abstract Levulinic acid derived from biomass is a versatile platform molecule, which can be used in manufacturing different compounds to replace fossil-based chemicals. In this study, the effect of sulfolane as solvent in sulphuric acid catalysed levulinic acid production from glucose was investigated. The broad sulfolane concentration range was systematically studied and a kinetic model was developed to describe the levulinic acid production. A significant increase in glucose conversion rate was observed when the proportion of sulfolane in the solvent mixture was increased. The maximum selectivity of the levulinic acid production was found to be slightly over 50% and independent of the solvent composition. Thus, with sulfolane solvent, the same yields can be obtained in a significantly shorter time or at a lower temperature as when water is used as solvent. Sulfolane was also found to keep the generated by-products in soluble form. This will decrease fouling of the process equipment, which has been a major issue in designing of levulinic acid production processes

Effect of organic solvents in separation section of levulinic acid production:synthesis of distillation sequences

Abstract This work highlights the system specific characteristics encountered when considering a distillation-based separation strategy for levulinic acid (LA) and the by-product formic acid (FA) in the presence of water and water-miscible sulfolane or γ-valerolactone (GVL) solvents. Simulation using Aspen Plus® was applied to identify the presence of distillation boundary surfaces and tangent pinches resulting from the non-ideal behaviour of the mixtures in question. In the applied feed composition regions, the separation performance of the GVL solvent system in particular is limited by these restricting conditions. Minimum energy requirements for the separation of valuable components are presented as the conceptual design performance indicators, allowing the benchmarking of separation strategies. Sidedraw column configurations offer advantages in enriching the dilute valuable compounds from the feed and performing difficult separations at lower solvent quantities. This is especially advantageous for the sulfolane system where both LA and FA are intermediate-boiling

Solubility and fractionation of Indulin AT kraft lignin in ethanol-water media

Abstract Lignin solubility is a varying property, as depending on the type of lignin and its origin, its solubility in different solvents will differ. This is due to the highly heterogeneous nature of lignin. Solubilizing lignin could improve its potential valorization by making it more conducive to chemical reactions. Solvent fractionation could be utilized as the first step in lignin refining to adjust some of its properties before further processing. It is known that kraft lignin is completely soluble in alkaline solvents such as aqueous NaOH. The purpose of this study was to assess the solubility of Indulin AT lignin in aqueous ethanol solvents and to determine the useful properties of the resulting fractions: namely, molar mass distribution and phenolic hydroxyl groups. The highest concentration of lignin was achieved in 60 wt% ethanol solution with 235.89 g/L at a solid-to-liquid ratio of 300 gLignin/LSolvent. The original lignin had a mass average molar mass of 4.7 kDa. When only water was utilized, the average molar mass of the dissolved fraction was between 1 and 2 kDa and the molecular size distribution was mostly between 0.1 and 1 kDa. When using pure ethanol, the molecular size distribution ranged from 0.1 kDa to 10 kDa, with a mass average molar mass between 1 and 1.3 kDa. With an ethanol content in the solvent higher than 90 wt%, the bigger molar mass molecules (>10 kDa) could be separated as the insoluble fraction. Additionally, the polydispersity of both fractions decreased with an ethanol concentration above 80 wt%. The hydroxyl group content of the insoluble fraction was higher when fractionating with less than 20 wt% ethanol, whereas with 20 wt% ethanol and higher, the soluble fraction retained most of the phenolic hydroxyls. Fractionating lignin prior to use or further processing may be potentially beneficial if the lower molar mass molecules can be used as they are, leaving only the higher molar mass molecules to be further processed or burned for energy