A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes. Metabolic changes in blood may help detect COPD in an earlier stage and predict prognosis. METHODS: We conducted a comprehensive study of circulating metabolites, measured by proton Nuclear Magnetic Resonance Spectroscopy, in relation with COPD and lung function. The discovery sample consisted of 5557 individuals from two large population-based studies in the Netherlands, the Rotterdam Study and the Erasmus Rucphen Family study. Significant findings were replicated in 12,205 individuals from the Lifelines-DEEP study, FINRISK and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) studies. For replicated metabolites further investigation of causality was performed, utilizing genetics in the Mendelian randomization approach. RESULTS: There were 602 cases of COPD and 4955 controls used in the discovery meta-analysis. Our logistic regression results showed that higher levels of plasma Glycoprotein acetyls (GlycA) are significantly associated with COPD (OR = 1.16, P = 5.6 × 10- 4 in the discovery and OR = 1.30, P = 1.8 × 10- 6 in the replication sample). A bi-directional two-sample Mendelian randomization analysis suggested that circulating blood GlycA is not causally related to COPD, but that COPD causally increases GlycA levels. Using the prospective data of the same sample of Rotterdam Study in Cox-regression, we show that the circulating GlycA level is a predictive biomarker of COPD incidence (HR = 1.99, 95%CI 1.52-2.60, comparing those in the highest and lowest quartile of GlycA) but is not significantly associated with mortality in COPD patients (HR = 1.07, 95%CI 0.94-1.20). CONCLUSIONS: Our study shows that circulating blood GlycA is a biomarker of early COPD pathology

A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease

Abstract Background Chronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes. Metabolic changes in blood may help detect COPD in an earlier stage and predict prognosis. Methods We conducted a comprehensive study of circulating metabolites, measured by proton Nuclear Magnetic Resonance Spectroscopy, in relation with COPD and lung function. The discovery sample consisted of 5557 individuals from two large population-based studies in the Netherlands, the Rotterdam Study and the Erasmus Rucphen Family study. Significant findings were replicated in 12,205 individuals from the Lifelines-DEEP study, FINRISK and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) studies. For replicated metabolites further investigation of causality was performed, utilizing genetics in the Mendelian randomization approach. Results There were 602 cases of COPD and 4955 controls used in the discovery meta-analysis. Our logistic regression results showed that higher levels of plasma Glycoprotein acetyls (GlycA) are significantly associated with COPD (OR = 1.16, P = 5.6 × 10− 4 in the discovery and OR = 1.30, P = 1.8 × 10− 6 in the replication sample). A bi-directional two-sample Mendelian randomization analysis suggested that circulating blood GlycA is not causally related to COPD, but that COPD causally increases GlycA levels. Using the prospective data of the same sample of Rotterdam Study in Cox-regression, we show that the circulating GlycA level is a predictive biomarker of COPD incidence (HR = 1.99, 95%CI 1.52–2.60, comparing those in the highest and lowest quartile of GlycA) but is not significantly associated with mortality in COPD patients (HR = 1.07, 95%CI 0.94–1.20). Conclusions Our study shows that circulating blood GlycA is a biomarker of early COPD pathology

Genome-wide association study identifies seven novel loci associating with circulating cytokines and cell adhesion molecules in Finns

Background: Inflammatory processes contribute to the pathophysiology of multiple chronic conditions. Genetic factors play a crucial role in modulating the inflammatory load, but the exact mechanisms are incompletely understood.Objective: To assess genetic determinants of 16 circulating cytokines and cell adhesion molecules (inflammatory phenotypes) in Finns.Methods: Genome-wide associations of the inflammatory phenotypes were studied in Northern Finland Birth Cohort 1966 (N=5284). A subsequent meta-analysis was completed for 10 phenotypes available in a previous genome-wide association study, adding up to 13 577 individuals in the study. Complementary association tests were performed to study the effect of the ABO blood types on soluble adhesion molecule levels.Results: We identified seven novel and six previously reported genetic associations (pConclusion: The present results extend the knowledge about genetic factors contributing to the inflammatory load. Our findings suggest that two distinct mechanisms contribute to the soluble adhesion molecule levels in the ABO locus and that elevated soluble adhesion molecule levels per se may not increase risk for cardiovascular disease.</p

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Genetic architecture of human plasma lipidome and its link to cardiovascular disease

Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 x10(-8)), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD

Koivun rumpukuorintaan vaikuttavat tekijät talvella

Työssä tutkittiin koivun kuorintaa ja sulatusta Metsä-Fibren Äänekosken sellutehtaan kuorimolla. Teoriaosassa perehdyttiin puun rakenteeseen sekä kuoren ja puun väliseen sidoslujuuteen vaikuttaviin tekijöihin. Kokeellisessa osuudessa puiden sulatusta tutkittiin laboratoriokokeissa. Lisäksi kuorintalinjastolla tutkittiin sulatusparametrien vaikutuksia kuorinta tulokseen. Työn tarkoituksena oli selvittää koivun rumpukuorintaan vaikuttavia tekijöitä talvella. Lisäksi tavoitteena oli kehittää koivun kuorintaa talviaikana riittävän kuorintatuloksen varmistamiseksi. Koivun sulatusta tutkittiin, koska koivun kuoren irrottamisessa oli havaittu ongelmia talviaikana. Talvella puiden kuorintaa vaikeuttaa alhainen ulkoilman lämpötila. Hakkeen sekaan joutuneen kuoren oli havaittu nostavan sellutehtaan lopputuotteen uuteainepitoisuuksia. Erityisesti koivun kuoren betulinoli on haitallinen lopputuotteen laadulle. Työssä näytepuita sulatettiin koelaitteistolla ja puihin siirtynyttä lämpöenergiaa mitattiin lämpömittarilla. Tavoitteena oli tutkia puiden ominaisuuksien vaikutusta sulatuksessa. Kuorintalinjastolla suoritetuissa koeajoissa sulatusparametrien vaikutuksia tutkittiin mittaamalla rummusta ulostulevien puiden pintalämpötiloja lämpökameralla. Yksittäisien puiden sulatuskokeet osoittivat, että puun pinnan kuiva-ainepitoisuudella oli suurin vaikutus puiden sulamiseen. Tulokset osoittivat myös, että puun pinta jäähtyy takaisin nopeasti. Kuorintalinjastolla suoritetut koeajot osoittivat, että sulatuskuljettimen sulatusveden lämpötilan nostolla päästään parhaimpaan kuorintatulokseen. Rummusta ulostulleiden puiden lämpötila korreloi vahvasti kuoren lämpötilan ja sulatuskuljettimelta palaavan veden lämpötilan kanssa. Tuloksista voidaan todeta, että puuhäviöt laskevat kun rummusta ulostulleiden puiden lämpötila nousee. Jokaisessa koeajossa puihin kiinni jääneen kuoren määrä oli hyväksytyllä tasolla. Laskennan avulla voitiin osoittaa, että tarvittava sulatusenergian määrä on riippuvainen tehtaalle tulevan puun tilavuuspainosta. Laskennan avulla voitiin myös osoittaa, että puumateriaalin järeydellä on merkittävä vaikutus tarvittavaan sulatusenergiaan. Tasalaatuinen puumateriaali takaisi parhaan sulatustuloksen ja sitä kautta parhaan kuorintatuloksen talviaikana.This study examines birch drum debarking and deiceing in Metsä-Fibre Äänekoski pulp mill. The theoretical part focuses on the structure of the wood and the adhesion strength between bark and wood. In the experimental part wood deiceing was studied in laboratory experiments. In addition, test runs were performed in drum debarking line to find out the impacts of deiceing parameters. The aim was to find out the factors affecting the birch drum debarking in winter. In addition, the aim was to develop birch debarking in Äänekoski pulp mill according to quality targets in winter. Birch deiceing was studied because of birch bark removal was the problem in wood room in winter. Lowered outside temperature complicates the bark removal in winter. Earlier, it was noticed that the bark amount in the wood chips was the reason for increased extractives in pulp. Birch extractive betulinol is harmful to the quality of the pulp. Logs were deiced in laboratory and the amount of heat energy transferred to the logs was measured with a thermometer. Aim was to find out differences between the transferred heat energy in the logs. In test runs, deiceing parameters affects were monitored with thermal camera measurements. Laboratory experiments showed that dry matter content of the logs surface had the greatest impact on deiceing. Results also showed that the surface temperature of the wood decreases rapidly after deiceing. Test runs performed in debarking line showed that the higher temperature of the water in deiceing conveyor makes possible the best debarking results. The correlation coefficients showed that the temperatures of the drum out coming logs correlates strong between bark temperature and the temperature of the deiceing convoyer out coming water. Results showed that the wood losses decrease when the temperature of the drum out coming logs increase. Amount of the bark that was attached to the logs after debarking was in approved level in each test run. Calculation showed that the amount of the energy required for heating the logs dependents on the density of the wood. Calculation showed also that size of the incoming logs have significant affect the amount of the energy required for heating the logs. Best deiceing result is possible when quality of wood is homogenous. It also guarantees the best debarking result in winter

Epidemiological investigations of circulating biomarkers for cardiometabolic diseases

Abstract Cardiometabolic diseases are a leading cause of morbidity and mortality worldwide. Although common risk factors are well known, there has been no success in changing the growing trend in these diseases. An earlier detection of underlying harmful changes in the body, as well as a deeper understanding of the biological changes related to these diseases, could help in the early prevention and development of novel treatment strategies. Different omics technologies combined with a large population and clinical cohorts allow for a more detailed exploration of the biological changes related to various diseases. In the current thesis, these methodologies were first utilised to explore the metabolic changes associated with incident stroke and its subtypes. The first study identified 10 metabolic measures associated with incident strokes. Second, metabolomic data, together with clinical variables, were used to investigate the metabolic characteristics of mortality risk among coronary angiography patients. Furthermore, the predictive properties of metabolic measures in mortality risk prediction were assessed. The second study demonstrated that metabolic changes associated with all-cause mortality were present also when controlling for important clinical variables. The metabolic measures slightly improved discrimination at the cost of calibration compared to clinical variables when assessing the utility of these measures in the prediction of all-cause mortality. Third, the potential role of circulating inflammatory cytokines as mediators in the pathway from increased adiposity measured by body mass index to relevant disease outcomes was assessed. The third study identified three cytokines driven by body mass index. Only weak associations were seen when further assessing the causal role of the identified cytokines in different inflammatory-related diseases. In conclusion, this thesis illustrates the utility of the application of omics data in three different epidemiological settings to study the mechanisms related to cardiometabolic diseases.Tiivistelmä Kardiometaboliset sairaudet ovat suurimpia sairastavuuden ja kuolleisuuden aiheuttajia maailmanlaajuisesti. Vaikka yleisimmät riskitekijät näille sairauksille tunnetaan hyvin, kasvavaa trendiä näiden sairauksien osalta ei ole kyetty muuttamaan. Kehossa olevien piilevien muutosten aikaisempi tunnistaminen sekä näihin sairauksiin liittyvien biologisten muutosten syvempi ymmärtäminen voisi auttaa varhaisessa ehkäisyssä sekä uusien hoitomuotojen kehittämisessä. Erilaiset omiikkateknologiat yhdistettyinä suuriin kliinisiin ja väestöaineistoihin mahdollistavat sairauksiin liittyvien erilaisten biologisten muutosten entistä tarkemman tarkastelun. Tässä väitöskirjassa näitä menetelmiä on hyödynnetty ensinnäkin aivohalvauksiin ja sen alatyyppeihin liittyvien aineenvaihduntamuutosten selvittämiseen. Ensimmäinen osatyö tunnisti kymmenen aineenvaihduntamuuttujaa, jotka olivat yhteydessä aivohalvauksiin. Toisessa työssä aineenvaihduntamuuttujia käytettiin kuolleisuuteen yhteydessä olevien metabolisten muutoksien selvittämiseen sydämen varjoainekuvauspotilailla. Lisäksi metabolisten muuttujien tuomaa lisähyötyä kliinisten muuttujien lisäksi kuolleisuusriskin ennustamisessa arvioitiin. Toinen osatyö osoitti, että aineenvaihduntamuutoksia on havaittavissa, vaikka analyysissä huomioitaisiin tärkeät kliiniset muuttujat. Aineenvaihduntamuuttujat paransivat hieman ennustemallin erottelukykyä kokonaiskuolleisuuden ennustamisessa, mutta samalla systemaattinen harha hieman lisääntyi verrattuna pelkkien kliinisten muuttujien käyttöön. Kolmanneksi verenkierron tulehdusproteiinien roolia painoindeksillä mitatun liikalihavuuden ja erilaisten relevanttien sairauksien syy-seuraussuhteiden välittäjinä arvioitiin. Kolmas osatyö tunnisti kolme painoindeksiin yhteydessä olevaa tulehdusproteiinia. Arvioitaessa näiden tulehdusproteiinien syy-seuraussuhteita eri tulehduksellisiin sairauksiin, nähtiin vain heikkoja yhteyksiä. Yhteenvetona tämä väitöskirjatyö osoittaa erilaisten omiikka-aineistojen soveltamisen hyödyn kardiometabolisiin sairauksiin liittyvien mekanismien tutkimisessa kolmea eri epidemiologista tutkimusasetelmaa hyödyntäen