Metabolomics and metagenomics in hypertension

While hypertension has been linked to various modifiable and fixed risk factors, the exact mechanisms behind blood pressure (BP) regulation and hypertension onset remain elusive. The rapid development in scientific branches studying genome, proteome, metabolome, and metagenome, coined collectively as ‘omics’, offer robust methods for studying complex biological phenomena in large population samples. The motivation of the current study was to assess the relation of the metabolome and metagenome with high BP in large Finnish cohorts. The specific aims were to estimate the association between gut microbiota and hypertension, to study the plasma metabolic profile of hypertension, and to elucidate if a family of circulating polyunsaturated fatty acid derived small molecule regulators of systemic inflammation, eicosanoids, are associated with BP. This and previous population studies demonstrate that gut microbiota is associated with human hypertension. Biologically reasonable pathophysiological mechanisms, including ones related to sodium intake, have been proposed to explain the phenomenon. However, the significance of these effects on population BP and health remains unclear and warrants further research. In this thesis, we demonstrate a strong association between circulating eicosanoids and BP in humans. We also use conventional statistical methods and multivariable machine learning models to define a metabolic profile of hypertension and blood pressure change using high abundance serum metabolic measures. Our results suggest that particularly serum lipids, and particularly low density lipoprotein-derived and very low density lipoprotein-derived cholesterol measures, and glucose metabolism abnormalities are associated with hypertension onset. Our studies improve the current knowledge on the associations of gut microbiota and circulating metabolites with BP. Metabolomics and metagenomics offer novel approaches to improve hypertension risk prediction and to discover potential targets for therapeutic intervention of elevated BP.Verenpainetaudin metabolomiikka ja metagenomiikka Verenpainetaudin ilmaantuminen on yhteydessä lukuisiin riskitekijöihin, joista osaan voimme vaikuttaa elintavoilla ja joista osa on synnynnäisiä. Tästä huolimatta ymmärryksemme verenpainetaudin synnystä on vielä puutteellinen. Viime vuosina tutkijoiden käyttöön on tullut laaja joukko uusia biomolekyylien tutkimusmenetelmiä, joita kutsutaan yhteisnimellä ’omiikat’. Tämän kehityksen myötä myös suurten kansallisten tutkimusaineistojen analysointi on muuttunut kustannustehokkaaksi. Väitöskirjani keskeisenä tutkimuskysymyksenä oli selvittää, tarjoavatko nämä biomolekyylien tutkimusmenetelmät uutta tietoa kohonneesta verenpaineesta suurissa suomalaisissa väestöaineistoissa. Väitöskirjani ensimmäisessä osassa tutkimme suolistobakteerien yhteyttä verenpainetautiin ja ravinnon suolaan. Väitöskirjani toisessa osassa tutkimme verenkierron aineenvaihduntatuotteiden yhteyttä verenpainetautiin. Tuloksemme yhdessä aikaisemman tutkimustiedon kanssa tukee käsitystä, että verenpaineen ja suolistobakteerien välillä on yhteys. Kykenemme myös jo kertyneen tiedon valossa esittämään hypoteeseja yhteyden tautiopillisesta perustasta. Erityisesti ravinnon suola vaikuttaa isäntälajin lisäksi myös suolistobakteerien elinolosuhteisiin. Emme kuitenkaan vielä kykene arvioimaan, onko suolistobakteerien ja verenpaineen välisellä yhteydellä kansanterveystieteellistä merkitystä, mutta odotamme tulevaisuuden tutkimusten vielä tuovan tähän kyymykseen vastauksen. Väitöskirjani jälkimmäinen puoli tukee verenkierrossa kulkevien pienten rasvaliukoisten tulehdusvälittäjäaineiden, eikosanoidien, yhteyttä verenpainetautiin. Tutkimme myös sekä perinteisiä tilastollisia menetelmiä että koneoppimismalleja käyttäen seerumin aineenvaihduntatuotteiden profiilia verenpainetaudissa. Tulostemme perusteella seerumin rasva- ja sokeriaineenvaihdunnan häiriöt, erityisesti korkea LDL- ja VLDL-kolesteroli, kytkeytyvät verenpainetaudin ilmaantuvuuteen. Väitöskirjani tuotti uutta tieteellistä tietoa suolistobakteerien ja verenkierron aineenvaihduntatuotteiden yhteydestä verenpainetautiin. Metabolomiikka ja metagenomiikka tarjoavat joukon tehokkaita uusia menetelmiä tutkimukselle, jonka tavoitteena on korkean verenpaineen ehkäiseminen tai hoitaminen

Kohonneen verenpaineen hoidonohjausjärjestelmä

Kohonnut verenpaine on monille sairauksille ja jopa äkkikuolemalle altistava riskitekijä, jonka hoito on tärkeää. Kohonneen verenpaineen tehokas hoito on nykytiedon valossa mahdollista, mutta silti Terveys 2011 -tutkimuksen mukaan kohonnutta verenpainetta sairastavista suomalaisista miehistä vain 50 % ja naisista vain 56 % on hoitotavoitteessa. Tilannetta ei ole kyetty parantamaan pelkästään ohjeita lisäämällä. Tietokoneella toteutettua Käypä hoito -suositukseen perustuvaa verenpainepotilaan hoidossa avustavaa päätöksenteon tukijärjestelmää voitaisiin käyttää toisaalta potilashoidon yhtenäistämisessä ja toisaalta yksilöllisesti räätälöidyn optimaalisen hoidon tarjoamiseksi potilaille. Tässä opinnäytetyössä esitellään kohonnut verenpaine merkittävänä terveitä elin- vuosia uhkaavana riskitekijänä ja sen hoitoon käytetyt keskeiset menetelmät. Veren- painepotilaan hoito perustuu elintapaohjaukseen ja lääkehoitoon, jossa käytetään useaan eri vaikutusmekanismiin perustuvaa verenpainelääkkeiden yhdistelmähoitoa. Suolan käytön vähentäminen, liikunnan lisääminen, tupakoinnin lopettaminen ja ylipainon laskeminen ovat tehokkaita tapoja laskea verenpainetta ja niitä tulisikin siksi käyttää. Pieniannoksinen yhdistelmähoito puolestaan tarjoaa potilaalle hyvää lääketehoa vähäisin haittavaikutuksin. Hoidonohjausjärjestelmä on potilashoidossa alikäytetty tietotekninen apuväline, jo- ka potilaasta tunnettua tietoa käsittelemällä kykenee tarjoamaan terveydenhuollon ammattilaiselle yksilöllisen suosituksen potilaan hoidosta. Suomessa kohonneen veren- paineen hoito pohjautuu Käypä hoito -suosituksiin ja kansainvälisissä sovelluksissa on käytettävissä vastaavia alueellisia hoitosuosituksia. Opinnäytetyö kuvailee Turun yli- opiston ja Terveyden ja hyvinvoinnin laitoksen yhteistyössä toteuttaman Kohonneen verenpaineen hoidonohjausjärjestelmän suunnittelun ja toteutuksen. Työssä kuvailtu- ja ideoita ja menetelmiä käyttäen on mahdollista laajentaa hoidonohjausjärjestelmää kohonneesta verenpaineesta myös muiden kansantautien, kuten diabeteksen hoitoon.Siirretty Doriast

Targeting Gut Microbiota to Treat Hypertension: A Systematic Review

While hypertension remains the leading modifiable risk factor for cardiovascular morbidity and mortality, the pathogenesis of essential hypertension remains only partially understood. Recently, microbial dysbiosis has been associated with multiple chronic diseases closely related to hypertension. In addition, multiple small-scale animal and human studies have provided promising results for the association between gut microbial dysbiosis and hypertension. Animal models and a small human pilot study, have demonstrated that high salt intake, a risk factor for both hypertension and cardiovascular disease, depletes certain Lactobacillus species while oral treatment of Lactobacilli prevented salt-sensitive hypertension. To date, four large cohort studies have reported modest associations between gut microbiota features and hypertension. In this systematic literature review, we examine the previously reported links between the gut microbiota and hypertension and what is known about the functional mechanisms behind this association

Predictors and Outcomes of Coronary Artery Bypass Grafting: A Systematic and Untargeted Analysis of More Than 120,000 Individuals and 1,300 Disease Traits

Objective: To perform an untargeted data-driven analysis on the correlates and outcomes of coronary artery bypass grafting (CABG).Design: FinnGen cohort study.Setting: The authors collected information on up to 1,327 disease traits before and after CABG from nationwide healthcare registers.Participants: A mixed population and patient sample of 127,911 individuals including 3,784 CABG patients.Interventions: The authors assessed the association between (1) traits and incident CABG and (2) CABG and incident traits using multivariate-adjusted Cox models.Main results: Patients who underwent CABG and were in the fourth quartile of a risk score based on the top predictors of mortality had 12.2-fold increased risk of dying (95% confidence interval [CI], 10.3-14.5) compared with those in the first quartile. Cardiovascular disease (CVD) and CVD risk factors were most strongly associated with incident CABG. However, CABG was associated with death due to cardiac causes (hazard ratio [HR], 3.7; 95% CI, 3.5-4.0) or other causes (HR, 2.5; 95% CI, 2.4-2.7). CABG also was related to increased risk of several non-CVD traits, including anemia (HR, 3.4; 95% CI, 2.8-4.1), gastrointestinal disorders (HR, 2.2; 95% CI, 1.8-2.6), acute renal failure (HR, 4.2; 95% CI, 3.5-5.1), septicemia (HR, 3.6; 95% CI, 3.1-4.1), lung cancer (HR, 2.3; 95% CI, 1.9-2.8), Alzheimer's disease (HR, 2.5; 95% CI, 2.2-2.7), and chronic obstuctive pulmonary disease (HR, 2.5; 95% CI, 2.2-2.9).Conclusions: Known CVD risk factors associate most strongly with incident CABG. However, CABG is associated with increased risk of several, somewhat unexpected, non-CVD traits. More detailed study of these links is warranted to establish potential causality and pathogenesis.</p

Comprehensive biomarker profiling of hypertension in 36 985 Finnish individuals

Objective: Previous studies on the association between metabolic biomarkers and hypertension have been limited by small sample sizes, low number of studied biomarkers, and cross-sectional study design. In the largest study to date, we assess the cross-sectional and longitudinal associations between high-abundance serum biomarkers and blood pressure (BP). Methods: We studied cross-sectional (N = 36 985; age 50.5 +/- 14.2; 53.1% women) and longitudinal (N = 4197; age 49.4 +/- 11.8, 55.3% women) population samples of Finnish individuals. We included 53 serum biomarkers and other detailed lipoprotein subclass measures in our analyses. We studied the associations between serum biomarkers and BP using both conventional statistical methods and a machine learning algorithm (gradient boosting) while adjusting for clinical risk factors. Results: Fifty-one of 53 serum biomarkers were cross-sectionally related to BP (adjusted P < 0.05 for all). Conventional linear regression modeling demonstrated that LDL cholesterol, remnant cholesterol, apolipoprotein B, and acetate were positively, and HDL particle size was negatively, associated with SBP change over time (adjusted P < 0.05 for all). Adding serum biomarkers (cross-sectional root-mean-square error: 16.27 mmHg; longitudinal: 17.61 mmHg) in the model with clinical measures (cross-sectional: 16.70 mmHg; longitudinal 18.52 mmHg) improved the machine learning model fit. Glucose, albumin, triglycerides in LDL, glycerol, VLDL particle size, and acetoacetate had the highest importance scores in models related to current or future BP. Conclusion: Our results suggest that serum lipids, and particularly LDL-derived and VLDL-derived cholesterol measures, and glucose metabolism abnormalities are associated with hypertension onset. Use of serum metabolite determination could improve identification of individuals at high risk of developing hypertension.Peer reviewe

A plasma metabolite score of three eicosanoids predicts incident type 2 diabetes : a prospective study in three independent cohorts

Introduction Peptide markers of inflammation have been associated with the development of type 2 diabetes. The role of upstream, lipid-derived mediators of inflammation such as eicosanoids, remains less clear. The aim of this study was to examine whether eicosanoids are associated with incident type 2 diabetes. Research design & methods In the FINRISK (Finnish Cardiovascular Risk Study) 2002 study, a population-based sample of Finnish men and women aged 25-74 years, we used directed, non-targeted liquid chromatography-mass spectrometry to identify 545 eicosanoids and related oxylipins in the participants' plasma samples (n=8292). We used multivariable-adjusted Cox regression to examine associations between eicosanoids and incident type 2 diabetes. The significant independent findings were replicated in the Framingham Heart Study (FHS, n=2886) and Dietary, Lifestyle and Genetic determinants of Obesity and Metabolic syndrome (DILGOM) 2007 (n=3905). Together, these three cohorts had 1070 cases of incident type 2 diabetes. Results In the FINRISK 2002 cohort, 76 eicosanoids were associated individually with incident type 2 diabetes. We identified three eicosanoids independently associated with incident type 2 diabetes using stepwise Cox regression with forward selection and a Bonferroni-corrected inclusion threshold. A three-eicosanoid risk score produced an HR of 1.56 (95% CI 1.41 to 1.72) per 1 SD increment for risk of incident diabetes. The HR for comparing the top quartile with the lowest was 2.80 (95% CI 2.53 to 3.07). In the replication analyses, the three-eicosanoid risk score was significant in FHS (HR 1.24 (95% CI 1.10 to 1.39, p Conclusions Plasma eicosanoid profiles predict incident type 2 diabetes and the clearest signals replicate in three independent cohorts. Our findings give new information on the biology underlying type 2 diabetes and suggest opportunities for early identification of people at risk.Peer reviewe

Association Between the Gut Microbiota and Blood Pressure in a Population Cohort of 6953 Individuals

Background Several small-scale animal studies have suggested that gut microbiota and blood pressure (BP) are linked. However, results from human studies remain scarce and conflicting. We wanted to elucidate the multivariable-adjusted association between gut metagenome and BP in a large, representative, well-phenotyped population sample. We performed a focused analysis to examine the previously reported inverse associations between sodium intake and Lactobacillus abundance and between Lactobacillus abundance and BP. Methods and Results We studied a population sample of 6953 Finns aged 25 to 74 years (mean age, 49.212.9 years; 54.9% women). The participants underwent a health examination, which included BP measurement, stool collection, and 24-hour urine sampling (N=829). Gut microbiota was analyzed using shallow shotgun metagenome sequencing. In age- and sex-adjusted models, the alpha (within-sample) and beta (between-sample) diversities of taxonomic composition were strongly related to BP indexes (P diversity was only associated with diastolic BP (P=0.032). However, we observed significant, mainly positive, associations between BP indexes and 45 microbial genera (P Conclusions Although the associations between overall gut taxonomic composition and BP are weak, individuals with hypertension demonstrate changes in several genera. We demonstrate strong negative associations of certain Lactobacillus species with sodium intake and BP, highlighting the need for experimental studies.Peer reviewe