42 research outputs found
Phenotypic and genetic subtyping of hypertension â toward personalized hypertension care
Current knowledge of phenotypic and genotypic hypertension risk factors has not been effectively translated into personalized hypertension care. The aim of this thesis was to explore hypertension subtyping by applying publicly available supervised and unsupervised subtyping algorithms to large datasets with extensive phenotyping and genotyping.
This thesis included participants from two large Finnish studies: 32,442 from FINRISK and 218,792 from FinnGen. FINRISK is a cross-sectional population survey carried out every five years on risk factors for chronic, non-communicable diseases. FinnGen is a public-private partnership research project combining imputed genotype data from biobanks, patient cohorts, and prospective epidemiological surveys. Because every Finnish citizen is linked to health registers via a personal identity code, accurate follow-up is possible for all major end points, including hypertension and cardiovascular disease. In addition, we used publicly available genome-wide association data from several large-scale studies, including the UK Biobank.
In FINRISK, we observed a phenotypic hypertension subgroup characterized by high blood sugar and elevated body mass index, conferring an increased risk for cardiovascular disease. In a genotyped subset of FINRISK, systolic and diastolic blood pressure polygenic risk scores improved the predictive power of an externally validated clinical hypertension risk equation. Using publicly available genetic association data, we observed four genetic hypertension components corresponding to recognizable clinical features and demonstrated their clinical relevance in FINRISK and FinnGen.
In conclusion, data support the existence of a hyperglycemic hypertension subtype and robust genetic hypertension subtypes. Our findings demonstrate the current ability and future potential of genetics together with methodological development to improve personalized hypertension care.Verenpainetaudin alatyypitys fenotyypin ja genotyypin avulla
NykyistÀ ymmÀrrystÀ verenpainetaudin fenotyypillisistÀ ja geneettisistÀ riskitekijöistÀ ei ole tehokkaasti hyödynnetty verenpainetaudin yksilöllisen hoidon mahdollistamiseksi. TÀmÀn vÀitöskirjatutkimuksen tavoitteena oli tutkia verenpainetaudin alatyypitystÀ soveltamalla julkisesti saatavilla olevia ohjatun ja ohjaamattoman oppimisen algoritmeja suuriin feno- ja genotyypitettyihin tutkimusaineistoihin.
Tutkimuksessa hyödynnettiin osallistujia kahdesta suuresta suomalaisesta tutkimuksesta: 32,442 FINRISKIstÀ ja 218,792 FinnGenistÀ. FINRISKI on viiden vuoden vÀlein toteutettava vÀestötutkimus kroonisten tarttumattomien tautien riski- ja suojatekijöistÀ. FinnGen on julkisen ja yksityisen sektorin yhteinen tutkimushanke joka yhdistÀÀ imputoitua geneettistÀ tietoa biopankeista, potilaskohorteista ja prospektiivisista epidemiologisista tutkimuksista. Koska jokainen Suomen kansalainen on yhdistetty terveydenhuollon rekistereihin henkilötunnuksella, pitkÀaikaisseuranta on mahdollista kaikkien merkittÀvien pÀÀtepisteiden osalta verenpainetauti ja sydÀn- ja verisuonitaudit mukaan lukien. LisÀksi tutkimuksessa hyödynnettiin julkisesti saatavilla olevaa tietoa geneettisistÀ assosiaatioista muun muassa UK Biobank -tutkimuksesta.
FINRISKIssÀ havaittiin fenotyypityksen perusteella verenpainetaudin alatyyppi, jonka erityispiirteitÀ olivat korkea verensokeri ja kohonnut painoindeksi. Alatyyppi oli yhteydessÀ kohonneeseen sydÀn- ja verisuonitautiriskiin. FINRISKIn genotyypitetyssÀ alaryhmÀssÀ osoitettiin, ettÀ systolisen ja diastolisen verenpaineen polygeeniset riskipisteet paransivat verenpainetaudin puhkeamista ennustavan kliinisen riskilaskurin ennustevoimaa. HyödyntÀmÀllÀ julkista tietoa verenpainetaudin geneettisistÀ assosiaatioista havaittiin neljÀ verenpainetaudin geneettistÀ osatekijÀÀ, joiden kliininen merkitys osoitettiin FINRISKIÀ ja FinnGeniÀ apuna kÀyttÀen.
Löydökset viittaavat verenpainetaudin hyperglykeemisen fenotyypin ja usean geneettisen alatyypin olemassaoloon. Genetiikkaa ja menetelmÀoppia yhdistÀmÀllÀ on nyt ja tulevaisuudessa mahdollista parantaa verenpainetaudin yksilöllistÀ hoitoa
VERENPAINETAUDIN GENEETTINEN TAUSTA
Kohonnut verenpaine (verenpainetauti), on yhÀ merkittÀvin yksittÀinen tautitaakan
aiheuttaja ja on vuosittain osallisena noin 11 miljoonan ihmisen kuolemaan. Jopa
puolella 40â79-vuotiaista suomalaisista on verenpainetauti. Verenpainetauti
aiheuttaa haitallisia rakenteellisia ja toiminnallisia muutoksia erityisesti sydÀmessÀ,
aivoissa, verkkokalvossa, munuaisissa ja verisuonissa. Verenpainetaudin hoito
puolestaan vÀhentÀÀ elinvaurioiden syntymistÀ.
Kaksostutkimuksista on ymmÀrretty, ettÀ verenpainetauti on osittain perinnöllinen.
Perhetutkimukset osoittavat, ettÀ jos vanhemmilla tai isovanhemmilla on
verenpainetauti, on lapsellakin kohonnut riski verenpainetautiin ympÀristötekijöistÀ
riippumatta. Sukuanamneesi on siten kÀypÀ työkalu sekÀ yksin ettÀ osana
laajempaa verenpainetaudin riskin arviointia. SillÀ on kuitenkin merkittÀviÀ
heikkouksia: epÀluotettavuus ja muuttuminen ajan kuluessa.
Verenpainetaudin geneettisistÀ riskitekijöistÀ tunnetaan tÀllÀ hetkellÀ noin 20
harvinaista geenivaihtelua ja yli 1400 yleistÀ pistemutaatiota, jotka yhdessÀ selittÀvÀt
verenpaineen vÀestötason vaihtelusta noin 6 %. NÀiden suora mittaus genomia
sekvensoimalla on viime vuosina huomattavasti halventunut. TÀssÀ katsauksessa
perehdytÀÀn verenpainetaudin harvinaisiin ja yleisiin perintötekijöihin, sekÀ
tarkastellaan tulevaisuuden suuntauksia verenpainetaudin genetiikan tutkimuksessa
ja soveltamisessa potilastyöhön
Polygenic Risk Scores Predict Hypertension Onset and Cardiovascular Risk
Although genetic risk scores have been used to predict hypertension, their utility in the clinical setting remains uncertain. Our study comprised N=218 792 FinnGen participants (mean age 58 years, 56% women) and N=22 624 well-phenotyped FINRISK participants (mean age 50 years, 53% women). We used public genome-wide association data to compute polygenic risk scores (PRSs) for systolic and diastolic blood pressure (BP). Using time-to-event analysis, we then assessed (1) the association of BP PRSs with hypertension and cardiovascular disease (CVD) in FinnGen and (2) the improvement in model discrimination when combining BP PRSs with the validated 4- and 10-year clinical risk scores for hypertension and CVD in FINRISK. In FinnGen, compared with having a 20 to 80 percentile range PRS, a PRS in the highest 2.5% conferred 2.3-fold (95% CI, 2.2-2.4) risk of hypertension and 10.6 years (95% CI, 9.9-11.4) earlier hypertension onset. In subgroup analyses, this risk was only 1.6-fold (95% CI, 1.5-1.7) for late-onset hypertension (age >= 55 years) but 2.8-fold (95% CI, 2.6-2.9) for early-onset hypertension (agePeer reviewe
Novel Biomarkers for Diagnosing Periprosthetic Joint Infection from Synovial Fluid and Serum
Background:Synovial fluid bacterial culture is the cornerstone of confirmation or exclusion of periprosthetic joint infection (PJI). The aim of this study was to assess synovial fluid and serum biomarker patterns of patients with total joint arthroplasty (TJA), and the association of these patterns with PJI.Methods:Synovial fluid and serum samples were collected from 35 patients who were admitted to the Arthroplasty Unit of the Department of Orthopaedics and Traumatology at Turku University Hospital. Of the 25 patients who were included in the study, 10 healthy patients with an elective TJA for osteoarthritis served as the control group, and 15 patients who were admitted due to clinical suspicion of PJI with local redness, swelling, wound drainage, pain, and/or fever and who had a positive synovial fluid bacterial culture served as the study group. Logistic regression was used to assess the ability of 37 biomarkers (including cytokines, chemokines, and growth factors) with commercially available tests to detect PJIs.Results:In synovial fluid, the concentrations of sTNF-R1 and sTNF-R2 (soluble tumor necrosis factor receptors 1 and 2) and BAFF (B-cell activating factor, also known as TNFSF13B) were significantly higher in the PJI group (p Conclusions:Synovial sTNF-R2 is a promising new biomarker for detecting PJI. We are not aware of any previous reports of the use of sTNF-R2 in PJI diagnosis. More research is needed to assess the clinical importance of our findings.Level of Evidence:Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence.</p
Systemic Blockade of Clever-1 Elicits Lymphocyte Activation Alongside Checkpoint Molecule Downregulation in Patients with Solid Tumors : Results from a Phase I/II Clinical Trial
Purpose: Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell-targeting therapies. Thus, agents able to reprogram macrophages toward a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of the macrophage scavenger receptor Clever-1 has shown benefit in inducing CD8 T-cell-mediated antitumor responses in mouse models of cancer, which supports the clinical development of Clever-1-targeting antibodies for cancer treatment. Patients and Methods: In this study, we analyzed the mode of action of a humanized IgG4 anti-Clever-1 antibody, FP-1305 (bexmarilimab), both in vitro and in patients with heavily pretreated metastatic cancer (n = 30) participating in part 1 (dose-finding) of a phase I/II open-label trial (NCT03733990). We studied the Clever-1 interactome in primary human macrophages in antibody pull-down assays and utilized mass cytometry, RNA sequencing, and cytokine profiling to evaluate FP-1305-induced systemic immune activation in patients with cancer. Results: Our pull-down assays and functional studies indicated that FP-1305 impaired multiprotein vacuolar ATPase-mediated endosomal acidification and improved the ability of macrophages to activate CD8(+)T-cells. In patients with cancer, FP-1305 administration led to suppression of nuclear lipid signaling pathways and a proinflammatory phenotypic switch in blood monocytes. These effects were accompanied by a significant increase and activation of peripheral T-cells with indications of antitumor responses in some patients. Conclusions: Our results reveal a nonredundant role played by the receptor Clever-1 in suppressing adaptive immune cells in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch, potentially leading to intratumoral proinflammatory responses in patients with metastatic cancer.Peer reviewe
Systemic Blockade of Clever-1 Elicits Lymphocyte Activation Alongside Checkpoint Molecule Downregulation in Patients with Solid Tumors: Results from a Phase I/II Clinical Trial
Purpose:Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cellâtargeting therapies. Thus, agents able to reprogram macrophages toward a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of the macrophage scavenger receptor Clever-1 has shown benefit in inducing CD8+ T-cellâmediated antitumor responses in mouse models of cancer, which supports the clinical development of Clever-1âtargeting antibodies for cancer treatment.Patients and Methods:In this study, we analyzed the mode of action of a humanized IgG4 antiâClever-1 antibody, FP-1305 (bexmarilimab), both in vitro and in patients with heavily pretreated metastatic cancer (n = 30) participating in part 1 (dose-finding) of a phase I/II open-label trial (NCT03733990). We studied the Clever-1 interactome in primary human macrophages in antibody pull-down assays and utilized mass cytometry, RNA sequencing, and cytokine profiling to evaluate FP-1305âinduced systemic immune activation in patients with cancer.Results:Our pull-down assays and functional studies indicated that FP-1305 impaired multiprotein vacuolar ATPaseâmediated endosomal acidification and improved the ability of macrophages to activate CD8+ T-cells. In patients with cancer, FP-1305 administration led to suppression of nuclear lipid signaling pathways and a proinflammatory phenotypic switch in blood monocytes. These effects were accompanied by a significant increase and activation of peripheral T-cells with indications of antitumor responses in some patients.Conclusions:Our results reveal a nonredundant role played by the receptor Clever-1 in suppressing adaptive immune cells in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch, potentially leading to intratumoral</p
The genomics of heart failure: design and rationale of the HERMES consortium
AIMS: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. METHODS AND RESULTS: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34â90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of â„1.10 for common variants (allele frequency â„ 0.05) and â„1.20 for low-frequency variants (allele frequency 0.01â0.05) at P < 5 Ă 10^{-8} under an additive genetic model. CONCLUSIONS: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction
The genomics of heart failure: design and rationale of the HERMES consortium
Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model.Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.Cardiolog
The genomics of heart failure: design and rationale of the HERMES consortium
Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genomeâwide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median followâup following heart failure diagnosis ranged from 2 to 116 months. Fortyânine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34â90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of â„1.10 for common variants (allele frequency â„ 0.05) and â„1.20 for lowâfrequency variants (allele frequency 0.01â0.05) at P < 5 Ă 10â8 under an additive genetic model. Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction