Phenotypic and genetic subtyping of hypertension – 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 Nykyistä ymmärrystä verenpainetaudin fenotyypillisistä ja geneettisistä riskitekijöistä ei ole tehokkaasti hyödynnetty verenpainetaudin yksilöllisen hoidon mahdollistamiseksi. Tämän väitöskirjatutkimuksen tavoitteena oli tutkia verenpainetaudin alatyypitystä soveltamalla julkisesti saatavilla olevia ohjatun ja ohjaamattoman oppimisen algoritmeja suuriin feno- ja genotyypitettyihin tutkimusaineistoihin. Tutkimuksessa hyödynnettiin osallistujia kahdesta suuresta suomalaisesta tutkimuksesta: 32,442 FINRISKIstä ja 218,792 FinnGenistä. FINRISKI on viiden vuoden välein toteutettava väestötutkimus kroonisten tarttumattomien tautien riski- ja suojatekijöistä. FinnGen on julkisen ja yksityisen sektorin yhteinen tutkimushanke joka yhdistää imputoitua geneettistä tietoa biopankeista, potilaskohorteista ja prospektiivisista epidemiologisista tutkimuksista. Koska jokainen Suomen kansalainen on yhdistetty terveydenhuollon rekistereihin henkilötunnuksella, pitkäaikaisseuranta on mahdollista kaikkien merkittävien päätepisteiden osalta verenpainetauti ja sydän- ja verisuonitaudit mukaan lukien. Lisäksi tutkimuksessa hyödynnettiin julkisesti saatavilla olevaa tietoa geneettisistä assosiaatioista muun muassa UK Biobank -tutkimuksesta. FINRISKIssä havaittiin fenotyypityksen perusteella verenpainetaudin alatyyppi, jonka erityispiirteitä olivat korkea verensokeri ja kohonnut painoindeksi. Alatyyppi oli yhteydessä kohonneeseen sydän- ja verisuonitautiriskiin. FINRISKIn genotyypitetyssä alaryhmässä osoitettiin, että systolisen ja diastolisen verenpaineen polygeeniset riskipisteet paransivat verenpainetaudin puhkeamista ennustavan kliinisen riskilaskurin ennustevoimaa. Hyödyntämällä julkista tietoa verenpainetaudin geneettisistä assosiaatioista havaittiin neljä verenpainetaudin geneettistä osatekijää, joiden kliininen merkitys osoitettiin FINRISKIä ja FinnGeniä apuna käyttäen. Löydökset viittaavat verenpainetaudin hyperglykeemisen fenotyypin ja usean geneettisen alatyypin olemassaoloon. Genetiikkaa ja menetelmäoppia yhdistämällä on nyt ja tulevaisuudessa mahdollista parantaa verenpainetaudin yksilöllistä hoitoa

VERENPAINETAUDIN GENEETTINEN TAUSTA

Kohonnut verenpaine (verenpainetauti), on yhä merkittävin yksittäinen tautitaakan aiheuttaja ja on vuosittain osallisena noin 11 miljoonan ihmisen kuolemaan. Jopa puolella 40—79-vuotiaista suomalaisista on verenpainetauti. Verenpainetauti aiheuttaa haitallisia rakenteellisia ja toiminnallisia muutoksia erityisesti sydämessä, aivoissa, verkkokalvossa, munuaisissa ja verisuonissa. Verenpainetaudin hoito puolestaan vähentää elinvaurioiden syntymistä. Kaksostutkimuksista on ymmärretty, että verenpainetauti on osittain perinnöllinen. Perhetutkimukset osoittavat, että jos vanhemmilla tai isovanhemmilla on verenpainetauti, on lapsellakin kohonnut riski verenpainetautiin ympäristötekijöistä riippumatta. Sukuanamneesi on siten käypä työkalu sekä yksin että osana laajempaa verenpainetaudin riskin arviointia. Sillä on kuitenkin merkittäviä heikkouksia: epäluotettavuus ja muuttuminen ajan kuluessa. Verenpainetaudin geneettisistä riskitekijöistä tunnetaan tällä hetkellä noin 20 harvinaista geenivaihtelua ja yli 1400 yleistä pistemutaatiota, jotka yhdessä selittävät verenpaineen väestötason vaihtelusta noin 6 %. Näiden suora mittaus genomia sekvensoimalla on viime vuosina huomattavasti halventunut. Tässä katsauksessa perehdytään verenpainetaudin harvinaisiin ja yleisiin perintötekijöihin, sekä 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-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</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 (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 × 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 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 &lt; 5 × 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