Publications by authors named "Veikko Salomaa"

601 Publications

Risk factors for major adverse cardiovascular events after the first acute coronary syndrome.

Ann Med 2021 12;53(1):817-823

Finnish Institute for Health and Welfare, Helsinki, Finland.

Aims: To evaluate risk factors for major adverse cardiac event (MACE) after the first acute coronary syndrome (ACS) and to examine the prevalence of risk factors in post-ACS patients.

Methods: We used Finnish population-based myocardial infarction register, FINAMI, data from years 1993-2011 to identify survivors of first ACS ( = 12686), who were then followed up for recurrent events and all-cause mortality for three years. Finnish FINRISK risk factor surveys were used to determine the prevalence of risk factors (smoking, hyperlipidaemia, diabetes and blood pressure) in post-ACS patients ( = 199).

Results: Of the first ACS survivors, 48.4% had MACE within three years of their primary event, 17.0% were fatal. Diabetes (p = 4.4 × 10), heart failure (HF) during the first ACS attack hospitalization (p = 6.8 × 10), higher Charlson index (p = 1.56 × 10) and older age ( = .026) were associated with elevated risk for MACE in the three-year follow-up, and revascularization ( = .0036) was associated with reduced risk. Risk factor analyses showed that 23% of ACS survivors continued smoking and cholesterol levels were still high (>5mmol/l) in 24% although 86% of the patients were taking lipid lowering medication.

Conclusion: Diabetes, higher Charlson index and HF are the most important risk factors of MACE after the first ACS. Cardiovascular risk factor levels were still high among survivors of first ACS.
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http://dx.doi.org/10.1080/07853890.2021.1924395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183550PMC
December 2021

Roles of allostatic load, lifestyle and clinical risk factors in mediating the association between education and coronary heart disease risk in Europe.

J Epidemiol Community Health 2021 May 28. Epub 2021 May 28.

Centre for Public Health, Queen's University Belfast, Belfast, UK.

Background: Previous studies have shown that differential exposure to lifestyle factors may mediate the association between education and coronary heart diseases (CHD). However, few studies have examined the potential roles of allostatic load (AL) or differential susceptibility.

Methods: 25 310 men and 26 018 women aged 35-74 and CHD free at baseline were identified from 21 European cohorts and followed for a median of 10 years, to investigate the mediating role of AL, as well as of smoking, alcohol use and body mass index (BMI), on educational differences in CHD incidence, applying marginal structural models and three-way decomposition.

Results: AL is a mediator of the association between educational status and CHD incidence, with the highest proportion mediated observed among women and largely attributable to differential exposure, (28% (95% CI 19% to 44%)), with 8% (95% CI 0% to 16%) attributable to differential susceptibility. The mediating effects of smoking, alcohol and BMI, compared with AL, were relatively small for both men and women.

Conclusion: Overall, the educational inequalities in CHD incidence were partially mediated through differential exposure to AL. By contrast, the mediation of the educational gradient in CHD by investigated lifestyle risk factors was limited. As differential susceptibility in men was found to have a predominant role in the accumulation of AL in low educational classes, the investigation of AL-related risk factors is warranted.
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http://dx.doi.org/10.1136/jech-2020-215394DOI Listing
May 2021

Associations of healthy food choices with gut microbiota profiles.

Am J Clin Nutr 2021 May 21. Epub 2021 May 21.

Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.

Background: Diet has a major influence on the human gut microbiota, which has been linked to health and disease. However, epidemiological studies on associations of a healthy diet with the microbiota utilizing a whole-diet approach are still scant.

Objectives: To assess associations between healthy food choices and human gut microbiota composition, and to determine the strength of association with functional potential.

Methods: This population-based study sample consisted of 4930 participants (ages 25-74; 53% women) in the FINRISK 2002 study. Intakes of recommended foods were assessed using a food propensity questionnaire, and responses were transformed into healthy food choices (HFC) scores. Microbial diversity (alpha diversity) and compositional differences (beta diversity) and their associations with the HFC score and its components were assessed using linear regression. Multiple permutational multivariate ANOVAs were run from whole-metagenome shallow shotgun-sequenced samples. Associations between specific taxa and HFC were analyzed using linear regression. Functional associations were derived from Kyoto Encyclopedia of Genes and Genomes orthologies with linear regression models.

Results: Both microbial alpha diversity (β/SD, 0.044; SE, 6.18 × 10-5; P = 2.21 × 10-3) and beta diversity (R2, 0.12; P ≤ 1.00 × 10-3) were associated with the HFC score. For alpha diversity, the strongest associations were observed for fiber-rich breads, poultry, fruits, and low-fat cheeses (all positive). For beta diversity, the most prominent associations were observed for vegetables, followed by berries and fruits. Genera with fiber-degrading and SCFA-producing capacities were positively associated with the HFC score. The HFC score was associated positively with functions such as SCFA metabolism and synthesis, and inversely with functions such as fatty acid biosynthesis and the sulfur relay system.

Conclusions: Our results from a large, population-based survey confirm and extend findings of other, smaller-scale studies that plant- and fiber-rich dietary choices are associated with a more diverse and compositionally distinct microbiota, and with a greater potential to produce SCFAs.
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http://dx.doi.org/10.1093/ajcn/nqab077DOI Listing
May 2021

Taxonomic signatures of cause-specific mortality risk in human gut microbiome.

Nat Commun 2021 05 11;12(1):2671. Epub 2021 May 11.

Division of Medicine, Turku University Hospital and University of Turku, Turku, Finland.

The collection of fecal material and developments in sequencing technologies have enabled standardised and non-invasive gut microbiome profiling. Microbiome composition from several large cohorts have been cross-sectionally linked to various lifestyle factors and diseases. In spite of these advances, prospective associations between microbiome composition and health have remained uncharacterised due to the lack of sufficiently large and representative population cohorts with comprehensive follow-up data. Here, we analyse the long-term association between gut microbiome variation and mortality in a well-phenotyped and representative population cohort from Finland (n = 7211). We report robust taxonomic and functional microbiome signatures related to the Enterobacteriaceae family that are associated with mortality risk during a 15-year follow-up. Our results extend previous cross-sectional studies, and help to establish the basis for examining long-term associations between human gut microbiome composition, incident outcomes, and general health status.
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http://dx.doi.org/10.1038/s41467-021-22962-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113604PMC
May 2021

Low testosterone concentrations and prediction of future heart failure in men and in women: evidence from the large FINRISK97 study.

ESC Heart Fail 2021 May 2. Epub 2021 May 2.

Department for Cardiology, University Heart & Vascular Center Hamburg, Hamburg, Germany.

Aims: The increased incidence of heart failure in men suggests that endogenous sex hormones might play a role in the development of heart failure, but epidemiological data remain sparse. Here, we evaluated the predictive value of low testosterone levels on future heart failure in the large population-based FINRISK97 study.

Methods And Results: Baseline serum testosterone concentrations were measured in 7855 subjects (3865 men and 3990 women) of the FINRISK97 study. During a median follow-up (FU) of 13.8 years, a total of 564 heart failure events were recorded. The age-adjusted baseline testosterone levels did not differ significantly between subjects developing incident heart failure during FU and those without incident events during FU (men: 16.6 vs. 17.1 nmol/L, P = 0.75; women: 1.15 vs. 1.17 nmol/L, P = 0.32). Relevant statistically significant correlations of testosterone levels were found with high-density lipoprotein cholesterol levels (R = 0.22; P < 0.001), body mass index (R = -0.23; P < 0.001), and waist-to-hip ratio (R = -0.21; P < 0.001) in men, while statistically significant correlations in women were negligible in effect size. In sex-stratified Cox regression analyses, taking age into account, a quite strong association between low testosterone and incident heart failure was found in men [hazard ratio (HR) 1.51 (95% confidence interval, CI: 1.09-2.10); P = 0.020 for lowest vs. highest quarter], but not in women [HR 0.70 (95% CI: 0.49-0.98); P = 0.086 for lowest vs. highest quarter]. Nevertheless, this association turned non-significant after full adjustment including body mass index and waist-to-hip ratio, and testosterone levels were no longer predictive for incident heart failure-neither in men [HR 0.99 (95% CI: 0.70-1.42); P = 0.77 for lowest vs. highest quarter] nor in women [HR 0.92 (95% CI: 0.64-1.33); P = 0.99 for lowest vs. highest quarter]. Accordingly, Kaplan-Meier analyses did not reveal significant association of testosterone levels with heart failure.

Conclusions: Low levels of testosterone do not independently predict future heart failure.
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http://dx.doi.org/10.1002/ehf2.13384DOI Listing
May 2021

ANGPTL8 protein-truncating variant associated with lower serum triglycerides and risk of coronary disease.

PLoS Genet 2021 Apr 28;17(4):e1009501. Epub 2021 Apr 28.

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.

Protein-truncating variants (PTVs) affecting dyslipidemia risk may point to therapeutic targets for cardiometabolic disease. Our objective was to identify PTVs that were associated with both lipid levels and the risk of coronary artery disease (CAD) or type 2 diabetes (T2D) and assess their possible associations with risks of other diseases. To achieve this aim, we leveraged the enrichment of PTVs in the Finnish population and tested the association of low-frequency PTVs in 1,209 genes with serum lipid levels in the Finrisk Study (n = 23,435). We then tested which of the lipid-associated PTVs were also associated with the risks of T2D or CAD, as well as 2,683 disease endpoints curated in the FinnGen Study (n = 218,792). Two PTVs were associated with both lipid levels and the risk of CAD or T2D: triglyceride-lowering variants in ANGPTL8 (-24.0[-30.4 to -16.9] mg/dL per rs760351239-T allele, P = 3.4 × 10-9) and ANGPTL4 (-14.4[-18.6 to -9.8] mg/dL per rs746226153-G allele, P = 4.3 × 10-9). The risk of T2D was lower in carriers of the ANGPTL4 PTV (OR = 0.70[0.60-0.81], P = 2.2 × 10-6) than noncarriers. The odds of CAD were 47% lower in carriers of a PTV in ANGPTL8 (OR = 0.53[0.37-0.76], P = 4.5 × 10-4) than noncarriers. Finally, the phenome-wide scan of the ANGPTL8 PTV showed that the ANGPTL8 PTV carriers were less likely to use statin therapy (68,782 cases, OR = 0.52[0.40-0.68], P = 1.7 × 10-6) compared to noncarriers. Our findings provide genetic evidence of potential long-term efficacy and safety of therapeutic targeting of dyslipidemias.
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http://dx.doi.org/10.1371/journal.pgen.1009501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109807PMC
April 2021

Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies.

Lancet Neurol 2021 05 25;20(5):351-361. Epub 2021 Mar 25.

Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

Background: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease.

Methods: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation.

Findings: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke.

Interpretation: Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk.

Funding: British Heart Foundation.
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http://dx.doi.org/10.1016/S1474-4422(21)00031-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062914PMC
May 2021

HDL-Mediated Cholesterol Efflux Associates with Incident Kidney Disease.

Clin Chem 2021 Mar;67(4):689-691

Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.

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http://dx.doi.org/10.1093/clinchem/hvab024DOI Listing
March 2021

Changes in the fine-scale genetic structure of Finland through the 20th century.

PLoS Genet 2021 Mar 4;17(3):e1009347. Epub 2021 Mar 4.

Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.

Information about individual-level genetic ancestry is central to population genetics, forensics and genomic medicine. So far, studies have typically considered genetic ancestry on a broad continental level, and there is much less understanding of how more detailed genetic ancestry profiles can be generated and how accurate and reliable they are. Here, we assess these questions by developing a framework for individual-level ancestry estimation within a single European country, Finland, and we apply the framework to track changes in the fine-scale genetic structure throughout the 20th century. We estimate the genetic ancestry for 18,463 individuals from the National FINRISK Study with respect to up to 10 genetically and geographically motivated Finnish reference groups and illustrate the annual changes in the fine-scale genetic structure over the decades from 1920s to 1980s for 12 geographic regions of Finland. We detected major changes after a sudden, internal migration related to World War II from the region of ceded Karelia to the other parts of the country as well as the effect of urbanization starting from the 1950s. We also show that while the level of genetic heterogeneity in general increases towards the present day, its rate of change has considerable differences between the regions. To our knowledge, this is the first study that estimates annual changes in the fine-scale ancestry profiles within a relatively homogeneous European country and demonstrates how such information captures a detailed spatial and temporal history of a population. We provide an interactive website for the general public to examine our results.
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http://dx.doi.org/10.1371/journal.pgen.1009347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932171PMC
March 2021

Links between gut microbiome composition and fatty liver disease in a large population sample.

Gut Microbes 2021 Jan-Dec;13(1):1-22

Department of Internal Medicine, University of Turku, Turku, Finland.

Fatty liver disease is the most common liver disease in the world. Its connection with the gut microbiome has been known for at least 80 y, but this association remains mostly unstudied in the general population because of underdiagnosis and small sample sizes. To address this knowledge gap, we studied the link between the Fatty Liver Index (FLI), a well-established proxy for fatty liver disease, and gut microbiome composition in a representative, ethnically homogeneous population sample of 6,269 Finnish participants. We based our models on biometric covariates and gut microbiome compositions from shallow metagenome sequencing. Our classification models could discriminate between individuals with a high FLI (≥60, indicates likely liver steatosis) and low FLI (<60) in internal cross-region validation, consisting of 30% of the data not used in model training, with an average AUC of 0.75 and AUPRC of 0.56 (baseline at 0.30). In addition to age and sex, our models included differences in 11 microbial groups from class , mostly belonging to orders and . Our models were also predictive of the high FLI group in a different Finnish cohort, consisting of 258 participants, with an average AUC of 0.77 and AUPRC of 0.51 (baseline at 0.21). Pathway analysis of representative genomes of the positively FLI-associated taxa in (NCBI) subclusters IV and XIVa indicated the presence of, e.g., ethanol fermentation pathways. These results support several findings from smaller case-control studies, such as the role of endogenous ethanol producers in the development of the fatty liver.
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http://dx.doi.org/10.1080/19490976.2021.1888673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928040PMC
March 2021

Polygenic Risk Scores Predict Hypertension Onset and Cardiovascular Risk.

Hypertension 2021 Apr 22;77(4):1119-1127. Epub 2021 Feb 22.

From the Department of Internal Medicine, University of Turku, Finland (F.V., A.K., K.S., T.N.).

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025831PMC
April 2021

Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants.

Mol Psychiatry 2021 Feb 1. Epub 2021 Feb 1.

Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.

Copy number variants (CNVs) are associated with syndromic and severe neurological and psychiatric disorders (SNPDs), such as intellectual disability, epilepsy, schizophrenia, and bipolar disorder. Although considered high-impact, CNVs are also observed in the general population. This presents a diagnostic challenge in evaluating their clinical significance. To estimate the phenotypic differences between CNV carriers and non-carriers regarding general health and well-being, we compared the impact of SNPD-associated CNVs on health, cognition, and socioeconomic phenotypes to the impact of three genome-wide polygenic risk score (PRS) in two Finnish cohorts (FINRISK, n = 23,053 and NFBC1966, n = 4895). The focus was on CNV carriers and PRS extremes who do not have an SNPD diagnosis. We identified high-risk CNVs (DECIPHER CNVs, risk gene deletions, or large [>1 Mb] CNVs) in 744 study participants (2.66%), 36 (4.8%) of whom had a diagnosed SNPD. In the remaining 708 unaffected carriers, we observed lower educational attainment (EA; OR = 0.77 [95% CI 0.66-0.89]) and lower household income (OR = 0.77 [0.66-0.89]). Income-associated CNVs also lowered household income (OR = 0.50 [0.38-0.66]), and CNVs with medical consequences lowered subjective health (OR = 0.48 [0.32-0.72]). The impact of PRSs was broader. At the lowest extreme of PRS for EA, we observed lower EA (OR = 0.31 [0.26-0.37]), lower-income (OR = 0.66 [0.57-0.77]), lower subjective health (OR = 0.72 [0.61-0.83]), and increased mortality (Cox's HR = 1.55 [1.21-1.98]). PRS for intelligence had a similar impact, whereas PRS for schizophrenia did not affect these traits. We conclude that the majority of working-age individuals carrying high-risk CNVs without SNPD diagnosis have a modest impact on morbidity and mortality, as well as the limited impact on income and educational attainment, compared to individuals at the extreme end of common genetic variation. Our findings highlight that the contribution of traditional high-risk variants such as CNVs should be analyzed in a broader genetic context, rather than evaluated in isolation.
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http://dx.doi.org/10.1038/s41380-021-01026-zDOI Listing
February 2021

The Role of Inflammatory Cytokines as Intermediates in the Pathway from Increased Adiposity to Disease.

Obesity (Silver Spring) 2021 02;29(2):428-437

MRC Integrative Epidemiology Unit at University of Bristol, Bristol, UK.

Objective: This study aimed to investigate the role of cytokines as intermediates in the pathway from increased adiposity to disease.

Methods: BMI and circulating levels of up to 41 cytokines were measured in individuals from three Finnish cohort studies (n = 8,293). Mendelian randomization (MR) was used to assess the impact of BMI on circulating cytokines and the impact of BMI-driven cytokines on risk of obesity-related diseases.

Results: Observationally, BMI was associated with 19 cytokines. For every SD increase in BMI, causal effect estimates were strongest for hepatocyte growth factor, monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and were as ratios of geometric means 1.13 (95% CI: 1.08-1.19), 1.08 (95% CI: 1.04-1.14), and 1.13 (95% CI: 1.04-1.21), respectively. TRAIL was associated with a small increase in the odds of coronary artery disease (odds ratio: 1.03; 95% CI: 1.00-1.06). There was inconsistent evidence for a protective role of MCP-1 against inflammatory bowel diseases.

Conclusions: Observational and MR estimates of the effect of BMI on cytokine levels were generally concordant. There was little evidence for an effect of raised levels of BMI-driven cytokines on disease. These findings illustrate the challenges of MR when applied in the context of molecular mediation.
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http://dx.doi.org/10.1002/oby.23060DOI Listing
February 2021

Low serum vitamin D level associated with incident advanced liver disease in the general population - a prospective study.

Scand J Gastroenterol 2021 Mar 21;56(3):299-303. Epub 2021 Jan 21.

Transplantation and Liver Surgery Clinic, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Background: Vitamin D deficiency is a common finding in chronic liver disease. It has also been linked to the pathogenesis of non-alcoholic fatty liver disease, hepatic fibrogenesis, decompensation and hepatocellular carcinoma.

Aims: We analyzed whether serum vitamin D is associated with incident advanced liver disease in the general population.

Methods: Serum 25-hydroxyvitamin D was measured in 13807 individuals participating in the Finnish population-based health examination surveys FINRISK 1997 and Health 2000. Data were linked with incident advanced liver disease (hospitalization, cancer or death related to liver disease). During a follow-up of 201444 person-years 148 severe liver events occurred. Analyses were performed using multivariable Cox regression analyses.

Results: Vitamin D level associated with incident advanced liver disease with the hazard ratio of 0.972 (95% confidence interval 0.943-0.976,  < .001), when adjusted for age, sex, blood sampling season and stratified by cohort.The association remained robust and significant in multiple different adjustment models adjusting sequentially for 22 potential confounders.

Conclusion: Low vitamin D level is linked to incident advanced liver disease at population level.
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http://dx.doi.org/10.1080/00365521.2021.1873412DOI Listing
March 2021

Unsupervised hierarchical clustering identifies a metabolically challenged subgroup of hypertensive individuals.

J Clin Hypertens (Greenwich) 2020 09 16;22(9):1546-1553. Epub 2020 Aug 16.

Department of Medicine, University of Turku, Turku, Finland.

The current classification of hypertension does not reflect the heterogeneity in characteristics or cardiovascular outcomes of hypertensive individuals. Our objective was to identify distinct phenotypes of hypertensive individuals with potentially different cardiovascular risk profiles using data-driven cluster analysis. We performed clustering, a procedure that identifies groups with similar characteristics, in 3726 individuals (mean age 59.4 years, 49% women) with grade 2 hypertension (blood pressure ≥160/100 mmHg or antihypertensive medication) selected from FINRISK 1997, 2002, and 2007 cohorts. We computed clusters based on eight factors associated with hypertension: mean arterial pressure, pulse pressure, non-high-density lipoprotein cholesterol, blood glucose, BMI, C-reactive protein, estimated glomerular filtration rate, and alcohol. After that, we used Cox regression models adjusted for age and sex to assess the relative risk of cardiovascular disease (CVD) outcomes between the clusters and a reference group of 11 020 individuals. We observed two comparable clusters in both men and women. The Metabolically Challenged (MC) cluster was characterized by high blood glucose (Z-score 4.4 ± 1.1 vs 0.2 ± 0.8, men; 3.5 ± 1.1 vs 0.0 ± 0.6, women) and elevated BMI (30.4 ± 4.1 vs 28.9 ± 4.3, men; 32.7 ± 4.9 vs 29.3 ± 5.5, women). Over a 10-year follow-up (1034 CVD events), MC had 1.6-fold (95% CI 1.1-2.4) CVD risk compared to non-MC and 2.5-fold (95% CI 1.7-3.7) CVD risk compared to the reference group (P ≤ .009 for both). Using unsupervised hierarchical clustering, we found two phenotypically distinct hypertension subgroups with different risks of CVD complications. This substratification could be used to design studies that explore the differential effects of antihypertensive therapies among subgroups of hypertensive individuals.
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http://dx.doi.org/10.1111/jch.13984DOI Listing
September 2020

Risk prediction of atrial fibrillation in the community combining biomarkers and genetics.

Europace 2021 May;23(5):674-681

Department of Cardiology, University Heart and Vascular Centre Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.

Aims: Classical cardiovascular risk factors (CVRFs), biomarkers, and common genetic variation have been suggested for risk assessment of atrial fibrillation (AF). To evaluate their clinical potential, we analysed their individual and combined ability of AF prediction.

Methods And Results: In N = 6945 individuals of the FINRISK 1997 cohort, we assessed the predictive value of CVRF, N-terminal pro B-type natriuretic peptide (NT-proBNP), and 145 recently identified single-nucleotide polymorphisms (SNPs) combined in a developed polygenic risk score (PRS) for incident AF. Over a median follow-up of 17.8 years, n = 551 participants (7.9%) developed AF. In multivariable-adjusted Cox proportional hazard models, NT-proBNP [hazard ratio (HR) of log transformed values 4.77; 95% confidence interval (CI) 3.66-6.22; P < 0.001] and the PRS (HR 2.18; 95% CI 1.88-2.53; P < 0.001) were significantly related to incident AF. The discriminatory ability improved asymptotically with increasing numbers of SNPs. Compared with a clinical model, AF risk prediction was significantly improved by addition of NT-proBNP and the PRS. The C-statistic for the combination of CVRF, NT-proBNP, and the PRS reached 0.83 compared with 0.79 for CVRF only (P < 0.001). A replication in the Dutch Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort revealed similar results. Comparing the highest vs. lowest quartile, NT-proBNP and the PRS both showed a more than three-fold increased AF risk. Age remained the strongest risk factor with a 16.7-fold increased risk of AF in the highest quartile.

Conclusion: The PRS and the established biomarker NT-proBNP showed comparable predictive ability. Both provided incremental predictive value over standard clinical variables. Further improvements for the PRS are likely with the discovery of additional SNPs.
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http://dx.doi.org/10.1093/europace/euaa334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139818PMC
May 2021

Alcohol consumption, cardiac biomarkers, and risk of atrial fibrillation and adverse outcomes.

Eur Heart J 2021 03;42(12):1170-1177

Department of Cardiology, University Heart & Vascular Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany.

Aims: There is inconsistent evidence on the relation of alcohol intake with incident atrial fibrillation (AF), in particular at lower doses. We assessed the association between alcohol consumption, biomarkers, and incident AF across the spectrum of alcohol intake in European cohorts.

Methods And Results: In a community-based pooled cohort, we followed 107 845 individuals for the association between alcohol consumption, including types of alcohol and drinking patterns, and incident AF. We collected information on classical cardiovascular risk factors and incident heart failure (HF) and measured the biomarkers N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I. The median age of individuals was 47.8 years, 48.3% were men. The median alcohol consumption was 3 g/day. N = 5854 individuals developed AF (median follow-up time: 13.9 years). In a sex- and cohort-stratified Cox regression analysis alcohol consumption was non-linearly and positively associated with incident AF. The hazard ratio for one drink (12 g) per day was 1.16, 95% CI 1.11-1.22, P < 0.001. Associations were similar across types of alcohol. In contrast, alcohol consumption at lower doses was associated with reduced risk of incident HF. The association between alcohol consumption and incident AF was neither fully explained by cardiac biomarker concentrations nor by the occurrence of HF.

Conclusions: In contrast to other cardiovascular diseases such as HF, even modest habitual alcohol intake of 1.2 drinks/day was associated with an increased risk of AF, which needs to be considered in AF prevention.
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http://dx.doi.org/10.1093/eurheartj/ehaa953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982286PMC
March 2021

Joint association between education and polygenic risk score for incident coronary heart disease events: a longitudinal population-based study of 26 203 men and women.

J Epidemiol Community Health 2021 Jan 6. Epub 2021 Jan 6.

Population Research Unit, University of Helsinki Faculty of Social Sciences, Helsinki, Finland.

Background: Genetic vulnerability to coronary heart disease (CHD) is well established, but little is known whether these effects are mediated or modified by equally well-established social determinants of CHD. We estimate the joint associations of the polygenetic risk score (PRS) for CHD and education on CHD events.

Methods: The data are from the 1992, 1997, 2002, 2007 and 2012 surveys of the population-based FINRISK Study including measures of social, behavioural and metabolic factors and genome-wide genotypes (N=26 203). Follow-up of fatal and non-fatal incident CHD events (N=2063) was based on nationwide registers.

Results: Allowing for age, sex, study year, region of residence, study batch and principal components, those in the highest quartile of PRS for CHD had strongly increased risk of CHD events compared with the lowest quartile (HR=2.26; 95% CI: 1.97 to 2.59); associations were also observed for low education (HR=1.58; 95% CI: 1.32 to 1.89). These effects were largely independent of each other. Adjustment for baseline smoking, alcohol use, body mass index, igh-density lipoprotein (HDL) and total cholesterol, blood pressure and diabetes attenuated the PRS associations by 10% and the education associations by 50%. We do not find strong evidence of interactions between PRS and education.

Conclusions: PRS and education predict CHD events, and these associations are independent of each other. Both can improve CHD prediction beyond behavioural risks. The results imply that observational studies that do not have information on genetic risk factors for CHD do not provide confounded estimates for the association between education and CHD.
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http://dx.doi.org/10.1136/jech-2020-214358DOI Listing
January 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

The Pi∗MZ Allele in Alpha-1 Antitrypsin Increases Liver-Related Outcomes in a Population-Based Study.

Gastroenterology 2021 Apr 29;160(5):1874-1875. Epub 2020 Dec 29.

Transplantation and Liver Surgery Clinic, Helsinki University Hospital and, University of Helsinki, Helsinki, Finland.

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http://dx.doi.org/10.1053/j.gastro.2020.10.061DOI Listing
April 2021

Metabolic profiling of angiopoietin-like protein 3 and 4 inhibition: a drug-target Mendelian randomization analysis.

Eur Heart J 2021 03;42(12):1160-1169

Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.

Aims: Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase (LPL) and represent emerging drug targets to lower circulating triglycerides and reduce cardiovascular risk. To investigate the molecular effects of genetic mimicry of ANGPTL3 and ANGPTL4 inhibition and compare them to the effects of genetic mimicry of LPL enhancement.

Methods And Results: Associations of genetic variants in ANGPTL3 (rs11207977-T), ANGPTL4 (rs116843064-A), and LPL (rs115849089-A) with an extensive serum lipid and metabolite profile (208 measures) were characterized in six cohorts of up to 61 240 participants. Genetic associations with anthropometric measures, glucose-insulin metabolism, blood pressure, markers of kidney function, and cardiometabolic endpoints via genome-wide summary data were also explored. ANGPTL4 rs116843064-A and LPL rs115849089-A displayed a strikingly similar pattern of associations across the lipoprotein and lipid measures. However, the corresponding associations with ANGPTL3 rs11207977-T differed, including those for low-density lipoprotein and high-density lipoprotein particle concentrations and compositions. All three genotypes associated with lower concentrations of an inflammatory biomarker glycoprotein acetyls and genetic mimicry of ANGPTL3 inhibition and LPL enhancement were also associated with lower C-reactive protein. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower waist-to-hip ratio, improved insulin-glucose metabolism, and lower risk of coronary heart disease and type 2 diabetes, whilst genetic mimicry of ANGPTL3 was associated with improved kidney function.

Conclusions: Genetic mimicry of ANGPTL4 inhibition and LPL enhancement have very similar systemic metabolic effects, whereas genetic mimicry of ANGPTL3 inhibition showed differing metabolic effects, suggesting potential involvement of pathways independent of LPL. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower risk of coronary heart disease and type 2 diabetes. These findings reinforce evidence that enhancing LPL activity (either directly or via upstream effects) through pharmacological approaches is likely to yield benefits to human health.
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http://dx.doi.org/10.1093/eurheartj/ehaa972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982288PMC
March 2021

Genetic Predisposition to Coronary Artery Disease in Type 2 Diabetes Mellitus.

Circ Genom Precis Med 2020 12 13;13(6):e002769. Epub 2020 Aug 13.

The Usher Institute of Population Health Sciences & Informatics (A.D.M.), University of Edinburgh, Edinburgh, U.K.

Background: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D).

Methods: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D).

Results: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background.

Conclusions: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.
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http://dx.doi.org/10.1161/CIRCGEN.119.002769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748049PMC
December 2020

Association of circulating metabolites in plasma or serum and risk of stroke: Meta-analysis from seven prospective cohorts.

Neurology 2020 Dec 2. Epub 2020 Dec 2.

Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands;

Objective: To conduct a comprehensive analysis of circulating metabolites and incident stroke in large prospective population-based settings.

Methods: We investigated the association of metabolites with risk of stroke in seven prospective cohort studies including 1,791 incident stroke events among 38,797 participants in whom circulating metabolites were measured by Nuclear Magnetic Resonance (H-NMR) technology. The relationship between metabolites and stroke was assessed using Cox proportional hazards regression models. The analyses were performed considering all incident stroke events and ischemic and hemorrhagic events separately.

Results: The analyses revealed ten significant metabolite associations. Amino acid histidine (hazard ratio (HR) per standard deviation (SD) = 0.90, 95% confidence interval (CI): 0.85, 0.94; = 4.45×10), glycolysis-related metabolite pyruvate (HR per SD = 1.09, 95% CI: 1.04, 1.14; = 7.45×10), acute phase reaction marker glycoprotein acetyls (HR per SD = 1.09, 95% CI: 1.03, 1.15; = 1.27×10), cholesterol in high-density lipoprotein (HDL) 2 and several other lipoprotein particles were associated with risk of stroke. When focusing on incident ischemic stroke, a significant association was observed with phenylalanine (HR per SD = 1.12, 95% CI: 1.05, 1.19; 4.13×10) and total and free cholesterol in large HDL particles.

Conclusions: We found association of amino acids, glycolysis-related metabolites, acute phase reaction markers, and several lipoprotein subfractions with the risk of stroke. These findings support the potential of metabolomics to provide new insights into the metabolic changes preceding stroke.
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http://dx.doi.org/10.1212/WNL.0000000000011236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055347PMC
December 2020

High-resolution population-specific recombination rates and their effect on phasing and genotype imputation.

Eur J Hum Genet 2021 Apr 28;29(4):615-624. Epub 2020 Nov 28.

Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.

Previous research has shown that using population-specific reference panels has a significant effect on downstream population genomic analyses like haplotype phasing, genotype imputation, and association, especially in the context of population isolates. Here, we developed a high-resolution recombination rate mapping at 10 and 50 kb scale using high-coverage (20-30×) whole-genome sequenced data of 55 family trios from Finland and compared it to recombination rates of non-Finnish Europeans (NFE). We tested the downstream effects of the population-specific recombination rates in statistical phasing and genotype imputation in Finns as compared to the same analyses performed by using the NFE-based recombination rates. We found that Finnish recombination rates have a moderately high correlation (Spearman's ρ = 0.67-0.79) with NFE, although on average (across all autosomal chromosomes), Finnish rates (2.268 ± 0.4209 cM/Mb) are 12-14% lower than NFE (2.641 ± 0.5032 cM/Mb). Finnish recombination map was found to have no significant effect in haplotype phasing accuracy (switch error rates ~2%) and average imputation concordance rates (97-98% for common, 92-96% for low frequency and 78-90% for rare variants). Our results suggest that haplotype phasing and genotype imputation mostly depend on population-specific contexts like appropriate reference panels and their sample size, but not on population-specific recombination maps. Even though recombination rate estimates had some differences between the Finnish and NFE populations, haplotyping and imputation had not been noticeably affected by the recombination map used. Therefore, the currently available HapMap recombination maps seem robust for population-specific phasing and imputation pipelines, even in the context of relatively isolated populations like Finland.
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http://dx.doi.org/10.1038/s41431-020-00768-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114909PMC
April 2021

Genetic analysis of obstructive sleep apnoea discovers a strong association with cardiometabolic health.

Eur Respir J 2021 May 6;57(5). Epub 2021 May 6.

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.

There is currently limited understanding of the genetic aetiology of obstructive sleep apnoea (OSA). We aimed to identify genetic loci associated with OSA risk, and to test if OSA and its comorbidities share a common genetic background.We conducted the first large-scale genome-wide association study of OSA using the FinnGen study (217 955 individuals) with 16 761 OSA patients identified using nationwide health registries.We estimated 0.08 (95% CI 0.06-0.11) heritability and identified five loci associated with OSA (p<5.0×10): rs4837016 near (GTPase activating protein and VPS9 domains 1), rs10928560 near (C-X-C motif chemokine receptor type 4), rs185932673 near (calcium/calmodulin-dependent protein kinase ID) and rs9937053 near (fat mass and obesity-associated protein; a variant previously associated with body mass index (BMI)). In a BMI-adjusted analysis, an association was observed for rs10507084 near / (rhabdomyosarcoma 2 associated transcript/NEDD1 γ-tubulin ring complex targeting factor). We found high genetic correlations between OSA and BMI (r=0.72 (95% CI 0.62-0.83)), and with comorbidities including hypertension, type 2 diabetes, coronary heart disease, stroke, depression, hypothyroidism, asthma and inflammatory rheumatic disease (r>0.30). The polygenic risk score for BMI showed 1.98-fold increased OSA risk between the highest and the lowest quintile, and Mendelian randomisation supported a causal relationship between BMI and OSA.Our findings support the causal link between obesity and OSA, and the joint genetic basis between OSA and comorbidities.
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http://dx.doi.org/10.1183/13993003.03091-2020DOI Listing
May 2021

Endotoxemia is associated with an adverse metabolic profile.

Innate Immun 2021 Jan 27;27(1):3-14. Epub 2020 Nov 27.

Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Our aim was to analyze whether endotoxemia, i.e. translocation of LPS to circulation, is reflected in the serum metabolic profile in a general population and in participants with cardiometabolic disorders. We investigated three Finnish cohorts separately and in a meta-analysis ( = 7178), namely population-based FINRISK97, FinnTwin16 consisting of young adult twins, and Parogene, a random cohort of cardiac patients. Endotoxemia was determined as serum LPS activity and metabolome by an NMR platform. Potential effects of body mass index (BMI), smoking, metabolic syndrome (MetS), and coronary heart disease (CHD) status were considered. Endotoxemia was directly associated with concentrations of VLDL, IDL, LDL, and small HDL lipoproteins, VLDL particle diameter, total fatty acids (FA), glycoprotein acetyls (GlycA), aromatic and branched-chain amino acids, and Glc, and inversely associated with concentration of large HDL, diameters of LDL and HDL, as well as unsaturation degree of FAs. Some of these disadvantageous associations were significantly stronger in smokers and subjects with high BMI, but did not differ between participants with different CHD status. In participants with MetS, however, the associations of endotoxemia with FA parameters and GlycA were particularly strong. The metabolic profile in endotoxemia appears highly adverse, involving several inflammatory characters and risk factors for cardiometabolic disorders.
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http://dx.doi.org/10.1177/1753425920971702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780360PMC
January 2021

An epigenome-wide association study of metabolic syndrome and its components.

Sci Rep 2020 11 25;10(1):20567. Epub 2020 Nov 25.

Genomics and Biobank Unit, Department of Public Health Solutions, National Institute for Health and Welfare, Biomedicum 1, Haartmaninkatu 8, 00290, Helsinki, Finland.

The role of metabolic syndrome (MetS) as a preceding metabolic state for type 2 diabetes and cardiovascular disease is widely recognised. To accumulate knowledge of the pathological mechanisms behind the condition at the methylation level, we conducted an epigenome-wide association study (EWAS) of MetS and its components, testing 1187 individuals of European ancestry for approximately 470 000 methylation sites throughout the genome. Methylation site cg19693031 in gene TXNIP -previously associated with type 2 diabetes, glucose and lipid metabolism, associated with fasting glucose level (P = 1.80 × 10). Cg06500161 in gene ABCG1 associated both with serum triglycerides (P = 5.36 × 10) and waist circumference (P = 5.21 × 10). The previously identified type 2 diabetes-associated locus cg08309687 in chromosome 21 associated with waist circumference for the first time (P = 2.24 × 10). Furthermore, a novel HDL association with cg17901584 in chromosome 1 was identified (P = 7.81 × 10). Our study supports previous genetic studies of MetS, finding that lipid metabolism plays a key role in pathology of the syndrome. We provide evidence regarding a close interplay with glucose metabolism. Finally, we suggest that in attempts to identify methylation loci linking separate MetS components, cg19693031 appears to represent a strong candidate.
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http://dx.doi.org/10.1038/s41598-020-77506-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688654PMC
November 2020