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Background: Sialorrhea is a common and uncomfortable adverse effect of clozapine, and its severity varies between patients. The aim of the study was to select broadly genes related to the regulation of salivation and study associations between sialorrhea and dry mouth and polymorphisms in the selected genes. Methods: The study population consists of 237 clozapine-treated patients, of which 172 were genotyped. Associations between sialorrhea and dry mouth with age, sex, BMI, smoking, clozapine dose, clozapine and norclozapine serum levels, and other comedication were studied. Genetic associations were analyzed with linear and logistic regression models explaining sialorrhea and dry mouth with each SNP added separately to the model as coefficients. Results: Clozapine dose, clozapine or norclozapine concentration and their ratio were not associated with sialorrhea or dryness of mouth. Valproate use (p = 0.013) and use of other antipsychotics (p = 0.015) combined with clozapine were associated with excessive salivation. No associations were found between studied polymorphisms and sialorrhea. In analyses explaining dry mouth with logistic regression with age and sex as coefficients, two proxy-SNPs were associated with dry mouth: epidermal growth factor receptor 4 (ERBB4) rs3942465 (adjusted p = 0.025) and tachykinin receptor 1 (TACR1) rs58933792 (adjusted p = 0.029). Conclusion: Use of valproate or antipsychotic polypharmacy may increase the risk of sialorrhea. Genetic variations in ERBB4 and TACR1 might contribute to experienced dryness of mouth among patients treated with clozapine. [ABSTRACT FROM AUTHOR]

Background: We investigated (a) whether polygenic risk for schizophrenia predicts different trajectories of social development among those who have not developed psychoses and (b) whether possible associations are PRSSCZ-specific or evident also for any polygenic risk for mental disorders, e.g. for major depression. Methods: Participants came from the population-based Young Finns Study (n = 2377). We calculated a polygenic risk score for schizophrenia (PRSSCZ) and for major depression (PRSDEP). Diagnoses of psychotic disorders were derived from the hospital care register. Social development from adolescence to middle age was measured by (a) perceived social support from friends, family, and a close other, (b) perceived sociability, and (c) family structure (partnership status, number of children, age of first-time parenthood). Results: Among those without manifest psychoses, high PRSSCZ predicted lower experienced support from friends (B = −0.04, p = 0.009–0.035) and family (B = −0.04, p = 0.009–0.035) especially after early adulthood, and also lower perceived sociability (B = −0.05, p = 0.010–0.026). PRSSCZ was not related to family structure. PRSDEP did not predict any domain of social development. Conclusions: Individuals at high PRSSCZ (not converted to psychosis) seem to experience a lower preference to be with others over being alone. Individuals with high (v. low) PRSSCZ seem to have a similar family structure in terms of partnership status or number of children but, nevertheless, they experience less support from their family. Among those not converted to psychosis in a typical age period, high PRSSCZ may predict a 'later risk phase' and reduced functional resilience when approaching middle age. [ABSTRACT FROM AUTHOR]

When effective treatments against neurodegenerative diseases become a reality, it will be important to know the age these pathologies begin to develop. We investigated alpha‐synuclein pathology in brain tissue of the Tampere Sudden Death Study—unselected forensic autopsies on individuals living outside hospital institutions in Finland. Of 562 (16–95 years) participants, 42 were positive for Lewy‐related pathology (LRP). The youngest LRP case was aged 54 years, and the frequency of LRP in individuals aged ≥50 years was 9%. This forensic autopsy study indicates LRP starts already in middle age and is more common than expected in the ≥50 years‐of‐age non‐hospitalized population. ANN NEUROL 2024;95:843–848 [ABSTRACT FROM AUTHOR]

Schizophrenia is often regarded as a disorder of premature aging. We investigated (a) whether polygenic risk for schizophrenia (PRSsch) relates to pace of epigenetic aging and (b) whether personal dispositions toward active and emotionally close relationships protect against accelerated epigenetic aging in individuals with high PRSsch. The sample came from the population‐based Young Finns Study (n = 1348). Epigenetic aging was measured with DNA methylation aging algorithms such as AgeAccelHannum, EEAAHannum, IEAAHannum, IEAAHorvath, AgeAccelHorvath, AgeAccelPheno, AgeAccelGrim, and DunedinPACE. A PRSsch was calculated using summary statistics from the most comprehensive genome‐wide association study of schizophrenia to date. Social dispositions were assessed in terms of extraversion, sociability, reward dependence, cooperativeness, and attachment security. We found that PRSsch did not have a statistically significant effect on any studied indicator of epigenetic aging. Instead, PRSsch had a significant interaction with reward dependence (p = 0.001–0.004), cooperation (p = 0.009–0.020), extraversion (p = 0.019–0.041), sociability (p = 0.003–0.016), and attachment security (p = 0.007–0.014) in predicting AgeAccelHannum, EEAAHannum, or IEAAHannum. Specifically, participants with high PRSsch appeared to display accelerated epigenetic aging at higher (vs. lower) levels of extraversion, sociability, attachment security, reward dependence, and cooperativeness. A rather opposite pattern was evident for those with low PRSsch. No such interactions were evident when predicting the other indicators of epigenetic aging. In conclusion, against our hypothesis, frequent social interactions may relate to accelerated epigenetic aging in individuals at risk for psychosis. We speculate that this may be explained by social‐cognitive impairments (perceiving social situations as overwhelming or excessively arousing) or ending up in less supportive or deviant social groups. [ABSTRACT FROM AUTHOR]

Objective: Cloninger's temperament dimensions have been studied widely in relation to genetics. In this study, we examined Cloninger's temperament dimensions grouped with cluster analyses and their association with single nucleotide polymorphisms (SNPs). This study included 212 genotyped Finnish patients from the Ostrobothnia Depression Study. Methods: The temperament clusters were analysed at baseline and at six weeks from the beginning of the depression intervention study. We selected depression-related catecholamine and serotonin genes based on a literature search, and 59 SNPs from ten different genes were analysed. The associations of single SNPs with temperament clusters were studied. Using the selected genes, genetic risk score (GRS) analyses were conducted considering appropriate confounding factors. Results: No single SNP had a significant association with the temperament clusters. Associations between GRSs and temperament clusters were observed in multivariate models that were significant after permutation analyses. Two SNPs from the DRD3 gene, two SNPs from the SLC6A2 gene, one SNP from the SLC6A4 gene, and one SNP from the HTR2A gene associated with the HHA/LRD/LP (high harm avoidance, low reward dependence, low persistence) cluster at baseline. Two SNPs from the HTR2A gene were associated with the HHA/LRD/LP cluster at six weeks. Two SNPs from the HTR2A gene and two SNPs from the COMT gene were associated with the HP (high persistence) cluster at six weeks. Conclusion: GRSs seem to associate with an individual's temperament profile, which can be observed in the clusters used. Further research needs to be conducted on these types of clusters and their clinical applicability. [ABSTRACT FROM AUTHOR]

Genetic architecture of plasma lipidome provides insights into regulation of lipid metabolism and related diseases. We applied an unsupervised machine learning method, PGMRA, to discover phenotype-genotype many-to-many relations between genotype and plasma lipidome (phenotype) in order to identify the genetic architecture of plasma lipidome profiled from 1,426 Finnish individuals aged 30–45 years. PGMRA involves biclustering genotype and lipidome data independently followed by their inter-domain integration based on hypergeometric tests of the number of shared individuals. Pathway enrichment analysis was performed on the SNP sets to identify their associated biological processes. We identified 93 statistically significant (hypergeometric p-value < 0.01) lipidome-genotype relations. Genotype biclusters in these 93 relations contained 5977 SNPs across 3164 genes. Twenty nine of the 93 relations contained genotype biclusters with more than 50% unique SNPs and participants, thus representing most distinct subgroups. We identified 30 significantly enriched biological processes among the SNPs involved in 21 of these 29 most distinct genotype-lipidome subgroups through which the identified genetic variants can influence and regulate plasma lipid related metabolism and profiles. This study identified 29 distinct genotype-lipidome subgroups in the studied Finnish population that may have distinct disease trajectories and therefore could be useful in precision medicine research. [ABSTRACT FROM AUTHOR]

Macrophages are integral to the pathogenesis of atherosclerosis, but the contribution of distinct macrophage subsets to disease remains poorly defined. Using single cell technologies and conditional ablation via a LysMCre+Clec4a2flox/DTR mouse strain, we demonstrate that the expression of the C-type lectin receptor CLEC4A2 is a distinguishing feature of vascular resident macrophages endowed with athero-protective properties. Through genetic deletion and competitive bone marrow chimera experiments, we identify CLEC4A2 as an intrinsic regulator of macrophage tissue adaptation by promoting a bias in monocyte-to-macrophage in situ differentiation towards colony stimulating factor 1 (CSF1) in vascular health and disease. During atherogenesis, CLEC4A2 deficiency results in loss of resident vascular macrophages and their homeostatic properties causing dysfunctional cholesterol metabolism and enhanced toll-like receptor triggering, exacerbating disease. Our study demonstrates that CLEC4A2 licenses monocytes to join the vascular resident macrophage pool, and that CLEC4A2-mediated macrophage homeostasis is critical to combat cardiovascular disease. The contribution of distinct subsets of macrophages to atherosclerosis is poorly understood. Here the authors describe a protective subset of vascular macrophages expressing the C-type lectin receptor CLEC4A2, which licenses monocytes to join the resident vascular macrophage pool and ensures vascular homeostasis. [ABSTRACT FROM AUTHOR]

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization. The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: The knowledge of factors influencing disease progression in patients with established coronary heart disease (CHD) is still relatively limited. One potential pathway is related to peroxisome proliferator–activated receptor gamma coactivator-1 alpha (PPARGC1A), a transcription factor linked to energy metabolism which may play a role in the heart function. Thus, its associations with subsequent CHD events remain unclear. We aimed to investigate the effect of three different SNPs in the PPARGC1A gene on the risk of subsequent CHD in a population with established CHD. Methods: We employed an individual-level meta-analysis using 23 studies from the GENetIcs of sUbSequent Coronary Heart Disease (GENIUS-CHD) consortium, which included participants (n = 80,900) with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. Three variants in the PPARGC1A gene (rs8192678, G482S; rs7672915, intron 2; and rs3755863, T528T) were tested for their associations with subsequent events during the follow-up using a Cox proportional hazards model adjusted for age and sex. The primary outcome was subsequent CHD death or myocardial infarction (CHD death/myocardial infarction). Stratified analyses of the participant or study characteristics as well as additional analyses for secondary outcomes of specific cardiovascular disease diagnoses and all-cause death were also performed. Results: Meta-analysis revealed no significant association between any of the three variants in the PPARGC1A gene and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline: rs8192678, hazard ratio (HR): 1.01, 95% confidence interval (CI) 0.98–1.05 and rs7672915, HR: 0.97, 95% CI 0.94–1.00; rs3755863, HR: 1.02, 95% CI 0.99–1.06. Similarly, no significant associations were observed for any of the secondary outcomes. The results from stratified analyses showed null results, except for significant inverse associations between rs7672915 (intron 2) and the primary outcome among 1) individuals aged ≥65, 2) individuals with renal impairment, and 3) antiplatelet users. Conclusion: We found no clear associations between polymorphisms in the PPARGC1A gene and subsequent CHD events in patients with established CHD at baseline. [ABSTRACT FROM AUTHOR]

Macrophages are integral to the pathogenesis of atherosclerosis, but the contribution of distinct macrophage subsets to disease remains poorly defined. Using single cell technologies and conditional ablation via a LysMCre+Clec4a2flox/DTR mouse strain, we demonstrate that the expression of the C-type lectin receptor CLEC4A2 is a distinguishing feature of vascular resident macrophages endowed with athero-protective properties. Through genetic deletion and competitive bone marrow chimera experiments, we identify CLEC4A2 as an intrinsic regulator of macrophage tissue adaptation by promoting a bias in monocyte-to-macrophage in situ differentiation towards colony stimulating factor 1 (CSF1) in vascular health and disease. During atherogenesis, CLEC4A2 deficiency results in loss of resident vascular macrophages and their homeostatic properties causing dysfunctional cholesterol metabolism and enhanced toll-like receptor triggering, exacerbating disease. Our study demonstrates that CLEC4A2 licenses monocytes to join the vascular resident macrophage pool, and that CLEC4A2-mediated macrophage homeostasis is critical to combat cardiovascular disease. The contribution of distinct subsets of macrophages to atherosclerosis is poorly understood. Here the authors describe a protective subset of vascular macrophages expressing the C-type lectin receptor CLEC4A2, which licenses monocytes to join the resident vascular macrophage pool and ensures vascular homeostasis. [ABSTRACT FROM AUTHOR]

The development of compassion for others might be influenced by the social experiences made during childhood and has a genetic component. No research has yet investigated whether the parent–child relationship quality interacts with genetic variation in the oxytocin and dopamine systems in predicting compassion over the life span. In the prospective Young Finns Study (N = 2099, 43.9% men), we examined the interaction between mother‐reported emotional warmth and intolerance toward their child assessed in 1980 (age of participants, 3–18 years) and two established genetic risk scores for oxytocin levels and dopamine signaling activity. Dispositional compassion for others was measured with the Temperament and Character Inventory 1997, 2001, and 2012 (age of participants, 20–50 years). We found a gene–environment interaction (p =.031) that remained marginally significant after adjustment for multiple testing. In line with the differential susceptibility hypothesis, only participants who carry alleles associated with low dopamine signaling activity had higher levels of compassion when growing up with emotionally warm parents, whereas they had lower levels of compassion when their parents were emotionally cold. Children's genetic variability in the dopamine system might result in plasticity to early environmental influences that have a long‐lasting effect on the development of compassion. However, our findings need replication. [ABSTRACT FROM AUTHOR]

Background: Non-coding RNA 886 (nc886) is coded from a maternally inherited metastable epiallele. We set out to investigate the determinants and dynamics of the methylation pattern at the nc886 epiallele and how this methylation status associates with nc886 RNA expression. Furthermore, we investigated the associations between the nc886 methylation status or the levels of nc886 RNAs and metabolic traits in the YFS and KORA cohorts. The association between nc886 epiallele methylation and RNA expression was also validated in induced pluripotent stem cell (iPSC) lines. Results: We confirm that the methylation status of the nc886 epiallele is mostly binomial, with individuals displaying either a non- or hemi-methylated status, but we also describe intermediately and close to fully methylated individuals. We show that an individual's methylation status is associated with the mother's age and socioeconomic status, but not with the individual's own genetics. Once established, the methylation status of the nc886 epiallele remains stable for at least 25 years. This methylation status is strongly associated with the levels of nc886 non-coding RNAs in serum, blood, and iPSC lines. In addition, nc886 methylation status associates with glucose and insulin levels during adolescence but not with the indicators of glucose metabolism or the incidence of type 2 diabetes in adulthood. However, the nc886-3p RNA levels also associate with glucose metabolism in adulthood. Conclusions: These results indicate that nc886 metastable epiallele methylation is tuned by the periconceptional conditions and it associates with glucose metabolism through the expression of the ncRNAs coded in the epiallele region. [ABSTRACT FROM AUTHOR]

Background and Objective: The newer adenosine diphosphate (ADP) receptor blockers ticagrelor and prasugrel are superior to clopidogrel in the long-term management of acute coronary syndrome (ACS). We evaluated the acute performance (prehospital loading) of these ADP receptor blockers in a primary percutaneous coronary intervention (PCI) for an ST-elevation myocardial infarction (STEMI). Methods: In a retrospective, single-center registry study, data on all STEMI patients admitted for their first primary PCI between January 2007 and April 2020 were analyzed (n = 3218). The three ADP receptor blockers were mainly used during consecutive periods (clopidogrel 2007–2010, prasugrel 2011–2014, and ticagrelor 2014–2020), and were compared with risk factor-adjusted multivariate logistic regression for acute 3- and 7-day mortality and culprit artery flow before and after PCI. Results: Of the 3218 total patients, 47.6% (n = 1532) were treated with ticagrelor, 22.1% (n = 711) were treated with prasugrel, and 30.3% (n = 975) were treated with clopidogrel. The use of ticagrelor or prasugrel as opposed to clopidogrel was associated with better culprit artery flow before PCI (odds ratio [OR] 1.21 for moderate or good flow, 95% confidence interval [CI] 1.03–1.42, p = 0.022), as well as lower acute mortality (OR 0.66 for 3-day mortality, 95% CI 0.46–0.95, p = 0.025; and OR 0.71 for 7-day mortality, 95% CI 0.52–0.98, p = 0.039). The results in regard to acute mortality were highlighted among patients with short treatment delays (disappearing with longer treatment delays; p < 0.05 for interaction). Conclusions: The newer ADP receptor blockers are associated with lower mortality and better culprit artery flow at presentation when compared with clopidogrel. There are no significant differences between the two newer drugs. As the drugs were mainly used during three consecutive periods, unmeasured confounding related to the development of cardiac care and changes in the population may contribute to the results. [ABSTRACT FROM AUTHOR]

Preterm birth (PTB) is associated with increased risk of type 2 diabetes and neurocognitive impairment later in life. We analyzed for the first time the associations of PTB with blood miRNA levels in adulthood. We also investigated the relationship of PTB associated miRNAs and adulthood phenotypes previously linked with premature birth. Blood MicroRNA profiling, genome-wide gene expression analysis, computer-based cognitive testing battery (CANTAB) and serum NMR metabolomics were performed for Young Finns Study subjects (aged 34–49 years, full-term n = 682, preterm n = 84). Preterm birth (vs. full-term) was associated with adulthood levels of hsa-miR-29b-3p in a fully adjusted regression model (p = 1.90 × 10–4, FDR = 0.046). The levels of hsa-miR-29b-3p were down-regulated in subjects with PTB with appropriate birthweight for gestational age (p = 0.002, fold change [FC] = − 1.20) and specifically in PTB subjects with small birthweight for gestational age (p = 0.095, FC = − 1.39) in comparison to individuals born full term. Hsa-miR-29b-3p levels correlated with the expressions of its target-mRNAs BCL11A and CS and the gene set analysis results indicated a target-mRNA driven association between hsa-miR-29b-3p levels and Alzheimer's disease, Parkinson's disease, Insulin signaling and Regulation of Actin Cytoskeleton pathway expression. The level of hsa-miR-29b-3p was directly associated with visual processing and sustained attention in CANTAB test and inversely associated with serum levels of VLDL subclass component and triglyceride levels. In conlcusion, adult blood levels of hsa-miR-29b-3p were lower in subjects born preterm. Hsa-miR-29b-3p associated with cognitive function and may be linked with adulthood morbidities in subjects born preterm, possibly through regulation of gene sets related to neurodegenerative diseases and insulin signaling as well as VLDL and triglyceride metabolism. [ABSTRACT FROM AUTHOR]

Background: We define compassion as an enduring disposition that centers upon empathetic concern for another person's suffering and the motivation to act to alleviate it. The contribution of specific candidate genes to the development of dispositional compassion for others is currently unknown. We examine candidate genes in the oxytocin and dopamine signaling pathways. Methods: In a 32-year follow-up of the Young Finns Study (N = 2,130, 44.0% men), we examined with multiple indicators latent growth curve modeling the molecular genetic underpinnings of dispositional compassion for others across the life span. We selected five single nucleotide polymorphisms (SNPs) whose functions are known in humans: rs2268498 (OXTR), rs3796863 (CD38) (related to lower oxytocin levels), rs1800497 (ANKK1/DRD2), rs4680 (COMT), and rs1611115 (DBH) (related to higher dopamine levels). Compassion was measured with Cloninger's Temperament and Character Inventory on three repeated observations spanning 15 years (1997–2012). Differences between gender were tested. Results: We did not find an effect of the five SNPs in oxytocin and dopamine pathway genes on the initial levels of dispositional compassion for others. Individuals who carry one or two copies of the T-allele of DBH rs1611115, however, tend to increase faster in compassion over time than those homozygotes for the C-allele, b = 0.063 (SE = 0.027; p = 0.018). This effect was largely driven by male participants, 0.206 (SE = 0.046; p < 0.001), and was not significant in female participants when analyzed separately. Conclusions: Men who are known to have, on average, lower compassion than women seem to reduce this difference over time if they carry the T-allele of DBH rs1611115. The direction of the association indicates that dopamine signaling activity rather than overall dopamine levels might drive the development of compassion. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

High blood pressure (BP) is a major risk factor for many noncommunicable diseases. The effect of mitochondrial DNA single-nucleotide polymorphisms (mtSNPs) on BP is less known than that of nuclear SNPs. We investigated the mitochondrial genetic determinants of systolic, diastolic, and mean arterial BP. MtSNPs were determined from peripheral blood by sequencing or with genome-wide association study SNP arrays in two independent Finnish cohorts, the Young Finns Study and the Finnish Cardiovascular Study, respectively. In total, over 4200 individuals were included. The effects of individual common mtSNPs, with an additional focus on sex-specificity, and aggregates of rare mtSNPs grouped by mitochondrial genes were evaluated by meta-analysis of linear regression and a sequence kernel association test, respectively. We accounted for the predicted pathogenicity of the rare variants within protein-encoding and the tRNA regions. In the meta-analysis of 87 common mtSNPs, we did not observe significant associations with any of the BP traits. Sex-specific and rare-variant analyses did not pinpoint any significant associations either. Our results are in agreement with several previous studies suggesting that mtDNA variation does not have a significant role in the regulation of BP. Future studies might need to reconsider the mechanisms thought to link mtDNA with hypertension. [ABSTRACT FROM AUTHOR]

Background: Inverted T waves in the electrocardiogram (ECG) have been associated with coronary heart disease (CHD) and mortality. The pathophysiology and prognostic significance of T‐wave inversion may differ between different anatomical lead groups, but scientific data related to this issue is scarce. Methods: A representative sample of Finnish subjects (n = 6,354) aged over 30 years underwent a health examination including a 12‐lead ECG in the Health 2000 survey. ECGs with T‐wave inversions were divided into three anatomical lead groups (anterior, lateral, and inferior) and were compared to ECGs with no pathological T‐wave inversions in multivariable‐adjusted Fine–Gray and Cox regression hazard models using CHD and mortality as endpoints. Results: The follow‐up for both CHD and mortality lasted approximately fifteen years (median value with interquartile ranges between 14.9 and 15.3). In multivariate‐adjusted models, anterior and lateral (but not inferior) T‐wave inversions associated with increased risk of CHD (HR: 2.37 [95% confidence interval 1.20–4.68] and 1.65 [1.27–2.15], respectively). In multivariable analyses, only lateral T‐wave inversions associated with increased risk of mortality in the entire study population (HR 1.51 [1.26–1.81]) as well as among individuals with no CHD at baseline (HR 1.59 [1.29–1.96]). Conclusions: The prognostic information of inverted T waves differs between anatomical lead groups. T‐wave inversion in the anterior and lateral lead groups is independently associated with the risk of CHD, and lateral T‐wave inversion is also associated with increased risk of mortality. Inverted T wave in the inferior lead group proved to be a benign phenomenon. [ABSTRACT FROM AUTHOR]

Background: Previous population studies have presented conflicting results regarding the prognostic impact of intraventricular conduction delays (IVCD). Methods: We studied long‐term prognostic impact and the association with comorbidities of eight IVCDs in a random sample of 6,299 Finnish subjects (2,857 men and 3,442 women, mean age 52.8, SD 14.9 years) aged 30 or over who participated in the health examination including 12‐lead ECG. For left bundle branch block (LBBB) and non‐specific IVCD (NSIVCD), two different definitions were used. Results: During 16.5 years' follow‐up, 1,309 of the 6,299 subjects (20.8%) died and of these 655 (10.4%) were cardiovascular (CV) deaths. After controlling for known clinical risk factors, the hazard ratio for CV death, compared with individuals without IVCD, was 1.55 for the Minnesota definition of LBBB (95% confidence interval 1.04–2.31, p =.032) and 1.27 (95% confidence interval 0.80–2.02, p =.308) for the Strauss' definition of LBBB. Subjects with NSIVCD were associated with twofold to threefold increase in CV mortality depending on the definition. While right bundle branch block, left anterior fascicular block and incomplete bundle branch blocks were associated with seemingly higher mortality, this was no longer the case after adjustment for age and sex. The presence of R‐R' pattern was not associated with any adverse outcome. Conclusions: In a population study with long‐term follow‐up, NSIVCD and Minnesota definition of LBBB were independently associated with CV mortality. Other IVCDs had no significant impact on prognosis. The prognostic impact of LBBB and NSIVCD was affected by the definition of the conduction disorder. [ABSTRACT FROM AUTHOR]

To study whether systemic hemodynamics, especially systemic vascular resistance, predicts the development of hypertension and improves the risk prediction of incident hypertension beyond common risk factors in the risk models in young adults. Typical risk factors for hypertension in the risk prediction models (systolic and diastolic blood pressure, parental history of hypertension, age, sex, body-mass index, smoking), laboratory values (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, insulin, C-reactive protein), heart rate (HR), stroke index (SI), and systemic vascular resistance index (SVRI) calculated by whole-body impedance cardiography were evaluated in 2007 and blood pressure in 2011 in 1293 Finnish adults (aged 30–45 years; females 56%; n = 1058 normotensive in 2007). Of hemodynamic variables, SVRI and HR evaluated in 2007 were independently associated with systolic blood pressure (p < 0.001 and p = 0.047, respectively) and SVRI with diastolic blood pressure measured in 2011 (p = 0.014), and SVRI and HR were independent predictors of incident hypertension (p < 0.001 and p = 0.024, respectively). SVRI was the most significant predictor of incident hypertension independently of other risk factors (odds ratio 2.73 per 1 standard deviation increase, 95% confidence interval 1.93–3.94, p < 0.001). The extended prediction model (including SVRI) improved the incident hypertension risk prediction beyond other risk factors, with an area under the receiver operating characteristic curve of 0.846 versus 0.817 (p = 0.042) and a continuous net reclassification improvement of 0.734 (p < 0.001). These findings suggest that systemic vascular resistance index predicts the incidence of hypertension in young adults and that the evaluation of systemic hemodynamics could provide an additional tool for hypertension risk prediction. [ABSTRACT FROM AUTHOR]

Coronary artery and peripheral artery diseases represent different clinical outcomes of atherosclerosis and despite sharing common risk factors the ultimate reasons determining disease presentation are still unclear. The present study sought to define and compare the serum lipid and apolipoprotein profiles of patients undergoing coronary artery bypass grafting and those treated invasively for symptomatic lower extremity peripheral artery disease. Altogether 218 coronary and 280 peripheral artery disease patients treated between 2013 and 2014 in the Tampere University Hospital, Tampere, Finland, with available lipid measurements within two years prior to the intervention were retrospectively analysed. The Extended Friedewald formula neural network model was used to obtain apolipoprotein and lipoprotein subfraction values. Patients undergoing coronary artery bypass surgery had a clear male predominance (82% versus 53%, p < 0.001), lower median age (69 versus 74 years, p < 0.001) and a lower prevalence of smoking (18% versus 32%, p = 0.001) and pulmonary disease (12% versus 20%, p = 0.023) compared to peripheral artery disease patients. There were some differences in the serum lipid profiles between the study groups in the univariable analyses. When controlling for the statistically significant differences in age, sex, urgency of treatment and comorbidities between the groups in a multivariable logistic regression model, higher serum concentrations of apolipoprotein A-I were significantly and independently associated with coronary artery disease (OR 1.11 for 0.01 g/L increase, p = 0.044). In conclusion, patients undergoing coronary artery bypass grafting appear to have higher apolipoprotein A-I levels when compared to patients treated for peripheral artery disease. [ABSTRACT FROM AUTHOR]

Objectives. Acute coronary syndrome (ACS) is associated with high mortality. Charlson comorbidity index (CCI) was designed over 30 years ago to measure the impact of pre-existing comorbidities on long-term survival of the patient. We wanted to re-evaluate the performance of CCI and its components in modern setting. Design. This is a retrospective study of 1576 consecutive patients undergoing invasive evaluation and treated for ACS in single tertiary center between 2015-2016. Mortality was analyzed in timeframes of 1, 6 and 24 months. CCI-scores were retrieved from written medical records and complimented with data from electronic sources. The performance of CCI and its components was compared to the GRACE-score measuring patients' status upon hospital admission. Results. Population mean age at baseline was 69.3 (SD 11.8) years and 69.1% of the patients were male (n = 1089). Most of the components of CCI associated significantly with mortality at all timeframes despite adjusting for age but only diabetes and congestive heart failure associated with mortality at all time points after adjusting for GRACE-score. CCI associated with mortality [GRACE adjusted HR-values of single unit increase of CCI after 1, 6 and 24-month follow-up: 1.12(95% CI:1.00-1.25), 1.17(1.07-1.29) and 1.24(1.16-1.33)]. CCI performed modestly with its AUC-values ranging between 0.755 and 0.784, with prognostic performance increasing with longer follow-up. Adding components of CCI did not significantly improve risk prediction over GRACE-score. Conclusions. In conclusion, CCI or its individual components measuring the impact of comorbidities on overall mortality does not provide any significant value compared to GRACE-score during up to 2 years of follow-up. [ABSTRACT FROM AUTHOR]

Introduction: Partial and advanced interatrial block (IAB) in the electrocardiographic (ECG) represents inter-atrial conduction delay. IAB is associated with atrial fibrillation (AF) and stroke in the general population. Material and methods: A representative sample of Finnish subjects (n = 6354) aged over 30 years (mean: 52.2 years, standard deviation: 14.6) underwent a health examination including a 12-lead ECG. Five different IAB groups based on automatic measurements were compared to normal P waves using multivariate-adjusted Cox proportional hazard model. Follow-up lasted up to 15 years. Results: The prevalence of advanced and partial IAB was 1.0% and 9.7%, respectively. In the multivariate model, both advanced (hazard ratio (HR): 1.63 (95% confidence interval (CI): 1.00−2.65)) and partial IAB (HR: 1.39 (1.09−1.77)) were associated with increased risk of AF. Advanced IAB was associated with increased risk of stroke or transient ischaemic attack (TIA) independently of associated AF (HR: 2.22 (1.20−4.13)). Partial IAB was also associated with increased risk of being diagnosed with coronary heart disease (HR: 1.26 (1.01−1.58)). Discussion: IAB is a rather frequent finding in the general population. IAB is a risk factor for AF and is associated with an increased risk of stroke or TIA independently of associated AF. Both partial and advanced interatrial block are associated with increased risk of atrial fibrillation in the general population. Advanced interatrial block is an independent risk factor for stroke and transient ischaemic attack. The clinical significance of interatrial block is dependent on the subtype classification. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether cardiorespiratory fitness (CRF) and heart rate recovery (HRR) associate with the risk of sudden cardiac death (SCD) independently of left ventricular ejection fraction (LVEF).Methods: The Finnish Cardiovascular Study is a prospective clinical study of patients referred to clinical exercise testing in 2001-2008 and follow-up until December 2013. Patients without pacemakers undergoing first maximal or submaximal exercise testing with cycle ergometer were included (n=3776). CRF in metabolic equivalents (METs) was estimated by achieving maximal work level. HRR was defined as the reduction in heart rate 1 min after maximal exertion. Adjudication of SCD was based on death certificates. LVEF was measured for clinical indications in 71.4% of the patients (n=2697).Results: Population mean age was 55.7 years (SD 13.1; 61% men). 98 SCDs were recorded during a median follow-up of 9.1 years (6.9-10.7). Mean CRF and HRR were 7.7 (SD 2.9) METs and 25 (SD 12) beats/min/min. Both CRF and HRR were associated with the risk of SCD in the entire study population (HRCRF0.47 (0.37-0.59), p<0.001 and HRHRR0.57 (0.48-0.67), p<0.001 with HR estimates corresponding to one SD increase in the exposure variables) and with CRF, HRR and LVEF in the same model (HRCRF0.60 (0.45-0.79), p<0.001, HRHRR0.65 (0.51-0.82), p<0.001) or adjusting additionally for all significant risk factors for SCD (LVEF, sex, creatinine level, history of myocardial infarction and atrial fibrillation, corrected QT interval) (HRCRF0.69 (0.52-0.93), p<0.01, HRHRR0.74 (0.58-0.95) p=0.02).Conclusions: CRF and HRR are significantly associated with the risk of SCD regardless of LVEF. [ABSTRACT FROM AUTHOR]

Motivation Selecting the optimal machine learning (ML) model for a given dataset is often challenging. Automated ML (AutoML) has emerged as a powerful tool for enabling the automatic selection of ML methods and parameter settings for the prediction of biomedical endpoints. Here, we apply the tree-based pipeline optimization tool (TPOT) to predict angiographic diagnoses of coronary artery disease (CAD). With TPOT, ML models are represented as expression trees and optimal pipelines discovered using a stochastic search method called genetic programing. We provide some guidelines for TPOT-based ML pipeline selection and optimization-based on various clinical phenotypes and high-throughput metabolic profiles in the Angiography and Genes Study (ANGES). Results We analyzed nuclear magnetic resonance-derived lipoprotein and metabolite profiles in the ANGES cohort with a goal to identify the role of non-obstructive CAD patients in CAD diagnostics. We performed a comparative analysis of TPOT-generated ML pipelines with selected ML classifiers, optimized with a grid search approach, applied to two phenotypic CAD profiles. As a result, TPOT-generated ML pipelines that outperformed grid search optimized models across multiple performance metrics including balanced accuracy and area under the precision-recall curve. With the selected models, we demonstrated that the phenotypic profile that distinguishes non-obstructive CAD patients from no CAD patients is associated with higher precision, suggesting a discrepancy in the underlying processes between these phenotypes. Availability and implementation TPOT is freely available via http://epistasislab.github.io/tpot/. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Aims: We investigated the combination of low systolic blood pressure (SBP) response, low exercise capacity (EC) and slow heart rate recovery (HRR) during an exercise test in mortality prediction. Patients and methods: Our population consisted of 3456 patients from the Finnish Cardiovascular Study. A failure of SBP to increase >42 mmHg was defined as a low response. Low EC was defined as < 8 metabolic equivalents. 1-minute HRR ≤18 bpm from maximum was defined as slow HRR. Results: During a median follow up of 10.0 years, 537 participants died. Reduced SBP response, low EC and slow HRR were independent predictors of all-cause and CV mortality (p <.001 for all). Patients with reduced SBP response, low EC and slow HRR had a very high mortality rate of 42.1% during follow up compared to only 4.5% of the patients without any of these risk factors. The hazard ratios for all-cause mortality in patients with one, two or three of the studied risk factors were 3.2, 6.0, and 10.6, respectively (p <.001 for all). Conclusion: The combination of reduced SBP response, low exercise capacity, and reduced HRR in an exercise test is associated with very high mortality and can be used in risk stratification. The combination of low blood pressure response, low exercise capacity and slow heart rate recovery in an exercise test is able to identify a group of patients in a very high mortality risk. These parameters are easily derived from an exercise test. All parameters are commonly available in clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: Type 2 diabetes (T2D) has been associated with depressive symptoms, but the causal direction of this association and the underlying mechanisms, such as increased glucose levels, remain unclear. We used instrumental-variable regression with a genetic instrument (Mendelian randomization) to examine a causal role of increased glucose concentrations in the development of depressive symptoms. Method: Data were from the population-based Cardiovascular Risk in Young Finns Study ( n = 1217). Depressive symptoms were assessed in 2012 using a modified Beck Depression Inventory (BDI-I). Fasting glucose was measured concurrently with depressive symptoms. A genetic risk score for fasting glucose (with 35 single nucleotide polymorphisms) was used as an instrumental variable for glucose. Results: Glucose was not associated with depressive symptoms in the standard linear regression ( B = −0.04, 95% CI [−0.12, 0.04], p = .34), but the instrumental-variable regression showed an inverse association between glucose and depressive symptoms ( B = −0.43, 95% CI [−0.79, −0.07], p = .020). The difference between the estimates of standard linear regression and instrumental-variable regression was significant ( p = .026) Conclusion: Our results suggest that the association between T2D and depressive symptoms is unlikely to be caused by increased glucose concentrations. It seems possible that T2D might be linked to depressive symptoms due to low glucose levels. [ABSTRACT FROM AUTHOR]

Objective: Investigation of the clinical potential of extensive phenotype data and machine learning (ML) in the prediction of mortality in acute coronary syndrome (ACS). Methods: The value of ML and extensive clinical data was analyzed in a retrospective registry study of 9066 consecutive ACS patients (January 2007 to October 2017). Main outcome was six-month mortality. Prediction models were developed using two ML methods, logistic regression and extreme gradient boosting (xgboost). The models were fitted in training set of patients treated in 2007–2014 and 2017 (81%, n = 7344) and validated in a separate validation set of patients treated in 2015–2016 with full GRACE score data available for comparison of model accuracy (19%, n = 1722). Results: Overall, six-month mortality was 7.3% (n = 660). Several variables were found to be significantly associated with six-month mortality by both ML methods. The xgboost scored the best performance: AUC 0.890 (0.864–0.916). The AUC values for logistic regression and GRACE score were 0.867(0.837–0.897) and 0.822 (0.785–0.859), respectively. The AUC value of xgboost was better when compared to logistic regression (p =.012) and GRACE score (p <.00001). Conclusions: The use of extensive phenotype data and novel machine learning improves prediction of mortality in ACS over traditional GRACE score. The collection of extensive cardiovascular phenotype data from electronic health records as well as from data recorded by physicians can be used highly effectively in prediction of mortality after acute coronary syndrome. Supervised machine learning methods such as logistic regression and extreme gradient boosting using extensive phenotype data significantly outperform conventional risk assessment by the current golden standard GRACE score. Integration of electronic health records and the use of supervised machine learning methods can be easily applied in a single centre level to model the risk of mortality. [ABSTRACT FROM AUTHOR]

Background: Individuals treated for abdominal aortic aneurysms (AAAs) are high-risk patients in whom better risk prediction could improve survival. Contemporary serum lipid parameters, such as apolipoproteins and lipoprotein subfractions, may improve or complement the prognostic value of traditional serum lipids. The aim of this study was to ascertain the extended serum lipid profiles, long-term prognosis and their association in AAA patients.Methods: Altogether 498 patients treated for AAAs and with available serum lipid values were retrospectively analysed. Contemporary lipid parameters were estimated using a neural network model, the extended Friedewald formula.Results: Younger age, smoking and urgent or emergency surgery were associated with an unfavourable, and coronary disease and previous stroke with a favourable lipid profile. In multivariable analysis—in addition to advanced age, aneurysm rupture, smoking, pulmonary disease and diabetes—high triglycerides and traditional LDL cholesterol were significant independent risk factors for mortality, HR 1.84 (95% CI 1.20-2.81) and 1.79 (95% CI 1.18-2.73), respectively, while higher EFW-IDL cholesterol was associated with better survival, HR 0.31 (95% CI 0.19-0.65). Including serum lipid parameters improved the prediction of 5-year survival (NRI = 17.7%, p = 0.016).Conclusions: Extended serum lipid parameters complement risk prediction of patients treated for AAAs. An unfavourable lipid profile is associated with treatment of AAA earlier in life and with inferior long-term survival. [ABSTRACT FROM AUTHOR]

Background: Prediabetes often occurs together with dyslipidaemia, which is paradoxically treated with statins predisposing to type 2 diabetes mellitus. We examined peripheral blood pathway profiles in prediabetic subjects with (PRD ) and without dyslipidaemia (PR0 ) and compared these to nonprediabetic controls without dyslipidaemia (C0 ).Methods: The participants were from the Cardiovascular Risk in Young Finns Study, including 1240 subjects aged 34 to 49 years. Genome-wide expression data of peripheral blood and gene set enrichment analysis were used to investigate the differentially expressed genes and enriched pathways between different subtypes of prediabetes.Results: Pathways for cholesterol synthesis, interleukin-12-mediated signalling events, and downstream signalling in naïve CD8+ T-cells were upregulated in the PR0 group in comparison with controls (C0 ). The upregulation of these pathways was independent of waist circumference, blood pressure, smoking status, and insulin. Adjustment for CRP left the CD8+ T-cell signalling and interleukin-12-mediated signalling event pathway upregulated. The cholesterol synthesis pathway was also upregulated when all prediabetic subjects (PR0 and PRD ) were compared with the nonprediabetic control group. No pathways were upregulated or downregulated when the PRD group was compared with the C0 group. Five genes in the PR0 group and 1 in the PRD group were significantly differentially expressed in comparison with the C0 group.Conclusions: Blood cell gene expression profiles differ significantly between prediabetic subjects with and without dyslipidaemia. Whether this classification may be used in detection of prediabetic individuals at a high risk of cardiovascular complications remains to be examined. [ABSTRACT FROM AUTHOR]

Background and purpose — Patients developing postoperative acute kidney injury (AKI) are at risk of higher morbidity and mortality. In arthroplasty patients, many pre- and perioperative factors are associated with AKI but some of the risk factors are unclear. We report the incidence of postoperative AKI, the conditions associated with it, and survival rates in AKI patients. Patients and methods — We obtained data from 20,575 consecutive hip or knee arthroplasties. Postoperative AKI, occurring within 7 days after the operation, was defined using the risk, injury, failure, loss, and end-stage (RIFLE) criteria. We analyzed independent risk factors for AKI using binary logistic regression. In addition, we reviewed the records of AKI patients and performed a survival analysis. Results — The AKI incidence was 3.3 per 1,000 operations. We found preoperative estimated glomerular filtration rate, ASA classification, body mass index, and duration of operation to be independent risk factors for AKI. Infections, paralytic ileus, and cardiac causes were the predominant underlying conditions, whereas half of all AKI cases occurred without any clear underlying condition. Survival rates were lower in AKI patients. Interpretation — Supporting earlier results, existing renal insufficiency and patient-related characteristics were found to be associated with an increased risk of postoperative AKI. Furthermore, duration of operation was identified as an independent risk factor. We suggest careful renal monitoring postoperatively for patients with these risk factors. [ABSTRACT FROM PUBLISHER]

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10−8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = −0.22, P = 5.5 × 10−13), T2D (Rg = −0.27, P = 1.1 × 10−6) and coronary artery disease (Rg = −0.30, P = 6.5 × 10−9). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10−4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated. [ABSTRACT FROM AUTHOR]

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation. [ABSTRACT FROM AUTHOR]

Aims: Genome-wide association studies (GWAS) have identified many variants associating with an increased risk of coronary artery disease (CAD).We studied the possible association between these variants and the risk of sudden cardiac death (SCD). Methods and results: Aweighted genetic risk score (GRSCAD) was formed from variants most strongly associating with CAD identified by the CARDIoGRAMplus C4D Consortium explaining 10.6% of the heritability of CAD [153 single-nucleotide polymorphisms with r2 < 0.2]. The association between GRSCAD and the occurrence of SCD was studied in three independent autopsy series of consecutive cases combining altogether 1035 autopsies with 306SCDs due to CAD(SCDCAD). The results were replicated in a prospective follow-up study of 2321 patients (mean follow-up time of 6.2 years with 48 incident SCDs of which 39 due to CAD) undergoing clinical exercise test at baseline. In a meta-analysis of the autopsy series, GRSCAD associated significantly with the risk of SCDCAD with age, body mass index, and sex adjusted odds ratio (OR) of 1.042 (1.023-1.061, P = 9.1 × 10-6) for one allele increase in GRSCAD. The same association was seen in both sexes. GRSCAD predicted significantly the risk of SCDCAD also in a prospective study setting (Cox regression analysis adjusted with all relevant clinical data): hazard ratio 1.049 (1.010-1.090, P = 0.014). In meta-analysis of all cohorts (adjusting further for other genetic markers related to traditional risk factors and QT-interval), the association was highly significant [OR 1.045 (1.028-1.063), P = 1.7 × 10-7]. Conclusion: Genetic risk estimate for CAD may also be used to predict SCD. [ABSTRACT FROM AUTHOR]

Proprotein convertase subtilisin/kexin (PCSK) enzymes cleave and convert their immature substrates into biologically active forms. Polymorphisms in the PCSK genes have been reported to associate with human diseases and phenotypes, including hypercholesterolemia and blood pressure (BP), and targeting PCSKs is considered a promising future form of drug therapy. PCSK processing is readily induced upon upregulation of the enzyme, but the genetic factors contributing to PCSK expression have not been thoroughly characterized. To gain a comprehensive understanding of the genetic regulation of PCSK expression, we performed, for the first time, a genome-wide expression quantitative trait loci (eQTL) analysis using mRNA expression in >1400 human peripheral blood samples from the Cardiovascular Risk in Young Finns Study and ca. ten million single-nucleotide polymorphisms (SNPs). The expression data showed clear expression for FURIN, PCSK5, PCSK7 and MBTPS1 (membrane-bound transcription factor peptidase, site 1) mRNAs in virtually all tested samples. A discovery analysis demonstrated a genome-wide significant ( p < 5 × 10) association with the selected PCSK probes for 1024 variants, which were located at ten independent loci. Of these loci, 5/10 could be confirmed to regulate PCSK expression in two additional and independent sample sets. Finally, a phenotypic analysis demonstrated that a novel cis-eQTL SNP rs4702 for FURIN is strongly associated with both diastolic ( p = 0.012) and systolic ( p = 0.035) BP levels, as well as peripheral vascular resistance ( p = 0.003). These findings indicate that the expression of the PCSK enzymes is regulated by genetic factors, which have biological roles in health and disease. [ABSTRACT FROM AUTHOR]

Upstream transcription factor 1 (USF1) allelic variants significantly influence future risk of cardiovascular disease and overall mortality in females. We investigated sex-specific effects of USF1 gene allelic variants on serum indices of lipoprotein metabolism, early markers of asymptomatic atherosclerosis and their changes during six years of follow-up. In addition, we investigated the cis-regulatory role of these USF1 variants in artery wall tissues in Caucasians. In the Cardiovascular Risk in Young Finns Study, 1,608 participants (56% women, aged 31.9 ± 4.9) with lipids and cIMT data were included. For functional study, whole genome mRNA expression profiling was performed in 91 histologically classified atherosclerotic samples. In females, serum total, LDL cholesterol and apoB levels increased gradually according to USF1 rs2516839 genotypes TT

ABSTRACT We hypothesized that bone resorption acts to increase bone strength through stimulation of periosteal expansion. Hence, we examined whether bone resorption, as reflected by serum β-C-telopeptides of type I collagen (CTX), is positively associated with periosteal circumference (PC), in contrast to inverse associations with parameters related to bone remodeling such as cortical bone mineral density (BMDC). CTX and mid-tibial peripheral quantitative computed tomography (pQCT) scans were available in 1130 adolescents (mean age 15.5 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC). Analyses were adjusted for age, gender, time of sampling, tanner stage, lean mass, fat mass, and height. CTX was positively related to PC ( β = 0.19 [0.13, 0.24]) (coefficient = SD change per SD increase in CTX, 95% confidence interval)] but inversely associated with BMDC ( β = -0.46 [-0.52,-0.40]) and cortical thickness [ β = -0.11 (-0.18, -0.03)]. CTX was positively related to bone strength as reflected by the strength-strain index (SSI) ( β = 0.09 [0.03, 0.14]). To examine the causal nature of this relationship, we then analyzed whether single-nucleotide polymorphisms (SNPs) within key osteoclast regulatory genes, known to reduce areal/cortical BMD, conversely increase PC. Fifteen such genetic variants within or proximal to genes encoding receptor activator of NF-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) were identified by literature search. Six of the 15 alleles that were inversely related to BMD were positively related to CTX ( p < 0.05 cut-off) ( n = 2379). Subsequently, we performed a meta-analysis of associations between these SNPs and PC in ALSPAC ( n = 3382), Gothenburg Osteoporosis and Obesity Determinants (GOOD) ( n = 938), and the Young Finns Study (YFS) ( n = 1558). Five of the 15 alleles that were inversely related to BMD were positively related to PC ( p < 0.05 cut-off). We conclude that despite having lower BMD, individuals with a genetic predisposition to higher bone resorption have greater bone size, suggesting that higher bone resorption is permissive for greater periosteal expansion. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. [ABSTRACT FROM AUTHOR]