Publications by authors named "Graciela E Delgado"

50 Publications

Meta-GWAS of PCSK9 levels detects two novel loci at APOB and TM6SF2.

Hum Mol Genet 2021 Sep 30. Epub 2021 Sep 30.

Institute for Medical Informatics, Statistics and Epidemiology, Medical Faculty, University of Leipzig, Leipzig, Germany.

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player in lipid metabolism, as it degrades LDL receptors from hepatic cell membranes. So far, only variants of the PCSK9 gene locus were found to be associated with PCSK9 levels. Here we aimed to identify novel genetic loci that regulate PCSK9 levels and how they relate to other lipid traits. Additionally, we investigated to what extend the causal effect of PCSK9 on coronary artery disease (CAD) is mediated by LDL-C.

Methods & Results: We performed a genome-wide association study meta-analysis of PCSK9 levels in up to 12,721 samples of European ancestry. The estimated heritability was 10.3%, which increased to 12.6% using only samples from patients without statin treatment. We successfully replicated the known PCSK9 hit consisting of three independent signals. Interestingly, in a study of 300 African Americans, we confirmed the locus with a different PCSK9 variant. Beyond PCSK9, our meta-analysis detected three novel loci with genome-wide significance. Co-localization analysis with cis-eQTLs and lipid traits revealed biologically plausible candidate genes at two of them: APOB and TM6SF2. In a bivariate Mendelian Randomization analysis, we detected a strong effect of PCSK9 on LDL-C, but not vice versa. LDL-C mediated 63% of the total causal effect of PCSK9 on CAD.

Conclusion: Our study identified novel genetic loci with plausible candidate genes affecting PCSK9 levels. Ethnic heterogeneity was observed at the PCSK9 locus itself. While the causal effect of PCSK9 on CAD is mainly mediated by LDL-C, an independent direct effect also occurs.
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http://dx.doi.org/10.1093/hmg/ddab279DOI Listing
September 2021

Combined Use of Serum Uromodulin and eGFR to Estimate Mortality Risk.

Front Med (Lausanne) 2021 8;8:723546. Epub 2021 Sep 8.

Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Serum uromodulin (sUmod) shows a strong direct correlation with eGFR in patients with impaired kidney function and an inverse association with mortality. However, there are patients in whom only one of both markers is decreased. Therefore, we aimed to investigate the effect of marker discordance on mortality risk. sUmod and eGFR were available in 3,057 participants of the Ludwigshafen Risk and Cardiovascular Health study and 529 participants of the VIVIT study. Both studies are monocentric prospective studies of patients that had been referred for coronary angiography. Participants were categorized into four groups according to the median values of sUmod (LURIC: 146 ng/ml, VIVIT: 156) and eGFR (LURIC: 84 ml/min/1.73 m, VIVIT: 87). In 945 LURIC participants both markers were high (UHGH), in 935 both were low (ULGL), in 589 only eGFR (UHGL), and in 582 only sUmod (ULGH) was low. After balancing the groups for cardiovascular risk factors, hazard ratios (95%CI) for all-cause mortality as compared to UHGH were 2.03 (1.63-2.52), 1.43 (1.13-1.81), and 1.32 (1.03-1.69) for ULGL, UHGL, and ULGH, respectively. In VIVIT, HRs were 3.12 (1.38-7.08), 2.38 (1.01-5.61), and 2.06 (0.81-5.22). Adding uromodulin to risk prediction models that already included eGFR as a covariate slightly increased the Harrell's C and significantly improved the AUC in LURIC. In UHGL patients, hypertension, heart failure and upregulation of the renin-angiotensin-aldosterone-system seem to be the driving forces of disease development, whereas in ULGH patients metabolic disturbances might be key drivers of increased mortality. In conclusion, SUmod/eGFR subgroups mirror distinct metabolic and clinical patterns. Assessing sUmod additionally to creatinine or cystatin C has the potential to allow a more precise risk modeling and might improve risk stratification.
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http://dx.doi.org/10.3389/fmed.2021.723546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8455921PMC
September 2021

The genomics of heart failure: design and rationale of the HERMES consortium.

ESC Heart Fail 2021 Sep 3. Epub 2021 Sep 3.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure.

Methods And Results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10 under an additive genetic model.

Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
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http://dx.doi.org/10.1002/ehf2.13517DOI Listing
September 2021

Alcohol consumption and mortality: The Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

Atherosclerosis 2021 10 12;335:119-125. Epub 2021 Aug 12.

Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena, Germany; Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig, Germany. Electronic address:

Background And Aims: One of the most important risk factors for morbidity and mortality is the consumption of alcohol. The aim of our study was to examine the effect of alcohol consumption on all-cause mortality and cardiovascular mortality.

Methods: The Ludwigshafen Risk and Cardiovascular Health (LURIC) study includes 3316 patients hospitalized for coronary angiography at a tertiary care centre in Southwest Germany. Patients were followed-up for a median of 9.9 (range 0.1-11.9 years) years. Total mortality number in the follow-up period was 995, and the number of incident cases, i.e. cardiovascular death, was 622. Information on alcohol consumption assessed by self-report questionnaires was used to calculate intake in grams of ethanol per day. Associations of alcohol consumption with morbidity and mortality were analysed using Cox proportional hazards regression.

Results: We found significantly increased mortality for patients in the highest alcohol intake group age- and sex-adjusted (hazard ratio of 1.59 (95%CI, 0.93-2.72)) and a reduced risk for the group of low-volume drinkers (hazard ratio of 0.75 (95%CI, 0.65-0.86)). After adjustment for cardiovascular risk factors, the risk difference between abstainers and low-volume drinkers was not significant anymore.

Conclusions: In the LURIC study, the risk of overall mortality and cardiovascular mortality is significantly increased in study participants with very high alcohol consumption and slightly increased in total abstainers as compared to participants with low consumption in unadjusted analysis, replicating the well-known J-curve. Adjusting for cardiovascular risk factors rendered the risk decrease observed for low-volume drinkers insignificant. Therefore, our results do not show a significant health benefit of low-volume alcohol consumption in a cohort of patients at medium-to-high cardiovascular risk.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.08.014DOI Listing
October 2021

Surrogate scores of advanced fibrosis in NAFLD/NASH do not predict mortality in patients with medium-to-high cardiovascular risk.

Am J Physiol Gastrointest Liver Physiol 2021 09 16;321(4):G252-G261. Epub 2021 Jun 16.

Clinical Cooperation Unit Healthy Metabolism, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Untreated non-alcoholic fatty liver disease (NAFLD) may have significant consequences including an increase in mortality and cardiovascular injury. Thus, early detection of NAFLD is currently believed not only to prevent liver-related but also cardiovascular mortality. However, almost nothing is known about coexisting NAFLD in patients with coronary artery disease (CAD). We investigated the impact of surrogate scores of fibrosis in NAFLD in a large cohort of patients referred to coronary angiography. Modeling the common NALFD and fibrosis scores, fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS), as splines revealed significant associations with all-cause and cardiovascular mortality when Cox regression models were only adjusted for cardiovascular risk factors that were not already included in the calculation of the scores. Stratifying the scores into quartiles yielded hazard ratios [95% confidence interval (CI)] for all-cause and cardiovascular mortality for the 4th quartile versus the 1st quartile of 2.28 (1.90-2.75) and 2.11 (1.67-2.67) for FIB-4 and of 3.21 (2.61-3.94) and 3.12 (2.41-4.04) for NFS. However, we did not observe an independent association of FIB-4 or NFS with overall or cardiovascular mortality in our prospective CAD cohort after full adjustment for all cardiovascular risk factors [all-cause mortality: HR 1.13 (0.904-1.41) and 1.17 (0.903-1.52); cardiovascular mortality: HR 1.06 (0.8-1.41) and 1.02 (0.738-1.41)]. Thus, neither FIB-4 nor NFS, as surrogate markers for NAFLD/NASH, were independent risk factors for overall or cardiovascular mortality in patients with CAD. Our data show that surrogate risk scores for NAFLD-related fibrosis do not add information in assessing the CVD events in patients with CAD proven by angiography. We investigated the impact of NAFLD surrogate markers in a large cohort of patients that had been referred to coronary angiography. In contrast to a repeatedly demonstrated increased link of cardiovascular events in patients with NALFD, we demonstrated that NAFLD surrogate markers were not independent risk factors for overall or cardiovascular mortality in patients with CAD. Thus, these markers may not be useful for primary prevention of cardiovascular events in patients with CAD.
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http://dx.doi.org/10.1152/ajpgi.00058.2021DOI Listing
September 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

FGL1 as a modulator of plasma D-dimer levels: Exome-wide marker analysis of plasma tPA, PAI-1, and D-dimer.

J Thromb Haemost 2021 08 30;19(8):2019-2028. Epub 2021 May 30.

Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.

Background: Use of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer.

Objectives: We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach.

Methods: Cohort-level analyses and fixed effects meta-analyses of PAI-1 (n = 15 603), tPA (n = 6876,) and D-dimer (n = 19 306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing.

Results: Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P < 5 × 10 ). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P < 1 × 10 in the discovery using an independent cohort. Replication was observed for three out of the five significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1 (fibrinogen-like-1) with increased plasma D-dimer levels. Additionally, a candidate-gene approach revealed a suggestive association for a coding variant (rs143202684-C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830-A) in SCARB1 associated with increased D-dimer levels.

Conclusion: This work provides new evidence for a role of FGL1 in hemostasis.
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http://dx.doi.org/10.1111/jth.15345DOI Listing
August 2021

Genome-wide analysis identifies novel susceptibility loci for myocardial infarction.

Eur Heart J 2021 03;42(9):919-933

Division Heart & Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, the Netherlands.

Aims: While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation.

Methods And Results: We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1β (vs. vehicle), and associated with smooth muscle cell migration in vitro.

Conclusions: A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.
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http://dx.doi.org/10.1093/eurheartj/ehaa1040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936531PMC
March 2021

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Hum Mol Genet 2021 04;30(5):393-409

Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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http://dx.doi.org/10.1093/hmg/ddab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098112PMC
April 2021

Immune Status and Mortality in Smokers, Ex-smokers, and Never-Smokers: The Ludwigshafen Risk and Cardiovascular Health Study.

Nicotine Tob Res 2021 06;23(7):1191-1198

Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Introduction: Elevated leukocyte counts are associated with cardiovascular disease. Smoking induces inflammation and alters levels of leukocyte subtypes.

Aims And Methods: Our aim was to investigate the effect of smoking on circulating immune cells and their association with mortality. Lymphocyte subtypes were identified by flow cytometry of fluorescent-labeled cells. We analyzed the association of leukocytes with mortality using Cox regression and assessed their effect on risk prediction based on principle components (PCs) using area under the receiver operating characteristic curve and net-reclassification in 2173 participants from the Ludwigshafen Risk and Cardiovascular Health Study, a prospective case-control study in patients who underwent coronary angiography.

Results: The numbers of T cells, monocytes, and neutrophils were higher and natural killer cells were lower in smokers compared with never-smokers. In never-smokers, lymphocyte counts were inversely associated with mortality while a positive association was observed for neutrophils. The neutrophil-to-lymphocyte ratio (NLR) had the strongest association in never-smokers with a hazard ratio (95% confidence interval) of 1.43 (1.26-1.61). No associations were found in smokers. Adding the first five PCs or the NLR to a risk prediction model based on conventional risk factors did not improve risk prediction in smokers, but significantly increased the area under the curve from 0.777 to 0.801 and 0.791, respectively, in never-smokers.

Conclusions: Lymphocyte counts were inversely associated with mortality in never-smokers but not in active smokers. Markers of innate immunity, namely total neutrophils and CD11b+/CD18+ and CD31+/CD40- granulocytes, were directly associated with mortality. Adding markers of immune function like PCs or the NLR to basic risk models improved risk prediction in never-smokers only.

Implications: Total leukocyte counts were higher in active smokers as compared to never-smokers due to elevated counts of neutrophils and monocytes but declined in ex-smokers with increasing time since quitting. In the never-smokers but not in smokers, lymphocyte counts were inversely associated with mortality while there was a direct association with neutrophils, even after adjustment for conventional cardiovascular risk factors. Adding markers of immune function to basic risk models improved risk prediction in never-smokers only. Our data indicate that smoking status has an important impact on the ability of leukocyte counts to predict long-term cardiovascular outcomes.
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http://dx.doi.org/10.1093/ntr/ntab011DOI Listing
June 2021

Association of double product and pulse pressure with cardiovascular and all-cause mortality in the LURIC study.

J Clin Hypertens (Greenwich) 2020 12 9;22(12):2332-2342. Epub 2020 Oct 9.

Fifth Department of Medicine, University Medical Center Mannheim UMM, Mannheim, Germany.

Systolic (SBP) and diastolic blood pressure (DBP) and mean arterial pressure (MAP) are risk factors for cardiovascular mortality (CVM). Pulse pressure (PP) is considered as an easily available marker of vascular stiffness and the double product (DP) as a marker of cardiac workload. Therefore, we have examined the predictive value of PP and DP in the Ludwigshafen Risk and Cardiovascular Health study, a monocentric cohort study of 3316 patients referred to coronary angiography. An increase of SBP or PP by 1mmHg increased the risk of CVM with hazard ratios of 1.009 (95% CI, 1.005-1.012) and 1.016 (1.012-1.020), respectively. Increasing DP by 100 mm Hg/min was associated with a 1.010 (1.007-1.013) higher risk of CVM. In patient subgroups with coronary artery disease (CAD) and heart failure (HF), PP and DP predicted CVM better than SBP or MAP. In a multivariate analysis adjusted for sex, BMI, diabetes, eGFR, hazard ratios for CVM for z-standardized PP, DP, SBP, and HR were 1.20, 1.16, 1.12, and 1.14. After adding age to the multivariate analysis, only DP and HR remained significant. We provide evidence that PP and DP are powerful predictors of CVM and all-cause mortality in a CV medium- to high-risk population, especially in patients with CAD and HF. While DP proved to be an independent predictor of cardiovascular and all-cause mortality also in multivariate analysis, PP was no independent predictor in our cohort with widespread antihypertensive treatment (>85%). PP is associated with age, presence of diabetes, obesity, and impaired renal function.
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http://dx.doi.org/10.1111/jch.14067DOI Listing
December 2020

Association of Factor V Leiden With Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data.

Circulation 2020 08 13;142(6):546-555. Epub 2020 Jul 13.

Department of Cardiology, Division Heart and Lungs (V.T., A.F.S., J.v.S., A.O.K., F.W.A.), UMC Utrecht, Utrecht University, the Netherlands.

Background: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD.

Methods: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality.

Results: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; =28%; -heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity.

Conclusions: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.045526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493828PMC
August 2020

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Nat Commun 2020 01 9;11(1):163. Epub 2020 Jan 9.

Department of Biostatistics, University of Liverpool, Liverpool, UK.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
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http://dx.doi.org/10.1038/s41467-019-13690-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952380PMC
January 2020

Bile Acids in Patients with Uncontrolled Type 2 Diabetes Mellitus - The Effect of Two Days of Oatmeal Treatment.

Exp Clin Endocrinol Diabetes 2020 Sep 2;128(9):624-630. Epub 2020 Jan 2.

Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Background: Beta-glucans are effective in binding bile acids (BA) thereby lowering cholesterol concentration. This might contribute to the beneficial effects of the consumption of β-glucan-rich foods like oatmeal on glucose homeostasis.

Objective: We measured BA serum concentrations in patients with uncontrolled type 2 diabetes (T2DM) to investigate the effect of two days of oatmeal treatment on BA concentration as compared to a conventional T2DM-adapted diet.

Methods: The OatMeal And Insulin Resistance study was performed as a randomized, open label crossover dietary intervention study with consecutive inclusion of 15 patients in an inpatient clinical setting. Bile acids were measured by high-resolution mass spectrometry. For statistical analysis, the differences in the concentration of serum BA and laboratory parameters between the fifth day and the third day of each inpatient stay were calculated and the effect compared between both phases by using the Wilcoxon test.

Results: Whereas there was a mean decrease in total BA following oatmeal treatment (-0.82±1.14 µmol/l), there was no decrease following the control treatment. Glycocholic acid was lower after oatmeal treatment but higher following control treatment (-0.09±0.17 vs. 0.05±0.11 µmol/l). The reduction in total BA was directly correlated with a decrease in proinsulin during the oatmeal phase. Decreases in blood lipids or apolipoproteins were mostly greater after oatmeal treatment, but these differences were not statistically significant.

Conclusion: Two days of oatmeal diet led to significant reductions in total BA as compared to a diabetes-adapted control diet. The magnitude of BA reduction was directly correlated with a decrease in proinsulin.
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http://dx.doi.org/10.1055/a-1069-7330DOI Listing
September 2020

LDL receptor traffic: in the fast lane.

Eur Heart J 2020 03;41(9):1054-1056

Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

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http://dx.doi.org/10.1093/eurheartj/ehz866DOI Listing
March 2020

Influence of smoking and smoking cessation on biomarkers of endothelial function and their association with mortality.

Atherosclerosis 2020 01 15;292:52-59. Epub 2019 Nov 15.

Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; European Center for Angioscience ECAS, Medical Faculty Mannheim of the University Heidelberg, Mannheim, Germany.

Background And Aims: Endothelial dysfunction precedes atherosclerosis and smoking is a well-known risk factor for the development of endothelial dysfunction. The aim of our study was to analyse the effect of smoking on circulating markers of endothelial function and to investigate whether such effects have an influence on the potential use of these markers to estimate cardiovascular risk.

Methods: Stratified for smoking, levels of sE-/sP-/sL-selectin, von Willebrand (vWF), sICAM-1 and sVCAM-1, their association with mortality using Cox regression, and their accuracy of risk prediction using area-under-the-ROC-curve and net-reclassification-index were analysed in 1926 participants from the Ludwigshafen Risk and Cardiovascular Health (LURIC) - a prospective case-control study in patients who underwent coronary angiography with a median mortality follow-up of 10.6 years.

Results: In smokers, higher concentrations of sICAM-1, sE-selectin sP-selectin, but lower concentrations of sL-selectin and sVCAM-1, were detected compared to never-smokers. A direct association with mortality was found for levels of sICAM-1, sVCAM-1 and vWF regardless of smoking. Low sL-selectin levels were inversely associated with mortality in heavy and light smokers, with hazard ratios of 0.72 and 0.67 per 1-SD increase, adjusted for cardiovascular risk factors. Adding sL-selectin to a model based on traditional risk factors significantly improved AUC from 0.725 to 0.752 (p = 0.034) with an NRI of 43% (16.9%-62.3%).

Conclusions: Smoking alters the concentration of circulating markers of endothelial function. sL-selectin is decreased in smokers, inversely associated with risk, and could be a useful marker to improve risk prediction.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.11.017DOI Listing
January 2020

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun 2019 10 31;10(1):4957. Epub 2019 Oct 31.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 CX, The Netherlands.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
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http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 2019

The association of high-normal international-normalized-ratio (INR) with mortality in patients referred for coronary angiography.

PLoS One 2019 15;14(8):e0221112. Epub 2019 Aug 15.

Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Aims: The international-normalized-ratio (INR) is typically used to monitor patients on warfarin or related oral anticoagulant therapy. The aim of our study was to investigate the association of the INR with mortality in coronary artery disease (CAD) patients not on oral anticoagulant therapy.

Methods And Results: Between 1997 to 2000 the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study enrolled 3316 patients of German ancestry that had been referred for coronary angiography. We excluded patients on coumarin therapy (n = 222) and patients with an INR more than 5 standard deviations (SD) away from the mean (n = 30). During a median follow-up of 9.9 years, 884 patients died, 547 patients from cardiovascular causes. After adjustment for cardiovascular risk factors the INR was associated with all-cause mortality in all patients and the CAD positive group with HRs (95% CI) of 1.14(1.07-1.21) and 1.16(1.09-1.23) per 1-SD increase, respectively. Adjustment for NT-proBNP rendered the association insignificant.

Conclusion: In LURIC, the INR was positively associated with mortality in patients with prevalent CAD not on oral anticoagulant therapy as well as in patients without CAD. Adjustment for NT-proBNP abolished the association suggesting clinical or subclinical heart failure strongly contributing to increased INR and higher mortality.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221112PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695160PMC
March 2020

Area-based socioeconomic status and mortality: the Ludwigshafen Risk and Cardiovascular Health study.

Clin Res Cardiol 2020 Jan 29;109(1):103-114. Epub 2019 May 29.

Vth Department of Medicine (Nephrology Hypertensiology, Rheumatology, Endocrinology, Diabetology) Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.

Background: Low individual socioeconomic status (SES) is a known risk factor for morbidity and mortality. A related measure is the area-based SES (abSES), which describes the average SES of a region. The association of measures of abSES with morbidity and mortality is less well studied.

Methods: The Ludwigshafen Risk and Cardiovascular Health study consists of 3316 patients hospitalized for coronary angiography between 1997 and 2000 at a tertiary care centre in Germany. Patients were followed up for a median of 10 years. Two measures of abSES were used: the regional purchasing index (PPI, data obtained from IQVIA GmbH) and the German Index of Socioeconomic Deprivation (GISD, developed by the Robert-Koch Institute). The association of abSES with disease and with mortality was analysed using logistic regression and Cox proportional hazards regression, respectively.

Results: Study participants living in regions with higher abSES had lower HbA1c and high-sensitive C-reactive protein. A higher abSES was associated with lower prevalence of active smoking, vitamin D deficiency and diabetes mellitus. We further found significantly increased mortality for participants in the lowest PPI quartile (age- and sex-adjusted hazard ratio (95% CI) of 0.58 (0.38-0.90) as compared to the first quartile), and in the highest GISD tertile (HR of 1.32 (1.13-1.54) as compared to the first tertile).

Conclusion: Living in an area with a low abSES was associated with a higher burden of diabetes mellitus, a higher percentage of severe vitamin D deficiency, higher systemic inflammation and a significant increase in mortality.
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http://dx.doi.org/10.1007/s00392-019-01494-yDOI Listing
January 2020

Genome-wide association study suggests impact of chromosome 10 rs139401390 on kidney function in patients with coronary artery disease.

Sci Rep 2019 02 26;9(1):2750. Epub 2019 Feb 26.

Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany.

Chronic kidney disease (CKD) is an independent risk factor for onset and progression of coronary artery disease (CAD). Discovery of predisposing loci for kidney function in CAD patients was performed using a genome-wide association approach. Inclusion criteria were CAD with ≥50% stenosis (≥1 coronary artery) and a creatinine-based estimated glomerular filtration rate (eGFR) of 30-75 ml/min/1.73 m. An association of rs139401390 located to a region 58.8 kb upstream of renalase (RNLS) with eGFR was detected in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study (n = 499, p = 7.88 × 10, mean eGFR 60.7 ml/min/1.73 m). Direct genotyping of rs139401390A > G suggested increased eGFR by 12.0 ml/min/1.73 m per A allele (p = 0.000004). Genome-wide replication of rs139401390A > G in the Coronary Artery Disease and Renal Failure (CAD-REF) registry with a mean eGFR of 47.8 ml/min/1.73 m (n = 574, p = 0.033) was only nominally significant. Comparison of rs139401390 genotypes for risk of reduced kidney function in the overall LURIC study revealed higher adjusted odds ratios (OR) for eGFR <60 ml/min/1.73 m for CAD patients (n = 1992, OR = 2.36, p = 0.008, G/A + G/G vs A/A) compared to patients with/without CAD (n = 2908, OR = 1.97, p = 0.014, G/A + G/G vs A/A). No significant risk elevation was detected in patients without CAD (n = 948, p = 0.571). rs139401390 may affect kidney function in CAD patients with mild reduction in eGFR.
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http://dx.doi.org/10.1038/s41598-019-39055-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391429PMC
February 2019

Soluble urokinase plasminogen activation receptor and long-term outcomes in persons undergoing coronary angiography.

Sci Rep 2019 01 24;9(1):475. Epub 2019 Jan 24.

Vth Department of Medicine, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany.

Soluble urokinase plasminogen activation receptor (suPAR) is risk factor for kidney disease and biomarker for cardiovascular outcomes but long term longitudinal analyses in a large European cohort have not been perfomed. To hus, we studied suPAR in participants of the Ludwigshafen Risk and Cardiovascular Health study over a very long follow-up time of nearly 10 years. We estimated overall risk of all-cause and cardiovascular death by Cox proportional hazards regression according to quartiles of suPAR, including age, sex, use of lipid-lowering drugs, body mass index, diabetes mellitus, hypertension, smoking, lipids, as well as glomerular filtration rate (eGFR), NT-proBNP, interleukin-6 and high-sensitive CRP as covariates. A total of 2940 participants (age 62.7 ± 10.5years) having a median eGFR of 83.8 mL/min/1.73 m were included. The median suPAR concentration was 3010 pg/mL (interquartile range, 2250-3988 pg/mL). Using the lowest quartile of suPAR as the reference, crude hazard ratio for cardiovascular mortality were 1.58 (95% CI 1.16-2.16), 1.85 (95% CI 1.37-2.52) and 2.75 (95% CI 2.03-3.71) in the second, third and fourth quartile, respectively. Adjusting for NT-proBNPeGFR or inflammation (interleukin-6 and high-sensitive CRP) confirmed results. suPAR predicts all-cause and cardiovascular death over a period of ten years in persons undergoing coronary angiography, independent of the natriuretic peptide NT-proBNP, kidney function and of markers of systemic inflammation. Future investigation into a potential causal role of suPAR in cardiovascular disease is warranted.
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http://dx.doi.org/10.1038/s41598-018-36960-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346054PMC
January 2019

A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology.

Blood 2019 02 14;133(9):967-977. Epub 2019 Jan 14.

Department of Neurology, School of Medicine, University of Maryland, Baltimore, MD.

Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a -ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel ( and ) and 6 known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing in HuH7 cells upregulated FVII, whereas silencing downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at and contribute to FVII activity by regulating expression levels. FVII activity appears to contribute to the etiology of IS in the general population.
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http://dx.doi.org/10.1182/blood-2018-05-849240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396174PMC
February 2019

Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.

Circulation 2019 01;139(5):620-635

Institute of Cardiovascular and Medical Sciences (P.W.), University of Glasgow, UK.

Background: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.

Methods: We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.

Results: We identified 13 novel genome-wide significant ( P≤2.5×10) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.

Conclusions: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.034532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438386PMC
January 2019

Associations of fats and carbohydrates with cardiovascular disease and mortality-PURE and simple?

Lancet 2018 04 26;391(10131):1680-1681. Epub 2018 Apr 26.

Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig, Jena, Germany; Institute of Nutrition, Friedrich Schiller University Jena, Jena, Germany; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria; Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany.

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http://dx.doi.org/10.1016/S0140-6736(18)30798-0DOI Listing
April 2018

Negative effect of vitamin D on kidney function: a Mendelian randomization study.

Nephrol Dial Transplant 2018 12;33(12):2139-2145

Divisione di Nefrologia, Fondazione Policlinico Universitario A. Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy.

Background: The kidney plays a central role in the regulation of vitamin D metabolism. It is not clear, however, whether vitamin D influences kidney function. Previous studies have reported conflicting results, which may have been influenced by reverse causation and residual confounding. We conducted a Mendelian randomization (MR) study to obtain unconfounded estimates of the association between genetically instrumented vitamin D metabolites and estimated glomerular filtration rate (eGFR) as well as the urinary albumin:creatinine ratio (UACR).

Methods: We performed a two-sample MR study based on three single nucleotide variants associated with 25(OH)D levels: rs2282679, rs10741657 and rs12785878, related to the genes GC, CYP2R1 and DHCR7, respectively. Estimates of the allele-dependent effects on serum 25(OH)D and eGFR/UACR were obtained from summary statistics of published genome-wide association meta-analyses. Additionally, we performed a one-sample MR analysis for both 25(OH)D and 1,25(OH)2 D using individual-level data from six cohorts.

Results: The combined MR estimate supported a negative causal effect of log transformed 25(OH)D on log transformed eGFR (β = -0.013, P = 0.003). The analysis of individual-level data confirmed the main findings and also revealed a significant association of 1,25(OH)2 D on eGFR (β = -0.094, P = 0.008). These results show that a 10% increase in serum 25(OH)D levels causes a 0.3% decrease in eGFR. There was no effect of 25(OH)D on UACR (β = 0.032, P = 0.265).

Conclusion: Our study suggests that circulating vitamin D metabolite levels are negatively associated with eGFR. Further studies are needed to elucidate the underlying mechanisms.
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http://dx.doi.org/10.1093/ndt/gfy074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275146PMC
December 2018

Prospective cohort studies of beta-trace protein and mortality in haemodialysis patients and patients undergoing coronary angiography.

Nephrol Dial Transplant 2018 11;33(11):1984-1991

Division of Nephrology, Department of Internal Medicine I, Medical University of Bonn, Bonn.

Background: Beta-trace protein (BTP) is a low-molecular-weight glycoprotein, which may serve as an endogenous biomarker of kidney function and cardiovascular risk.

Methods: We examined cardiovascular and all-cause mortality according to BTP concentrations in 2962 individuals referred for coronary angiography from the Ludwigshafen Risk and Cardiovascular Health study and in 907 patients with Type 2 diabetes mellitus undergoing haemodialysis from the German Diabetes and Dialysis (4D) study.

Results: Haemodialysis patients had considerably higher median (interquartile range) BTP concentrations [6.00 (4.49-7.96) mg/L] and experienced a 4-fold increased mortality rate compared with coronary angiography patients [BTP concentration: 0.55 (0.44-0.67) mg/L]. After adjustment for age, sex, cardiovascular risk factors and creatinine, 4D patients in the highest quartile (>7.96 mg/L) had a 1.6-fold increased rate of all-cause mortality [hazard ratio (HR) 1.62, 95% confidence interval (CI) 1.19-2.20] compared with the lowest quartile (<4.49 mg/L) (P = 0.002) In patients undergoing coronary angiography, the adjusted HRs (95% CI) for all-cause and cardiovascular mortality were 1.23 (1.0-1.51) and 1.27 (0.99-1.63) in the highest (>0.67 mg/L) compared with the lowest (<0.44 mg/L) quartile (P = 0.043 and 0.062). In both cohorts, the BTP/creatinine ratio was a stronger predictor of all-cause and cardiovascular mortality compared with BTP.

Conclusion: BTP was associated with all-cause mortality independently of renal function in haemodialysis patients. The BTP/creatinine ratio was more predictive for all-cause and cardiovascular mortality in haemodialysis patients and individuals referred for angiography compared with BTP as single marker.
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http://dx.doi.org/10.1093/ndt/gfy025DOI Listing
November 2018

Saturated fatty acids and mortality in patients referred for coronary angiography-The Ludwigshafen Risk and Cardiovascular Health study.

J Clin Lipidol 2018 Mar - Apr;12(2):455-463.e3. Epub 2018 Jan 31.

Omegametrix, Martinsried, Germany; Department of Preventive Cardiology, Medizinische Klinik und Poliklinik I, Ludwig Maximilians University, Munich, Germany.

Background: Saturated fatty acids are thought to be harmful by increasing the risk for cardiovascular events.

Objective: We examined the associations of erythrocyte saturated fatty acids with total and cardiovascular mortality in patients referred for coronary angiography.

Methods: Red blood cell saturated fatty acid (RBC SFA) proportions were measured by gas chromatography at baseline in 3259 participants of the Ludwigshafen Risk and Cardiovascular Health study. Associations of saturated fatty acid concentrations with mortality were investigated using Cox proportional hazards regression.

Results: During a median follow-up of 9.9 years, 975 patients (29.9%) died and 614 patients (18.8%) died of cardiovascular causes. The proportion of palmitic acid (PA, C16:0) ranged from 15.1% to 27.4% with a mean (standard deviation) of 21.9% (1.15%) and was associated with an increased risk for mortality in models adjusted for conventional cardiovascular risk factors. An increase of 1-standard deviation in PA was associated with a hazard ratio (95% confidence interval) of 1.08 (1.01-1.16) for all cause and 1.05 (0.96-1.15) for cardiovascular mortality after adjustment for cardiovascular risk factors. For the other investigated RBC SFA (C14:0, C18:0, C20:0, C22:0, and C24:0), there was no association with mortality and also not for the sum of all saturated fatty acids.

Conclusions: Our results reveal association with increased mortality risk only for PA but not for the other RBC SFAs or the sum of all RBC SFAs and emphasize the need to investigate each fatty acid individually rather than studying groups of fatty acids.
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http://dx.doi.org/10.1016/j.jacl.2018.01.007DOI Listing
September 2019

Genetic Determinants of Circulating Estrogen Levels and Evidence of a Causal Effect of Estradiol on Bone Density in Men.

J Clin Endocrinol Metab 2018 03;103(3):991-1004

Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Laboratory of Clinical and Experimental Endocrinology, Leuven, Belgium.

Context: Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability.

Objective: To investigate the genetic regulation of serum E2 and E1 in men.

Design, Setting, And Participants: Genome-wide association study in 11,097 men of European origin from nine epidemiological cohorts.

Main Outcome Measures: Genetic determinants of serum E2 and E1 levels.

Results: Variants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10-8) and Xq27.3, rs5951794 (P = 3.1 × 10-10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10-23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10-14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10-8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10-12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance.

Conclusions: Our findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1.
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http://dx.doi.org/10.1210/jc.2017-02060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868407PMC
March 2018
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