Showing papers by "Winfried März published in 2016"
TL;DR: Distinct plasma ceramide ratios are significant predictors of CV death both in patients with stable CAD and ACS, over and above currently used lipid markers.
Abstract: All authors:Reijo Laaksonen, Kim Ekroos, Marko Sysi-Aho, Mika Hilvo, Terhi Vihervaara, Dimple Kauhanen, Matti Suoniemi, Reini Hurme, Winfried Marz, Hubert Scharnagl, Tatjana Stojakovic, Efthymia Vlachopoulou, Marja-Liisa Lokki, Markku S. Nieminen, Roland Klingenberg, Christian M. Matter, Thorsten Hornemann, Peter Juni, Nicolas Rodondi, Lorenz Raber, Stephan Windecker, Baris Gencer, Eva Ringdal Pedersen, Grethe S. Tell, Ottar Nygard, Francois Mach, Juha Sinisalo, Thomas F. Lusche
402 citations
TL;DR: Current available evidence does not support cardiovascular benefits or harms of vitamin D supplementation with the commonly used doses, and whether vitamin D has cardiovascular effects in individuals with overt vitamin D deficiency remains to be evaluated.
Abstract: Vitamin D is a precursor of the steroid hormone calcitriol that is crucial for bone and mineral metabolism. Both the high prevalence of vitamin D deficiency in the general population and the identification of the vitamin D receptor in the heart and blood vessels raised interest in the potential cardiovascular effects of vitamin D. Experimental studies have demonstrated various cardiovascular protective actions of vitamin D, but vitamin D intoxication in animals is known to induce vascular calcification. In meta-analyses of epidemiological studies, vitamin D deficiency is associated with an increased cardiovascular risk. Findings from Mendelian randomization studies and randomized, controlled trials (RCTs) do not indicate significant effects of a general vitamin D supplementation on cardiovascular outcomes. Previous RCTs, however, were not adequately designed to address extraskeletal events, and did not focus on vitamin D-deficient individuals. Therefore, currently available evidence does not support cardiovascular benefits or harms of vitamin D supplementation with the commonly used doses, and whether vitamin D has cardiovascular effects in individuals with overt vitamin D deficiency remains to be evaluated. Here, we provide an update on clinical studies on vitamin D and cardiovascular risk, discuss ongoing vitamin D research, and consider the management of vitamin D deficiency from a cardiovascular health perspective.
237 citations
Tuomas O. Kilpeläinen1, Tuomas O. Kilpeläinen2, Tuomas O. Kilpeläinen3, Jayne F. Martin Carli4 +224 more•Institutions (71)
TL;DR: In this article, the authors performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and identified five loci robustly associated with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO.
Abstract: Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
158 citations
TL;DR: The low concentrations of total TFAs found in LURIC were inversely associated with adverse cardiac outcomes, while the naturally occurring TFA C16:1n-7t was associated with reduced risk, no increased risk was found for industrially produced TFAs.
Abstract: Aims Trans -fatty acids (TFAs) are generated by the food industry and also occur naturally in trace amounts in dairy products. For the latter, beneficial health effects have been claimed, while there are numerous reports about TFA of industrial origin being hazardous to human health. Therefore, we aimed to investigate the association of TFA with mortality in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.
Methods and results The fatty acid composition of erythrocyte membranes was analysed using the HS-Omega-3 Index® methodology in 3259 participants of the LURIC study at baseline. During a median of 10.0 years of follow-up, a total of 975 (29.9%) study participants died, 614 (18.8%) from cardiovascular causes including 254 (7.8%) sudden cardiac deaths (SCDs). Association of TFA with clinical outcome was investigated with Cox proportional hazards regression. Total TFAs were inversely associated with mortality due to cardiovascular causes or SCD. This was mainly driven by the naturally occurring TFA C16:1n-7t ( trans -palmitoleic acid). The reduced risk of SCD associated with C16:1n-7t persisted after multivariate adjustment with a hazard ratio of 0.63 (0.46–0.86) for the third tertile compared with the first tertile. There was no association of any TFA subgroup with an increased risk of adverse outcomes.
Conclusions In contrast to previous findings, the low concentrations of total TFAs found in LURIC were inversely associated with adverse cardiac outcomes. While the naturally occurring TFA C16:1n-7t was associated with reduced risk, no increased risk was found for industrially produced TFAs.
120 citations
TL;DR: There is possible evidence from RCTs for protective vitamin D effects on TB and likely evidence for protective effects on acute airway infection.
Abstract: Vitamin D has immuno-modulatory properties, and deficient levels of circulating 25-hydroxyvitamin D (<30 nmol/l) may contribute to increased risk of infectious illnesses. This narrative review summarises data on vitamin D status in Europe and updates results of randomised controlled trials (RCTs) regarding vitamin D and airway infections such as tuberculosis (TB) and acute upper respiratory tract infection. In Europe, the prevalence of vitamin D deficiency is up to 37 % in the general population and up to 80 % in nursing home residents and non-European immigrants. Half of TB patients have a migration background. While results of RCTs do not support the concept of beneficial adjunctive effects of vitamin D supplements in anti-TB treatment [odds ratio (OR) = 0.86; 95 % CI 0.62–1.19], the few published RCTs on the prophylaxis of TB suggest some protective vitamin D effects in individuals with deficient circulating 25-hydroxyvitamin D levels. Regarding acute respiratory tract infection, RCTs indicate a significant risk reduction by vitamin D supplements [OR = 0.65; 95 % confidence interval (CI) 0.50–0.85]. There is evidence that daily administration is more effective than high-dose bolus administration [OR = 0.48 (95 % CI 0.30–0.77) vs. OR = 0.87 (95 % CI 0.67–1.14)] and that individuals with deficient or insufficient (30–50 nmol/l) circulating 25-hydroxyvitamin D levels benefit most. Several vitamin D effects on innate immunity may explain these protective effects. In summary, there is possible evidence from RCTs for protective vitamin D effects on TB and likely evidence for protective effects on acute airway infection. Since vitamin D deficiency is prevalent in Europe, especially in institutionalised individuals and non-European immigrants, daily oral vitamin D intake, e.g. 1000 international units, is an inexpensive measure to ensure adequate vitamin D status in individuals at risk.
90 citations
Harvard University1, Brigham and Women's Hospital2, Boston University3, National Institutes of Health4, University of Queensland5, VU University Amsterdam6, Ludwig Maximilian University of Munich7, Heidelberg University8, Los Angeles Biomedical Research Institute9, University of Sydney10, University of Wisconsin–Milwaukee11, Johns Hopkins University School of Medicine12, University of Copenhagen13, King's College London14, University of Michigan15, Pierre-and-Marie-Curie University16, University of Minnesota17, Wellcome Trust Centre for Human Genetics18, Mashhad University of Medical Sciences19, Fred Hutchinson Cancer Research Center20, University College Dublin21, Royal College of Surgeons in Ireland22, Frederiksberg Hospital23, University of Texas Health Science Center at Houston24, Science for Life Laboratory25, Royal North Shore Hospital26, University of Glasgow27, University of Cambridge28, Wellcome Trust Sanger Institute29, University of California, Davis30, University of Newcastle31, University of Helsinki32, Erasmus University Rotterdam33, University of Bristol34, Leiden University Medical Center35, University of Hamburg36, Technische Universität München37, Group Health Research Institute38, Cedars-Sinai Medical Center39, University of Split40, Aix-Marseille University41, Novo Nordisk Foundation42, University of Edinburgh43, Medical University of Graz44, Greifswald University Hospital45, University of Mainz46, University of Vermont47, University of Washington48, St George's, University of London49
TL;DR: A genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry identified 41 genome- wide significant fibrinogen loci; of which, 18 were newly identified.
Abstract: Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.
86 citations
Imperial College London1, Nanyang Technological University2, St George's, University of London3, University of Western Australia4, University of Amsterdam5, University of the Witwatersrand6, University of Manchester7, Masaryk University8, Saint Joseph's University9, Sultan Qaboos University10, Medical University of Łódź11, University of Oslo12, Instituto Nacional de Saúde Dr. Ricardo Jorge13, Institute of Chartered Accountants of Nigeria14, Charles University in Prague15, Innsbruck Medical University16, University of Ljubljana17, University of Lisbon18, McGill University19, Peking Union Medical College20, Ege University21, National University of Singapore22, University of Latvia23, Saarland University24, University of Ioannina25, Capital Medical University26, Tallaght Hospital27, University of Cape Town28, Heidelberg University29, Kyrgyz State Medical Academy30, University of Basel31, Universiti Teknologi MARA32, Linköping University33, University of Copenhagen34, University of Debrecen35, Vilnius University36, University of Zagreb37, Mashhad University of Medical Sciences38, University of the Philippines39, Technische Universität München40, United Arab Emirates University41, University of Monastir42, National Taiwan University43, University of Malta44, The Chinese University of Hong Kong45, Slovak Medical University46, University of Helsinki47, Osaka University48, University of Milan49
TL;DR: The European Atherosclerosis Society FH Studies Collaboration (EAS FHSC) is a new initiative of international stakeholders which will help establish a global FH registry to generate large-scale, robust data on the burden of FH worldwide.
85 citations
European Bioinformatics Institute1, Wellcome Trust Sanger Institute2, McGill University3, University of Washington4, Vita-Salute San Raffaele University5, University of Bristol6, University of Cambridge7, University of Trieste8, University Medical Center Groningen9, Harokopio University10, Karolinska Institutet11, Harvard University12, Erasmus University Medical Center13, King's College London14, University of Verona15, Queen Mary University of London16, Wellcome Trust Centre for Human Genetics17, Imperial College London18, National Institute for Health Research19, The Catholic University of America20, Qatar Airways21, National Institutes of Health22, Fred Hutchinson Cancer Research Center23, Synlab Group24, Heidelberg University25, Medical University of Graz26, John Radcliffe Hospital27, New York University28, University of Wisconsin–Milwaukee29
TL;DR: Genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry is applied, followed by association analysis with 20 quantitative cardiometabolic and hematological traits, resulting in 17 new associations.
Abstract: Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5%) variants with platelet count (PLT), red blood cell indices (MCH and MCV) and HDL cholesterol. Applying fine-mapping analysis to 233 known and new loci associated with the 20 traits, we resolve the associations of 59 loci to credible sets of 20 or fewer variants and describe trait enrichments within regions of predicted regulatory function. These findings improve understanding of the allelic architecture of risk factors for cardiometabolic and hematological diseases and provide additional functional insights with the identification of potentially novel biological targets.
70 citations
Harvard University1, Uppsala University2, Boston University3, University of Eastern Finland4, University of Washington5, University of Liverpool6, University of Oxford7, University of Tartu8, Leipzig University9, Imperial College London10, Heidelberg University11, Medical University of Graz12, University of Michigan13, University of Copenhagen14, University of Maryland, Baltimore15, Lund University16, University of Tübingen17, University of Cambridge18, University of Exeter19, University of Valencia20, University of California, Los Angeles21, Steno Diabetes Center22, Cedars-Sinai Medical Center23, Yeshiva University24, Minerva Foundation Institute for Medical Research25, University of Helsinki26, National Institute for Health and Welfare27, New York Academy of Medicine28, University of Pittsburgh29, Icahn School of Medicine at Mount Sinai30, University of Gothenburg31, Aalborg University32, Newcastle University33, National Institutes of Health34, University of North Carolina at Chapel Hill35, Augsburg College36, Group Health Cooperative37, Stanford University38
TL;DR: A genome-wide association study of the modified Stumvoll Insulin Sensitivity Index (ISI) was performed within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium, identifying two novel loci and replicated known variants associated with insulin sensitivity.
Abstract: Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.
62 citations
TL;DR: The frequency and the spectrum of FH causing mutations in Germany are investigated and this study further substantiates the mutation spectrum for FH in German patients and confirms the clinical and genetic heterogeneity of the disease.
39 citations
Journal Article•
TL;DR: It is documented in meta-analyses of randomized controlled trials that vitamin D3 supplementation is associated with a moderate, yet statistically significant, reduction in mortality, and this latter finding must be interpreted in light of some limitations such as incomplete follow-up data.
Abstract: In this narrative review, we aim to summarize and discuss the current evidence linking vitamin D and mortality. Low 25-hydroxyvitamin D [25(OH)D] concentrations are associated with an increased risk of mortality. This has been shown in different cohort studies including general populations, as well as various patient cohorts. Some single-study results and meta-analyses indicate that the shape of the relationship between 25(OH)D and mortality follows a U- or a reverse J-shaped curve. Interassay and laboratory differences are, however, a limitation of most previous surveys, and standardization of 25(OH)D measurements is needed for future investigations. Apart from observational data, it has been documented in meta-analyses of randomized controlled trials that vitamin D3 supplementation is associated with a moderate, yet statistically significant, reduction in mortality. This latter finding must be interpreted in light of some limitations such as incomplete follow-up data, but such a reduction of mortality with vitamin D3 supplementation as the finding of meta-analyses of randomized controlled trials strongly argues for the benefits and, importantly, also the safety of vitamin D.
TL;DR: The proprotein convertase subtilisin/kexin type 9 (PCSK9) plasma levels did not correlate with kidney function and were not associated with cardiovascular events in patients with reduced renal function.
Abstract: BACKGROUND
Impaired renal function causes dyslipidemia that contributes to elevated cardiovascular risk in patients with chronic kidney disease (CKD). The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a regulator of the LDL receptor and plasma cholesterol concentrations. Its relationship to kidney function and cardiovascular events in patients with reduced glomerular filtration rate (GFR) has not been explored.
METHODS
Lipid parameters including PCSK9 were measured in two independent cohorts. CARE FOR HOMe (Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Forth Homburg evaluation) enrolled 443 patients with reduced GFR (between 90 and 15 ml/min/1.73 m2) referred for nephrological care that were prospectively followed for the occurrence of a composite cardiovascular endpoint. As a replication cohort, PCSK9 was quantitated in 1450 patients with GFR between 90 and 15 ml/min/1.73 m2 enrolled in the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) that were prospectively followed for cardiovascular deaths.
RESULTS
PCSK9 concentrations did not correlate with baseline GFR (CARE FOR HOMe: r = -0.034; p = 0.479; LURIC: r = -0.017; p = 0.512). 91 patients in CARE FOR HOMe and 335 patients in LURIC reached an endpoint during a median follow-up of 3.0 [1.8-4.1] years and 10.0 [7.3-10.6] years, respectively. Kaplan-Meier analyses showed that PCSK9 concentrations did not predict cardiovascular events in either cohort [CARE FOR HOMe (p = 0.622); LURIC (p = 0.729)]. Sensitivity analyses according to statin intake yielded similar results.
CONCLUSION
In two well characterized independent cohort studies, PCSK9 plasma levels did not correlate with kidney function. Furthermore, PCSK9 plasma concentrations were not associated with cardiovascular events in patients with reduced renal function.
TL;DR: Using anti‐PCSK9 antibodies as add‐on therapy to other lipid‐lowering treatments or as monotherapy for patients unable to tolerate statins may help patients with high cardiovascular risk to achieve their LDL‐C goals.
Abstract: Aims
Two anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies, alirocumab and evolocumab, have been approved for the treatment of hypercholesterolaemia in certain patients. We reviewed data from Phase 3 studies to evaluate the efficacy and safety of these antibodies.
Methods
We systematically reviewed Phase 3 English-language studies in patients with hypercholesterolaemia, published between 1 January 2005 and 20 October 2015. Congress proceedings from 16 November 2012 to 16 November 2015 were also reviewed.
Results
We identified 12 studies of alirocumab and nine of evolocumab, including over 10 000 patients overall. Most studies enrolled patients with hypercholesterolaemia and used anti-PCSK9 antibodies with statins. The ODYSSEY FH I, FH II and HIGH FH alirocumab studies and the RUTHERFORD-2 evolocumab study exclusively recruited patients with heterozygous familial hypercholesterolaemia. Two evolocumab studies focused mainly on homozygous familial hypercholesterolaemia (HoFH): TESLA Part B and TAUSSIG (a TESLA sub-study); only those data for HoFH are reported here. All comparator studies demonstrated a reduction in LDL cholesterol (LDL-C) with the anti-PCSK9 antibodies. No head-to-head studies were conducted between alirocumab and evolocumab. Up to 87% of patients receiving alirocumab and up to 98% receiving evolocumab reached LDL-C goals. Both antibodies were effective and well tolerated across a broad population of patients and in specific subgroups, such as those with type 2 diabetes.
Conclusions
Using anti-PCSK9 antibodies as add-on therapy to other lipid-lowering treatments or as monotherapy for patients unable to tolerate statins may help patients with high cardiovascular risk to achieve their LDL-C goals.
TL;DR: High Lp(a) concentrations and LMW apo( a) isoforms are risk predictors for all-cause mortality and death due to infection in haemodialysis patients with diabetes mellitus and these associations are modified by age.
Abstract: Background High lipoprotein(a) [Lp(a)] concentrations and low molecular weight (LMW) apolipoprotein(a) [apo(a)] isoforms are associated with cardiovascular disease and mortality in the general population. We examined the association of both with all-cause mortality and cardiovascular endpoints in haemodialysis patients with diabetes mellitus. Methods This is a post hoc analysis of the prospective 4D Study (German Diabetes Dialysis Study) that evaluated atorvastatin compared with placebo in 1255 haemodialysis patients with type 2 diabetes mellitus (median follow-up 4 years). The association of natural logarithm-transformed Lp(a) concentrations (increment one unit) and apo(a) isoforms with outcomes was analysed by Cox proportional hazards regression. The influence of age (median 66 years) was evaluated by stratified survival analyses. Results The median baseline Lp(a) concentration was 11.5 mg/dL (IQR 5.0-41.8). A quarter of patients had at least one LMW apo(a) isoform. Increased Lp(a) concentrations were associated with all-cause mortality in the total group [hazard ratio (HR) 1.09 (95% CI 1.03-1.16), P = 0.004]. LMW apo(a) isoforms were only associated with all-cause mortality in patients ≤ 66 years [HR 1.38 (95% CI 1.05-1.80), P = 0.02]. The strongest association for Lp(a) concentrations and LMW apo(a) isoforms was found for death due to infection in patients ≤ 66 years [HR 1.39 (95% CI 1.14-1.71), P = 0.001; HR 2.17 (95% CI 1.26-3.75), P = 0.005]. Lp(a) concentrations were also associated with fatal stroke in patients ≤66 years of age [HR 1.54 (95% CI 1.05-2.24), P = 0.03]. Neither Lp(a) nor LMW apo(a) isoforms were associated with other atherosclerosis-related events. Conclusions High Lp(a) concentrations and LMW apo(a) isoforms are risk predictors for all-cause mortality and death due to infection in haemodialysis patients with diabetes mellitus. These associations are modified by age.
TL;DR: After 4 years of atorvastatin treatment in diabetic hemodialysis patients, similar effects on outcomes were found after 11.5 years of follow-up as were found at the end of the original study, and there was no evidence of emerging hazards in the long term.
University of Lübeck1, University of Tartu2, Stanford University3, Harvard University4, Wellcome Trust Centre for Human Genetics5, University of Oxford6, Science for Life Laboratory7, University of Tampere8, Queen Mary University of London9, Heidelberg University10, Icahn School of Medicine at Mount Sinai11, Glenfield Hospital12, University of Leicester13, University of Ottawa14, University of Pennsylvania15, Leipzig University16, Broad Institute17, Samsung Medical Center18, Technische Universität München19, Ealing Hospital20, Imperial College London21, Population Health Research Institute22, Harokopio University23, French Institute of Health and Medical Research24, Duke University25, University of Leeds26, Karolinska Institutet27, Cleveland Clinic28, Uppsala University29, Massachusetts Institute of Technology30, University of Liverpool31, National Institutes of Health32, Lebanese American University33, Imperial College Healthcare34, Kaiser Permanente35, Synlab Group36, Medical University of Graz37, University of Helsinki38, University of Oklahoma Health Sciences Center39, Wellcome Trust Sanger Institute40, King Abdulaziz University41
TL;DR: A comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts found none of the investigated models revealed genome-wide significant associations for any variant.
Abstract: In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.
TL;DR: To investigate the efficacy of vitamin D supplementation on glycaemic control, a large number of animals were tested and it was found that animals that received vitamin D supplements during the dry season had a higher chance of survival than those that did not.
Abstract: Aim
To investigate the efficacy of vitamin D supplementation on glycaemic control.
Methods
The Styrian Vitamin D Hypertension Trial was a single-centre, double-blind, placebo-controlled study conducted between 2011 and 2014 at the Medical University of Graz, Austria. We enrolled 200 people with arterial hypertension and 25-hydroxyvitamin D [25(OH)D] concentrations <30 ng/mL. Study participants were randomized to receive either 2800 IU of vitamin D or placebo per day for 8 weeks. The present study was a post hoc analysis that incorporated an analysis of covariance (ancova) approach, while adjusting for baseline differences.
Results
A total of 185 participants [mean ± standard deviation age, 60.1 ± 11.3 years; 47% women; mean 25(OH)D 21.2 ± 5.6 ng/mL, mean glycated haemoglobin (HbA1c) 44.8 ± 11.8 mmol/mol and mean body mass index 30.4 ± 5.4 kg/m2] completed the trial. ancova showed a mean treatment effect [95% confidence interval (CI)] on HbA1c of −3.52 (−6.7 to −0.34) mmol/mol (p = .045). There was no difference in fasting glucose −4.7 mg/dL (95% CI −16.3 to 6.9; p = .426).
Conclusions
Vitamin D supplementation in obese hypertensive patients with low 25(OH)D reduces HbA1c levels. This finding warrants further investigation into potential vitamin D effects on glucose homeostasis.
Journal Article•
TL;DR: New light is shed on the role of sunlight, skin pigmentation and vitamin D for human evolution in human evolution by testing the hypothesis that variants of several genes involved in different aspects of skin Pigmentation are predictive of serum 25(OH)D levels.
Abstract: Vitamin D deficiency is common and associated with higher risk for and unfavourable outcome of many diseases. Limited data exist on genetic determinants of serum 25(OH)D concentration. In a cohort of the LURIC study (n=2974, median 25(OH)D concentration 15.5 ng/ml), we tested the hypothesis that variants (SNPs, n=244) of several genes (n=15) involved in different aspects of skin pigmentation, including melanosomal biogenesis (ATP7A, DTNBP1, BLOC1S5, PLDN, PMEL), melanosomal transport within melanocytes (RAB27A, MYO5A, MLPH); or various melanocyte signaling pathways (MC1R, MITF, PAX3, SOX10, DKK1, RACK1, CNR1) are predictive of serum 25(OH)D levels. Eleven SNPs located in 6 genes were associated (p<0.05) with low or high serum 25(OH)D levels, 3 out of these 11 SNPs reached the aimed significance level after correction for multiple comparisons (FDR). In the linear regression model adjusted for sex, body mass index (BMI), year of birth and month of blood sample rs7565264 (MLPH), rs10932949 (PAX3), and rs9328451 (BLOC1S5) showed a significant association with 25(OH)D. The combined impact on variation of 25(OH)D serum levels (coefficient of determination (R(2))) for the 11 SNPs was 1.6% and for the 3 SNPs after FDR 0.3%. In Cox Regression we identified rs2292881 (MLPH) as having a significant association (advantage) with overall survival. Kaplan-Meier analysis did not show any significant impact of individual SNPs on overall survival. In conclusion, these results shed new light on the role of sunlight, skin pigmentation and vitamin D for human evolution.
TL;DR: A daily vitamin D supplement of 2800 IU for eight weeks did not improve Hb levels or anemic status in hypertensive patients, and future trials should focus on anemic patients with deficient 25OHD levels.
Abstract: Epidemiological evidence suggests that circulating 25-hydroxyvitamin D (25OHD) levels are inversely associated with hemoglobin (Hb) levels and anemia risk. We evaluated whether vitamin D supplementation improves Hb levels and reduces anemia risk in hypertensive patients. Two hundred patients with 25OHD levels 50 nmol/L. The mean (95% confidence interval) vitamin D effect on Hb levels was 0.04 (-0.14 to 0.22) g/dL (P = 0.661). Moreover, vitamin D treatment did not influence anemic status significantly (P > 0.999). Likewise, vitamin D had no significant effect on Hb levels in the subgroups of anemic patients or in patients with initial 25OHD levels <30 nmol/L. In conclusion, a daily vitamin D supplement of 2800 IU for eight weeks did not improve Hb levels or anemic status in hypertensive patients. Future trials should focus on anemic patients with deficient 25OHD levels (e.g., <30 nmol/L). This trial is registered with clinicaltrials.gov [NCT02136771].
TL;DR: In conclusion, AGXT2 variations may be involved in the pathogenesis of AF and its age-related thromboembolic complications.
Abstract: Asymmetric and symmetric dimethylarginines (ADMA and SDMA) impair nitric oxide bioavailability and have been implicated in the pathogenesis of atrial fibrillation (AF). Alanine-glyoxylate aminotransferase 2 (AGXT2) is the only enzyme capable of metabolizing both of the dimethylarginines. We hypothesized that two functional AGXT2 missense variants (rs37369, V140I; rs16899974, V498L) are associated with AF and its cardioembolic complications. Association analyses were conducted using 1,834 individulas with AF and 7,159 unaffected individuals from two coronary angiography cohorts and a cohort comprising patients undergoing clinical exercise testing. In coronary angiography patients without structural heart disease, the minor A allele of rs16899974 was associated with any AF (OR = 2.07, 95% CI 1.59-2.68), and with paroxysmal AF (OR = 1.98, 95% CI 1.44-2.74) and chronic AF (OR = 2.03, 95% CI 1.35-3.06) separately. We could not replicate the association with AF in the other two cohorts. However, the A allele of rs16899974 was nominally associated with ischemic stroke risk in the meta-analysis of WTCCC2 ischemic stroke cohorts (3,548 cases, 5,972 controls) and with earlier onset of first-ever ischemic stroke (360 cases) in the cohort of clinical exercise test patients. In conclusion, AGXT2 variations may be involved in the pathogenesis of AF and its age-related thromboembolic complications.
National Institutes of Health1, Boston University2, Ludwig Maximilian University of Munich3, University of Iceland4, Johns Hopkins University5, Cleveland Clinic6, University of Washington7, Wake Forest University8, Heidelberg University9, Harvard University10, University of Groningen11, Leiden University12, Erasmus University Rotterdam13, University of Greifswald14, Broad Institute15, Technische Universität München16, University of Minnesota17, University of California, Los Angeles18, Group Health Cooperative19, University of Colorado Denver20, University of Glasgow21, Greifswald University Hospital22, Emory University23, Medical University of Graz24, Synlab Group25
TL;DR: A large-scale association analysis of gene-gene interactions with AF performed in 8,173 AF cases and 65,237 AF-free referents collected from 15 studies for discovery did not find significant interactions that were associated with AF susceptibility.
Abstract: Atrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The objective of our study is to examine the effect of gene-gene interaction on AF susceptibility. We performed a large-scale association analysis of gene-gene interactions with AF in 8,173 AF cases, and 65,237 AF-free referents collected from 15 studies for discovery. We examined putative interactions between genome-wide SNPs and 17 known AF-related SNPs. The top interactions were then tested for association in an independent cohort for replication, which included more than 2,363 AF cases and 114,746 AF-free referents. One interaction, between rs7164883 at the HCN4 locus and rs4980345 at the SLC28A1 locus, was found to be significantly associated with AF in the discovery cohorts (interaction OR = 1.44, 95% CI: 1.27–1.65, P = 4.3 × 10–8). Eight additional gene-gene interactions were also marginally significant (P < 5 × 10–7). However, none of the top interactions were replicated. In summary, we did not find significant interactions that were associated with AF susceptibility. Future increases in sample size and denser genotyping might facilitate the identification of gene-gene interactions associated with AF.
TL;DR: Cross‐sectional data from the Styrian Hypertension Study suggest a direct interrelationship between PTH and nocturnal BP regulation, and whether lowering high PTH concentrations reduces the burden of high noCTurnal BP remains to be shown in future studies.
Abstract: High parathyroid hormone (PTH) has been linked with high blood pressure (BP), but the relationship with 24-hour ambulatory blood pressure monitoring is largely unknown. The authors therefore analyzed cross-sectional data of 292 hypertensive patients participating in the Styrian Hypertension Study (mean age, 61±11 years; 53% women). Median plasma PTH (interquartile range) determined after an overnight fast was 49 pg/mL (39-61), mean daytime BP was 131/80±12/9 mm Hg, and mean nocturnal BP was 115/67±14/9 mm Hg. In multivariate regression analyses adjusted for BP and PTH-modifying parameters, PTH was significantly related to nocturnal systolic and diastolic BP (adjusted β-coefficient 0.140 [P=.03] and 0.175 [P<.01], respectively). PTH was not correlated with daytime BP readings. These data suggest a direct interrelationship between PTH and nocturnal BP regulation. Whether lowering high PTH concentrations reduces the burden of high nocturnal BP remains to be shown in future studies.
TL;DR: This paper presents a meta-analyses of six major types of human papillomavirus: namely, coronavirus, Crimean-Tournaisian, Westphalian, North African, North American and West European varieties.
TL;DR: It is concluded that increased renin and angiotensin-II are independent predictors of mortality in active smokers and life-time non-smokers of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study as well as the utility of RAAS parameter for risk prediction.
Abstract: High concentrations of renin and aldosterone are risk factors for cardiovascular diseases (CVD) which are the leading cause of morbidity and mortality worldwide. Enhanced activation of the renin-angiotensin-aldosterone system (RAAS) by cigarette smoking has been reported. The aim of our study was to analyze the effect of cigarette smoking on parameters of the RAAS in active smokers (AS) and life-time non-smokers (NS) of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study as well as the utility of RAAS parameter for risk prediction. We determined the concentration of aldosterone, renin, angiotensin-I and angiotensin-II in participants of the LURIC study. Smoking status was assessed by a questionnaire and the measurement of plasma cotinine concentration. Parameters were log transformed before entering analyses, where appropriate. We used a multivariate Cox regression analysis to assess the effect of parameters on mortality. From the 3316 LURIC participants 777 were AS and 1178 NS. Within a median observation period of 10 years 221 (28.4 %) AS and 302 (25.6 %) NS died. After adjustment for age, gender, and the use of anti-hypertensive medication, only angiotensin-I was significantly different in AS compared to NS with an estimated marginal mean (95 % CI) of 1607 (1541–1673) ng/L and 1719 (1667–1772) ng/L, respectively. For both NS and AS renin and angiotensin-II were directly associated with mortality in the multivariate Cox regression analysis. Angiotensin-I was only associated with increased risk for mortality in NS (HR (95 % CI) of 0.69 (0.53–0.89)). We conclude that increased renin and angiotensin-II are independent predictors of mortality in AS and NS, while angiotensin-I was associated with reduced risk of death in NS only.
TL;DR: It is concluded that increased adiponectin is a strong and independent predictor of mortality in both active smokers and life-time non-smokers of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study.
Abstract: Cardiovascular diseases (CVD) are an important cause of morbidity and mortality worldwide. A decreased concentration of adiponectin has been reported in smokers. The aim of this study was to analyze the effect of cigarette smoking on the concentration of adiponectin and potassium in active smokers (AS) and life-time non-smokers (NS) of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study, and the use of these two markers for risk prediction. Smoking status was assessed by a questionnaire and measurement of plasma cotinine concentration. The serum concentration of adiponectin was measured by ELISA. Adiponectin was binned into tertiles separately for AS and NS and the Cox regression was used to assess the effect on mortality. There were 777 AS and 1178 NS among the LURIC patients. Within 10 years (median) of follow-up 221 AS and 302 NS died. In unadjusted analyses, AS had lower concentrations of adiponectin. However, after adjustment for age and gender there was no significant difference in adiponectin concentration between AS and NS. In the Cox regression model adjusted for age and gender, adiponectin was significantly associated with mortality in AS, but not in NS, with hazard ratio (95 % CI) of 1.60 (1.14–2.24) comparing the third with first tertile. In a model further adjusted for the risk factors, such as diabetes mellitus, hypertension, coronary artery disease, body mass index, LDL-cholesterol and HDL-cholesterol, adiponectin was significantly associated with mortality with hazard ratio of 1.83 (1.28–2.62) and 1.56 (1.15–2.11) for AS and NS, respectively. We conclude that increased adiponectin is a strong and independent predictor of mortality in both AS and NS. The determination of adiponectin concentration could be used to identify individuals at increased mortality risk.
TL;DR: Die genetische Diagnostik kommt bei Verdacht auf primare HLP infrage, aber wenig konventionellen Risikofaktoren und bei Patienten mit rapide voranschreitender Atherosklerose wird bereits in Leitlinien empfohlen.
Abstract: Klinisch bleiben Storungen des Fettstoffwechsels oft ohne Symptome. Hinweisend konnen Hauterscheinungen sein. Sekundare Hyperlipoproteinamien (HLP) sind haufiger als primare; sie konnen durch die Behandlung der Grunderkrankung (teilweise) gebessert werden. Neben Cholesterin, Triglyzeriden, LDL-Cholesterin (LDL-C) und HDL-Cholesterin (HDL-C) sind meist Bestimmungen von Glukose, HbA1C, TSH, Transaminasen, Kreatinin, Harnstoff, Eiweis und Eiweis im Urin sinnvoll. Da praktisch alle Routinemethoden fur LDL-C durch hohe Triglyzeride gestort werden, ist bei Triglyzeriden uber 400 mg/dl (4,7 mmol/l) eine Lipoproteinelektrophorese indiziert. Primare HLP haben bekannte oder noch nicht bekannte genetische Ursachen. An eine differenzialdiagnostisch bedeutsame primare HLP ist vor allem dann zu denken, wenn es sich um junge Patienten handelt, die Konzentrationen des LDL uber 190 mg/dl (4,9 mmol/l) und/oder der Triglyzeride uber 200 mg/dl (2,3 mmol/l) liegen und eine sekundare HLP (Adipositas, Alkohol, Diabetes mellitus, Nierenerkrankungen) ausgeschlossen ist. Die Basisdiagnostik wird durch die Messung von Lipoprotein (a) (Lp(a)) sinnvoll erweitert. Sie ist indiziert bei intermediarem Risiko fur Gefaserkrankungen, familiarer Hypercholesterinamie, bei Patienten mit fruhzeitiger Koronarkrankheit, aber wenig konventionellen Risikofaktoren und bei Patienten mit rapide voranschreitender Atherosklerose. Konzentrationen uber 30 mg/dl sollten dazu veranlassen, LDL besonders intensiv zu behandeln. Die genetische Diagnostik kommt bei Verdacht auf primare HLP infrage. Sie ist am haufigsten indiziert bei Verdacht auf familiare Hypercholesterinamie (FH, autosomal dominante Hypercholesterinamie, ADH) und wird bereits in Leitlinien empfohlen.