Publications by authors named "Simone Wahl"

62 Publications

Randomized test-treatment studies with an outlook on adaptive designs.

BMC Med Res Methodol 2021 06 1;21(1):110. Epub 2021 Jun 1.

Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg, 20246, Germany.

Background: Diagnostic accuracy studies aim to examine the diagnostic accuracy of a new experimental test, but do not address the actual merit of the resulting diagnostic information to a patient in clinical practice. In order to assess the impact of diagnostic information on subsequent treatment strategies regarding patient-relevant outcomes, randomized test-treatment studies were introduced. Various designs for randomized test-treatment studies, including an evaluation of biomarkers as part of randomized biomarker-guided treatment studies, are suggested in the literature, but the nomenclature is not consistent.

Methods: The aim was to provide a clear description of the different study designs within a pre-specified framework, considering their underlying assumptions, advantages as well as limitations and derivation of effect sizes required for sample size calculations. Furthermore, an outlook on adaptive designs within randomized test-treatment studies is given.

Results: The need to integrate adaptive design procedures in randomized test-treatment studies is apparent. The derivation of effect sizes induces that sample size calculation will always be based on rather vague assumptions resulting in over- or underpowered study results. Therefore, it might be advantageous to conduct a sample size re-estimation based on a nuisance parameter during the ongoing trial.

Conclusions: Due to their increased complexity, compared to common treatment trials, the implementation of randomized test-treatment studies poses practical challenges including a huge uncertainty regarding study parameters like the expected outcome in specific subgroups or disease prevalence which might affect the sample size calculation. Since research on adaptive designs within randomized test-treatment studies is limited so far, further research is recommended.
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http://dx.doi.org/10.1186/s12874-021-01293-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167391PMC
June 2021

The Alzheimer's Association international guidelines for handling of cerebrospinal fluid for routine clinical measurements of amyloid β and tau.

Alzheimers Dement 2021 09 31;17(9):1575-1582. Epub 2021 Mar 31.

Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

The core cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers amyloid beta (Aβ42 and Aβ40), total tau, and phosphorylated tau, have been extensively clinically validated, with very high diagnostic performance for AD, including the early phases of the disease. However, between-center differences in pre-analytical procedures may contribute to variability in measurements across laboratories. To resolve this issue, a workgroup was led by the Alzheimer's Association with experts from both academia and industry. The aim of the group was to develop a simplified and standardized pre-analytical protocol for CSF collection and handling before analysis for routine clinical use, and ultimately to ensure high diagnostic performance and minimize patient misclassification rates. Widespread application of the protocol would help minimize variability in measurements, which would facilitate the implementation of unified cut-off levels across laboratories, and foster the use of CSF biomarkers in AD diagnostics for the benefit of the patients.
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http://dx.doi.org/10.1002/alz.12316DOI Listing
September 2021

DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures.

Clin Epigenetics 2021 01 7;13(1). Epub 2021 Jan 7.

Center for Life Course Health Research, University of Oulu, Oulu University Hospital, Oulu, Finland.

Background: The discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances.

Results: We conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value < 4.7 × 10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations.

Conclusion: Our study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.
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http://dx.doi.org/10.1186/s13148-020-00957-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789600PMC
January 2021

Pre-analytical protocol for measuring Alzheimer's disease biomarkers in fresh CSF.

Alzheimers Dement (Amst) 2020 18;12(1):e12137. Epub 2020 Dec 18.

Clinical Memory Research Unit Department of Clinical Sciences Malmö Lund University Malmö Sweden.

Introduction: We aimed to establish a standardized, routine-use pre-analytical protocol for measuring Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF).

Methods: The effect of pre-analytical factors (sample collection/handling/storage/transportation) on biomarker levels was assessed using freshly collected CSF. Tube type/sterilization was assessed using previously frozen samples. A low-bind false-bottom tube (FBT, Sarstedt) was used for all experiments, except tube types/sterilization experiments. Biomarkers were measured using Elecsys CSF assays.

Results: Amyloid beta (Aβ) levels varied by tube type, using a low-bind FBT reduced variation. Aβ levels were higher with no mixing versus roller/inversion mixing. Aβ levels were lower with horizontal versus upright transportation; this was resolved by maximal tube filling and storage at 2°C to 8°C. Aβ levels were less strongly affected. Phospho-tau and total-tau levels were largely unaffected.

Discussion: We propose an easy-to-use, standardized, routine-use pre-analytical protocol, using low-bind FBTs, for measuring AD CSF biomarkers in clinical practice.
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http://dx.doi.org/10.1002/dad2.12137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748029PMC
December 2020

Obesity Genes and Weight Loss During Lifestyle Intervention in Children With Obesity.

JAMA Pediatr 2021 Jan 4;175(1):e205142. Epub 2021 Jan 4.

Department of Prevention and Sports Medicine, Centre for Sports Cardiology, University Hospital "Klinikum rechts der Isar," Technical University of Munich, Munich, Germany.

Importance: Genome-wide association studies have identified genetic loci influencing obesity risk in children. However, the importance of these loci in the associations with weight reduction through lifestyle interventions has not been investigated in large intervention trials.

Objective: To evaluate the associations between various obesity susceptibility loci and changes in body weight in children during an in-hospital, lifestyle intervention program.

Design, Setting, And Participants: Long-term Effects of Lifestyle Intervention in Obesity and Genetic Influence in Children (LOGIC), an interventional prospective cohort study, enrolled 1429 children with overweight or obesity to participate in an in-hospital lifestyle intervention program. Genotyping of 56 validated obesity single-nucleotide variants (SNVs) was performed, and the associations between the SNVs and body weight reduction during the intervention were evaluated using linear mixed-effects models for each SNV. The LOGIC study was conducted from January 6, 2006, to October 19, 2013; data analysis was performed from July 15, 2015, to November 6, 2016.

Exposures: A 4- to 6-week standardized in-hospital lifestyle intervention program (daily physical activity, calorie-restricted diet, and behavioral therapy).

Main Outcomes And Measures: The association between 56 obesity-relevant SNVs and changes in body weight and body mass index.

Results: Of 1429 individuals enrolled in the LOGIC Study, 1198 individuals (mean [SD] age, 14.0 [2.2] years; 670 [56%] girls) were genotyped. A mean (SD) decrease was noted in body weight of -8.7 (3.6) kg (95% CI, -15.7 to -1.8 kg), and body mass index (calculated as weight in kilograms divided by height in meters squared) decreased by -3.3 (1.1) (95% CI, -5.4 to -1.1) (both P < .05). Five of 56 obesity SNVs were statistically significantly associated with a reduction of body weight or body mass index (all P < 8.93 × 10-4 corresponding to Bonferroni correction for 56 tests). Compared with homozygous participants without the risk allele, homozygous carriers of the rs7164727 (LOC100287559: 0.42 kg; 95% CI, 0.31-0.53 kg, P = 4.00 × 10-4) and rs12940622 (RPTOR: 0.35 kg; 95% CI, 0.18-0.52 kg; P = 1.86 × 10-5) risk alleles had a lower reduction of body weight, whereas carriers of the rs13201877 (IFNGR1: 0.65 kg; 95% CI, 0.51-0.79 kg; P = 2.39 × 10-5), rs10733682 (LMX1B: 0.45 kg; 95% CI, 0.27-0.63 kg; P = 6.37 × 10-4), and rs2836754 (ETS2: 0.56 kg; 95% CI, 0.38-0.74 kg; P = 1.51 × 10-4) risk alleles were associated with a greater reduction of body weight after adjustment for age and sex.

Conclusions And Relevance: Genes appear to play a minor role in weight reduction by lifestyle in children with overweight or obesity. The findings suggest that environmental, social, and behavioral factors are more important to consider in obesity treatment strategies.
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http://dx.doi.org/10.1001/jamapediatrics.2020.5142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737153PMC
January 2021

A genome-wide analysis of DNA methylation identifies a novel association signal for Lp(a) concentrations in the LPA promoter.

PLoS One 2020 28;15(4):e0232073. Epub 2020 Apr 28.

Department of Genetics and Pharmacology, Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria.

Lipoprotein(a) [Lp(a)] is a major cardiovascular risk factor, which is largely genetically determined by one major gene locus, the LPA gene. Many aspects of the transcriptional regulation of LPA are poorly understood and the role of epigenetics has not been addressed yet. Therefore, we conducted an epigenome-wide analysis of DNA methylation on Lp(a) levels in two population-based studies (total n = 2208). We identified a CpG site in the LPA promoter which was significantly associated with Lp(a) concentrations. Surprisingly, the identified CpG site was found to overlap the SNP rs76735376. We genotyped this SNP de-novo in three studies (total n = 7512). The minor allele of rs76735376 (1.1% minor allele frequency) was associated with increased Lp(a) values (p = 1.01e-59) and explained 3.5% of the variation of Lp(a). Statistical mediation analysis showed that the effect on Lp(a) is rather originating from the base change itself and is not mediated by DNA methylation levels. This finding is supported by eQTL data from 208 liver tissue samples from the GTEx project, which shows a significant association of the rs76735376 minor allele with increased LPA expression. To evaluate, whether the association signal at rs76735376 may actually be derived from a stronger eQTL signal in LD with this SNP, eQTL association results of all correlated SNPs (r2≥0.1) were integrated with genetic association results. This analysis pinpointed to rs10455872 as the potential trigger of the effect of rs76735376. Furthermore, both SNPs coincide with short apo(a) isoforms. Adjusting for both, rs10455872 and the apo(a) isoforms diminished the effect size of rs76735376 to 5.38 mg/dL (p = 0.0463). This indicates that the effect of rs76735376 can be explained by both an independent effect of the SNP and a strong correlation with rs10455872 and apo(a) isoforms.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232073PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188291PMC
July 2020

Predicting clinical decline and conversion to Alzheimer's disease or dementia using novel Elecsys Aβ(1-42), pTau and tTau CSF immunoassays.

Sci Rep 2019 12 13;9(1):19024. Epub 2019 Dec 13.

Clinical Memory Research Unit, Lund University, Malmö, Sweden.

We evaluated the performance of CSF biomarkers for predicting risk of clinical decline and conversion to dementia in non-demented patients with cognitive symptoms. CSF samples from patients in two multicentre longitudinal studies (ADNI, n = 619; BioFINDER, n = 431) were analysed. Aβ(1-42), tTau and pTau CSF concentrations were measured using Elecsys CSF immunoassays, and tTau/Aβ(1-42) and pTau/Aβ(1-42) ratios calculated. Patients were classified as biomarker (BM)-positive or BM-negative at baseline. Ability of biomarkers to predict risk of clinical decline and conversion to AD/dementia was assessed using pre-established cut-offs for Aβ(1-42) and ratios; tTau and pTau cut-offs were determined. BM-positive patients showed greater clinical decline than BM-negative patients, demonstrated by greater decreases in MMSE scores (all biomarkers: -2.10 to -0.70). Risk of conversion to AD/dementia was higher in BM-positive patients (HR: 1.67 to 11.48). Performance of Tau/Aβ(1-42) ratios was superior to single biomarkers, and consistent even when using cut-offs derived in a different cohort. Optimal pTau and tTau cut-offs were approximately 27 pg/mL and 300 pg/mL in both BioFINDER and ADNI. Elecsys pTau/Aβ(1-42) and tTau/Aβ(1-42) are robust biomarkers for predicting risk of clinical decline and conversion to dementia in non-demented patients, and may support AD diagnosis in clinical practice.
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http://dx.doi.org/10.1038/s41598-019-54204-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911086PMC
December 2019

Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease.

Circulation 2019 08 19;140(8):645-657. Epub 2019 Aug 19.

Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle (J.A.B., J.S.F., K.L.W.).

Background: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.

Methods: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.

Results: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts.

Conclusion: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.039357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812683PMC
August 2019

Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-κB-driven inflammation and cardiovascular risk.

Proc Natl Acad Sci U S A 2019 06 21;116(23):11370-11379. Epub 2019 May 21.

Institute of Epidemiology, Helmholtz Zentrum München - German Research Centre for Environmental Health, D-85764 Neuherberg, Germany.

Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate expression. These age/stress-related epigenetic effects were recapitulated in a cellular model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher mRNA with a proinflammatory profile and altered NF-κB-related gene networks. Accordingly, experiments in immune cells showed that higher promotes inflammation by strengthening the interactions of NF-κB regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-κB. Further, the age/stress-related epigenetic signature enhanced response to NF-κB through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that aging/stress-driven FKBP5-NF-κB signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.
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http://dx.doi.org/10.1073/pnas.1816847116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561294PMC
June 2019

Characterization of missing values in untargeted MS-based metabolomics data and evaluation of missing data handling strategies.

Metabolomics 2018 09 20;14(10):128. Epub 2018 Sep 20.

Institute of Computational Biology, Helmholtz-Zentrum München, Neuherberg, Germany.

Background: Untargeted mass spectrometry (MS)-based metabolomics data often contain missing values that reduce statistical power and can introduce bias in biomedical studies. However, a systematic assessment of the various sources of missing values and strategies to handle these data has received little attention. Missing data can occur systematically, e.g. from run day-dependent effects due to limits of detection (LOD); or it can be random as, for instance, a consequence of sample preparation.

Methods: We investigated patterns of missing data in an MS-based metabolomics experiment of serum samples from the German KORA F4 cohort (n = 1750). We then evaluated 31 imputation methods in a simulation framework and biologically validated the results by applying all imputation approaches to real metabolomics data. We examined the ability of each method to reconstruct biochemical pathways from data-driven correlation networks, and the ability of the method to increase statistical power while preserving the strength of established metabolic quantitative trait loci.

Results: Run day-dependent LOD-based missing data accounts for most missing values in the metabolomics dataset. Although multiple imputation by chained equations performed well in many scenarios, it is computationally and statistically challenging. K-nearest neighbors (KNN) imputation on observations with variable pre-selection showed robust performance across all evaluation schemes and is computationally more tractable.

Conclusion: Missing data in untargeted MS-based metabolomics data occur for various reasons. Based on our results, we recommend that KNN-based imputation is performed on observations with variable pre-selection since it showed robust results in all evaluation schemes.
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http://dx.doi.org/10.1007/s11306-018-1420-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153696PMC
September 2018

Derivation of cutoffs for the Elecsys amyloid β (1-42) assay in Alzheimer's disease.

Alzheimers Dement (Amst) 2018 11;10:698-705. Epub 2018 Aug 11.

Indiana University School of Medicine, Indianapolis, IN, USA.

Introduction: An Elecsys® Amyloid β (Aβ [1-42]) immunoassay cutoff for classification of patients with Alzheimer's disease was investigated.

Methods: Cerebrospinal fluid samples collected from patients with mild-to-moderate Alzheimer's disease were analyzed by Elecsys® immunoassays: (1) Aβ (1-42), (2) total tau, and (3) phosphorylated tau. Cutoffs (Aβ [1-42] and ratios with tau) were estimated by method comparison between AlzBio3 ( = 206), mixture modeling ( = 216), and concordance with florbetapir F 18 imaging-based classification ( = 75).

Results: A 1065-pg/mL (95% confidence interval: 985-1153) Elecsys® Aβ (1-42) cutoff provided 94% overall percentage agreement with AlzBio3. Comparable cutoff estimates (95% confidence interval) were derived from mixture modeling (equally weighted: 1017 [949-1205] pg/mL; prevalence weighted: 1172 [1081-1344] pg/mL) and concordance with florbetapir F 18 imaging (visual read: 1198 [998-1591] pg/mL; automated: 1198 [1051-1638] pg/mL).

Discussion: Based on three approaches, a 1100-pg/mL Elecsys® Aβ (1-42) cutoff is suitable for clinical trials with similar populations and preanalytical handling.
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http://dx.doi.org/10.1016/j.dadm.2018.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222032PMC
August 2018

Diagnostic performance of Elecsys immunoassays for cerebrospinal fluid Alzheimer's disease biomarkers in a nonacademic, multicenter memory clinic cohort: The ABIDE project.

Alzheimers Dement (Amst) 2018 12;10:563-572. Epub 2018 Sep 12.

Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Introduction: We compared the automated Elecsys and manual Innotest immunoassays for cerebrospinal fluid (CSF) Alzheimer's disease biomarkers in a multicenter diagnostic setting.

Methods: We collected CSF samples from 137 participants in eight local memory clinics. Amyloid β(1-42) (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) were centrally analyzed with Innotest and Elecsys assays. Concordances between methods were assessed.

Results: Biomarker results strongly correlated between assays with Spearman's ρ 0.94 for Aβ42, 0.98 for t-tau, and 0.98 for p-tau. Using Gaussian mixture modeling, cohort-specific cut-points were estimated at 1092 pg/mL for Aβ42, 235 pg/mL for t-tau, and 24 pg/mL for p-tau. We found an excellent concordance of biomarker abnormality between assays of 97% for Aβ42 and 96% for both t-tau and p-tau.

Discussion: The high concordances between Elecsys and Innotest in this nonacademic, multicenter cohort support the use of Elecsys for CSF Alzheimer's disease diagnostics and allow conversion of results between methods.
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http://dx.doi.org/10.1016/j.dadm.2018.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215060PMC
September 2018

Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.

Am J Hum Genet 2018 11;103(5):691-706

Department of Epidemiology and Prevention, Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
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http://dx.doi.org/10.1016/j.ajhg.2018.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218410PMC
November 2018

Metastable DNA methylation sites associated with longitudinal lung function decline and aging in humans: an epigenome-wide study in the NAS and KORA cohorts.

Epigenetics 2018 21;13(10-11):1039-1055. Epub 2018 Oct 21.

c Office of Research , Dana-Farber/Harvard Cancer Institute , Boston , MA , USA.

DNA methylation is an epigenetic regulator of gene transcription, which has been found to be both metastable and variable within human cohort studies. Currently, few studies have been done to identify metastable DNA methylation biomarkers associated with longitudinal lung function decline in humans. The identification of such biomarkers is important for screening vulnerable populations. We hypothesized that quantifiable blood-based DNA methylation alterations would serve as metastable biomarkers of lung function decline and aging, which may help to discover new pathways and/or mechanisms related to pulmonary pathogenesis. Using linear mixed models, we performed an Epigenome Wide Association Study (EWAS) between DNA methylation at CpG dinucleotides and longitudinal lung function (FVC, FEV, FEF) decline and aging with initial discovery in the Normative Aging Study, and replication in the Cooperative Health Research in the Region of Augsburg cohort. We identified two metastable epigenetic loci associated with either poor lung function and aging, cg05575921 (AHRR gene), or lung function independently of aging, cg06126421 (IER3 gene). These loci may inform basic mechanisms associated with pulmonary function, pathogenesis, and aging. Human epigenomic variation, may help explain features of lung function decline and related pathophysiology not attributable to DNA sequence alone, such as accelerated pulmonary decline in smokers, former smokers, and perhaps non-smokers. Our EWAS across two cohorts, therefore, will likely have implications for the human population, not just the elderly.
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http://dx.doi.org/10.1080/15592294.2018.1529849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342072PMC
March 2019

Prenatal Alcohol Exposure Is Associated With Adverse Cognitive Effects and Distinct Whole-Genome DNA Methylation Patterns in Primary School Children.

Front Behav Neurosci 2018 26;12:125. Epub 2018 Jun 26.

Department of Child and Adolescent Mental Health, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.

Prenatal alcohol exposure (PAE) is known to elicit a broad range of systemic effects, including neurophysiological alterations that result in adverse behavioral and cognitive outcomes. However, molecular pathways underlying these long-term intrauterine effects remain to be investigated. Here, we tested a hypothesis that PAE may lead to epigenetic alterations to the DNA resulting in attentional and cognitive alterations of the children. We report the results of the study that included 156 primary school children of the Franconian Cognition and Emotion Studies (FRANCES) cohort which were tested for an objective marker of PAE, ethyl glucuronide (EtG) in meconium at birth. Thirty-two newborns were found to be exposed to alcohol with EtG values above 30 ng/g (EtG+). Previously we described PAE being associated with lower IQ and smaller amplitude of the event-related potential component P3 in go trials (Go-P3), which indicates a reduced capacity of attentional resources. Whole-genome methylation analysis of the buccal cell DNA revealed 193 differentially methylated genes in children with positive meconium EtG, that were clustered into groups involved in epigenetic modifications, neurodegeneration, neurodevelopment, axon guidance and neuronal excitability. Furthermore, we detected mediation effects of the methylation changes in and genes on the EtG related cognitive and attention-related deficits. Our results suggest that system-wide epigenetic changes are involved in long-term effects of PAE. In particular, we show an epigenetic mediation of PAE effects on cognition and attention-related processes.
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http://dx.doi.org/10.3389/fnbeh.2018.00125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028559PMC
June 2018

Cerebrospinal fluid biomarkers measured by Elecsys assays compared to amyloid imaging.

Alzheimers Dement 2018 11 2;14(11):1460-1469. Epub 2018 Mar 2.

Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Introduction: Levels of amyloid β peptide 42 (Aβ42), total tau, and phosphorylated tau-181 are well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease, but variability in manual plate-based assays has limited their use. We examined the relationship between CSF biomarkers, as measured by a novel automated immunoassay platform, and amyloid positron emission tomography.

Methods: CSF samples from 200 individuals underwent separate analysis for Aβ42, total tau, and phosphorylated tau-181 with automated Roche Elecsys assays. Aβ40 was measured with a commercial plate-based assay. Positron emission tomography with Pittsburgh Compound B was performed less than 1 year from CSF collection.

Results: Ratios of CSF biomarkers (total tau/Aβ42, phosphorylated tau-181/Aβ42, and Aβ42/Aβ40) best discriminated Pittsburgh Compound B-positive from Pittsburgh Compound B-negative individuals.

Discussion: CSF biomarkers and amyloid positron emission tomography reflect different aspects of Alzheimer's disease brain pathology, and therefore, less-than-perfect correspondence is expected. Automated assays are likely to increase the utility of CSF biomarkers.
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http://dx.doi.org/10.1016/j.jalz.2018.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119652PMC
November 2018

Allele-specific methylation of type 1 diabetes susceptibility genes.

J Autoimmun 2018 05 8;89:63-74. Epub 2017 Dec 8.

Institute of Diabetes and Obesity, Helmholtz Zentrum München, Neuherberg, Germany; Center for Regenerative Therapies - Dresden, Faculty of Medicine Carl Gustav Carus, Technische Universität, Dresden, Germany; Forschergruppe Diabetes e.V., Neuherberg, Germany. Electronic address:

The susceptibility to autoimmune diseases is influenced by genes encoding major histocompatibility complex (MHC) proteins. By examining the epigenetic methylation maps of cord blood samples, we found marked differences in the methylation status of CpG sites within the MHC genes (cis-metQTLs) between carriers of the type 1 diabetes risk haplotypes HLA-DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) and HLA-DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8). These differences were found in children and adults, and were accompanied by reduced HLA-DR protein expression in immune cells with the HLA-DR3-DQ2 haplotype. Extensive cis-metQTLs were identified in all 45 immune and non-immune type 1 diabetes susceptibility genes analyzed in this study. We observed and validated a novel association between the methylation status of CpG sites within the LDHC gene and the development of insulin autoantibodies in early childhood in children who are carriers of the highest type 1 diabetes risk genotype. Functionally relevant epigenetic changes in susceptibility genes may represent therapeutic targets for type 1 diabetes.
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http://dx.doi.org/10.1016/j.jaut.2017.11.008DOI Listing
May 2018

DNA-Methylation and Body Composition in Preschool Children: Epigenome-Wide-Analysis in the European Childhood Obesity Project (CHOP)-Study.

Sci Rep 2017 10 30;7(1):14349. Epub 2017 Oct 30.

Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, Ludwig-Maximilians Universität München (LMU), Munich, Germany.

Adiposity and obesity result from the interaction of genetic variation and environmental factors from very early in life, possibly mediated by epigenetic processes. Few Epigenome-Wide-Association-Studies have identified DNA-methylation (DNAm) signatures associated with BMI and body composition in children. Body composition by Bio-Impedance-Analysis and genome-wide DNAm in whole blood were assessed in 374 pre-school children from four European countries. Associations were tested by linear regression adjusted for sex, age, centre, education, 6 WBC-proportions according to Houseman and 30 principal components derived from control probes. Specific DNAm variants were identified to be associated with BMI (212), fat-mass (230), fat-free-mass (120), fat-mass-index (24) and fat-free-mass-index (15). Probes in genes SNED1(IRE-BP1), KLHL6, WDR51A(POC1A), CYTH4-ELFN2, CFLAR, PRDM14, SOS1, ZNF643(ZFP69B), ST6GAL1, C3orf70, CILP2, MLLT4 and ncRNA LOC101929268 remained significantly associated after Bonferroni-correction of P-values. We provide novel evidence linking DNAm with (i) altered lipid and glucose metabolism, (ii) diabetes and (iii) body size and composition in children. Both common and specific epigenetic signatures among measures were also revealed. The causal direction with phenotypic measures and stability of DNAm variants throughout the life course remains unclear and longitudinal analysis in other populations is required. These findings give support for potential epigenetic programming of body composition and obesity.
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http://dx.doi.org/10.1038/s41598-017-13099-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662763PMC
October 2017

Long-Term Stability of Human Plasma Metabolites during Storage at -80 °C.

J Proteome Res 2018 01 28;17(1):203-211. Epub 2017 Nov 28.

Lehrstuhl für Experimentelle Genetik, Technische Universität München , 85350 Freising-Weihenstephan, Germany.

Prolonged storage of biospecimen can lead to artificially altered metabolite concentrations and thus bias data analysis in metabolomics experiments. To elucidate the potential impact of long-term storage on the metabolite profile, a pooled human plasma sample was aliquoted and stored at -80 °C. During a time period of five years, 1012 of the aliquots were measured with the Biocrates AbsoluteIDQ p180 targeted-metabolomics assay at 193 time points. Modeling the concentration courses over time revealed that 55 out of 111 metabolites remained stable. The statistically significantly changed metabolites showed on average an increase or decrease of +13.7% or -14.5%, respectively. In detail, increased concentration levels were observed for amino acids (mean: + 15.4%), the sum of hexoses (+7.9%), butyrylcarnitine (+9.4%), and some phospholipids mostly with chain lengths exceeding 40 carbon atoms (mean: +18.0%). Lipids tended to exhibit decreased concentration levels with the following mean concentration changes: acylcarnitines, -12.1%; lysophosphatidylcholines, -15.1%; diacyl-phosphatidylcholines, -17.0%; acyl-alkyl-phosphatidylcholines, -13.3%; sphingomyelins, -14.8%. We conclude that storage of plasma samples at -80 °C for up to five years can lead to altered concentration levels of amino acids, acylcarnitines, glycerophospholipids, sphingomyelins, and the sum of hexoses. These alterations must be considered when analyzing metabolomics data from long-term epidemiological studies.
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http://dx.doi.org/10.1021/acs.jproteome.7b00518DOI Listing
January 2018

The dynamics of smoking-related disturbed methylation: a two time-point study of methylation change in smokers, non-smokers and former smokers.

BMC Genomics 2017 Oct 18;18(1):805. Epub 2017 Oct 18.

Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764, Neuherberg, Bavaria, Germany.

Background: The evidence for epigenome-wide associations between smoking and DNA methylation continues to grow through cross-sectional studies. However, few large-scale investigations have explored the associations using observations for individuals at multiple time-points. Here, through the use of the Illumina 450K BeadChip and data collected at two time-points separated by approximately 7 years, we investigate changes in methylation over time associated with quitting smoking or remaining a former smoker, and those associated with continued smoking.

Results: Our results indicate that after quitting smoking the most rapid reversion of altered methylation occurs within the first two decades, with reversion rates related to the initial differences in methylation. For 52 CpG sites, the change in methylation from baseline to follow-up is significantly different for former smokers relative to the change for never smokers (lowest p-value 3.61 x 10 for cg26703534, gene AHRR). Most of these sites' respective regions have been previously implicated in smoking-associated diseases. Despite the early rapid change, dynamism of methylation appears greater in former smokers vs never smokers even four decades after cessation. Furthermore, our study reveals the heterogeneous effect of continued smoking: the methylation levels of some loci further diverge between smokers and non-smokers, while others re-approach. Though intensity of smoking habit appears more significant than duration, results remain inconclusive.

Conclusions: This study improves the understanding of the dynamic link between cigarette smoking and methylation, revealing the continued fluctuation of methylation levels decades after smoking cessation and demonstrating that continuing smoking can have an array of effects. The results can facilitate insights into the molecular mechanisms behind smoking-induced disturbed methylation, improving the possibility for development of biomarkers of past smoking behavior and increasing the understanding of the molecular path from exposure to disease.
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http://dx.doi.org/10.1186/s12864-017-4198-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389045PMC
October 2017

pulver: an R package for parallel ultra-rapid p-value computation for linear regression interaction terms.

BMC Bioinformatics 2017 Sep 29;18(1):429. Epub 2017 Sep 29.

Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.

Background: Genome-wide association studies allow us to understand the genetics of complex diseases. Human metabolism provides information about the disease-causing mechanisms, so it is usual to investigate the associations between genetic variants and metabolite levels. However, only considering genetic variants and their effects on one trait ignores the possible interplay between different "omics" layers. Existing tools only consider single-nucleotide polymorphism (SNP)-SNP interactions, and no practical tool is available for large-scale investigations of the interactions between pairs of arbitrary quantitative variables.

Results: We developed an R package called pulver to compute p-values for the interaction term in a very large number of linear regression models. Comparisons based on simulated data showed that pulver is much faster than the existing tools. This is achieved by using the correlation coefficient to test the null-hypothesis, which avoids the costly computation of inversions. Additional tricks are a rearrangement of the order, when iterating through the different "omics" layers, and implementing this algorithm in the fast programming language C++. Furthermore, we applied our algorithm to data from the German KORA study to investigate a real-world problem involving the interplay among DNA methylation, genetic variants, and metabolite levels.

Conclusions: The pulver package is a convenient and rapid tool for screening huge numbers of linear regression models for significant interaction terms in arbitrary pairs of quantitative variables. pulver is written in R and C++, and can be downloaded freely from CRAN at https://cran.r-project.org/web/packages/pulver/ .
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http://dx.doi.org/10.1186/s12859-017-1838-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622569PMC
September 2017

Metabolite ratios as potential biomarkers for type 2 diabetes: a DIRECT study.

Diabetologia 2018 Jan 25;61(1):117-129. Epub 2017 Oct 25.

Molecular Epidemiology Research Group, Max Delbrück Center for Molecular Medicine, Berlin Buch, Germany.

Aims/hypothesis: Circulating metabolites have been shown to reflect metabolic changes during the development of type 2 diabetes. In this study we examined the association of metabolite levels and pairwise metabolite ratios with insulin responses after glucose, glucagon-like peptide-1 (GLP-1) and arginine stimulation. We then investigated if the identified metabolite ratios were associated with measures of OGTT-derived beta cell function and with prevalent and incident type 2 diabetes.

Methods: We measured the levels of 188 metabolites in plasma samples from 130 healthy members of twin families (from the Netherlands Twin Register) at five time points during a modified 3 h hyperglycaemic clamp with glucose, GLP-1 and arginine stimulation. We validated our results in cohorts with OGTT data (n = 340) and epidemiological case-control studies of prevalent (n = 4925) and incident (n = 4277) diabetes. The data were analysed using regression models with adjustment for potential confounders.

Results: There were dynamic changes in metabolite levels in response to the different secretagogues. Furthermore, several fasting pairwise metabolite ratios were associated with one or multiple clamp-derived measures of insulin secretion (all p < 9.2 × 10). These associations were significantly stronger compared with the individual metabolite components. One of the ratios, valine to phosphatidylcholine acyl-alkyl C32:2 (PC ae C32:2), in addition showed a directionally consistent positive association with OGTT-derived measures of insulin secretion and resistance (p ≤ 5.4 × 10) and prevalent type 2 diabetes (OR 2.64 [β 0.97 ± 0.09], p = 1.0 × 10). Furthermore, Val_PC ae C32:2 predicted incident diabetes independent of established risk factors in two epidemiological cohort studies (HR 1.57 [β 0.45 ± 0.06]; p = 1.3 × 10), leading to modest improvements in the receiver operating characteristics when added to a model containing a set of established risk factors in both cohorts (increases from 0.780 to 0.801 and from 0.862 to 0.865 respectively, when added to the model containing traditional risk factors + glucose).

Conclusions/interpretation: In this study we have shown that the Val_PC ae C32:2 metabolite ratio is associated with an increased risk of type 2 diabetes and measures of insulin secretion and resistance. The observed effects were stronger than that of the individual metabolites and independent of known risk factors.
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http://dx.doi.org/10.1007/s00125-017-4436-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448944PMC
January 2018

Immediate reduction of serum citrulline but no change of steroid profile after initiation of metformin in individuals with type 2 diabetes.

J Steroid Biochem Mol Biol 2017 11 8;174:114-119. Epub 2017 Aug 8.

German Center for Diabetes Research, Neuherberg, Germany; Clinical Cooperation Group Subclassification of Type 2 Diabetes, Helmholtz Zentrum Muenchen, Munich, Germany; Medizinische Klinik und Poliklinik IV, Diabetes Research Group, Klinikum der Universitaet Muenchen, Munich, Germany. Electronic address:

Metformin is the most important first-line treatment for type 2 diabetes mellitus (T2DM) but its exact mode of action remains unknown. In this study, we used targeted metabolomics to gain new insights into the metabolic effects of metformin in humans with T2DM. We also examined changes in the serum steroid hormone profile. We quantified 167 serum metabolites and 19 steroid hormones using liquid chromatography-tandem mass spectrometry at three time points in individuals with previously untreated T2DM: before the start of metformin therapy (time point A), after the first dose (B) and after short-term therapy for 4-6 weeks (C). For metabolite analysis, we split the study cohort into a discovery and a replication study of 88 and 45 subjects, respectively. The statistical analysis was done using linear mixed-effects models. Among the metabolites quantified, citrulline showed the most pronounced changes. Compared to its baseline serum concentration, citrulline was reduced by 17% after the first dose of metformin (p=1.34E-07) and by 24% after short-term therapy (p=2.84E-08) in the discovery study. These results were confirmed in the replication study. The only other metabolite significantly changed after correction for multiple testing was PC ae C36:4 between baseline and 4-6 weeks. The serum steroid hormone profile showed no significant changes after metformin intake. In summary, we observed an immediate and sustained reduction of serum citrulline by metformin in humans. This may be relevant for some of the wanted or unwanted effects of the drug.
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http://dx.doi.org/10.1016/j.jsbmb.2017.08.004DOI Listing
November 2017

Transcriptome-Wide Analysis Identifies Novel Associations With Blood Pressure.

Hypertension 2017 10 7;70(4):743-750. Epub 2017 Aug 7.

From the General and Interventional Cardiology, University Heart Center Hamburg, Germany (T.Z., C.M., A.J., M.K., J.T.N., R.B.S., F.O., S.B.); DZHK (German Centre for Cardiovascular Research), Germany (T.Z., C.S., C.M., P.S.W., A.T., A.S., A.K., A.J., M.K., J.T.N., T.K., R.B.S., M.D., T.M., K.J.L., S.B.F., U.L., A.Z., U.V., S.B.); Institute of Human Genetics (K.S., T.M., H.P.), Molecular Epidemiology (C.G., S.W.), and Institute of Epidemiology II (C.G., S.W.), Helmholtz Zentrum München, Germany; Institut für Medizinische Biometrie und Statistik, Universitätsklinikum Schleswig-Holstein, Germany (C.M., A.S., A.Z.); Institute for Translational Genomics and Population Sciences, UCLA Medical Center (S.K., J.I.R., X.G.); Preventive Cardiology and Preventive Medicine (P.S.W.), Institute of Clinical Chemistry and Laboratory Medicine (K.J.L.), and Center for Thrombosis and Hemostasis (P.S.W.), University Medical Center of the Johannes Gutenberg-University Mainz, Germany; Institute for Community Medicine (A.T.) and Department of Internal Medicine B (M.D., S.B.F.), University Medicine Greifswald, Germany; Interfaculty Institute for Genetics and Functional Genomics, University Greifswald, Germany (C.S., T.K., U.V., G.H.); Department of Internal Medicine (D.H., J.D.) and Department of Epidemiology and Prevention (Y.L.), Wake Forest School of Medicine, Winston-Salem, NC; Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli IS, Italy (L.I., S.C.); Department of Cardiology and Pneumology, Charite, Universitätsmedizin Berlin, Germany (A.K., U.L.); National Institute for Health and Welfare, Helsinki, Finland (K.K.); Institute for Clinical Diabetology, German Diabetes Center, Duesseldorf, Germany (M.R., M.C.-K., C.H.); Department of Endocrinology and Diabetology, Medical Faculty Düsseldorf, Germany (M.R.); German Center for Diabetes Research (DZD), Munich, Germany (M.R., S.W., M.C.-K., C.H.); Sorbonne Universités, UPMC, INSERM, UMR_S 1166, ICAN Institute for Cardiometabolism and Nutrition, Paris, France (D.-A.T.); Institute of Human Genetics, Technische Universität München, Germany (T.M., P.W., H.P.); ZIK_FunGene, Universität Greifswald, Germany (U.V., G.H.); and Columbia University Medical Center, New York, NY (W.P.).

Hypertension represents a major cardiovascular risk factor. The pathophysiology of increased blood pressure (BP) is not yet completely understood. Transcriptome profiling offers possibilities to uncover genetics effects on BP. Based on 2 populations including 2549 individuals, a meta-analyses of monocytic transcriptome-wide profiles were performed to identify transcripts associated with BP. Replication was performed in 2 independent studies of whole-blood transcriptome data including 1990 individuals. For identified candidate genes, a direct link between long-term changes in BP and gene expression over time and by treatment with BP-lowering therapy was assessed. The predictive value of protein levels encoded by candidate genes for subsequent cardiovascular disease was investigated. Eight transcripts (, , , , , , and ) were identified jointly accounting for up to 13% (95% confidence interval, 8.7-16.2) of BP variability. Changes in , , , , , , and expression associated with BP changes-among these, gene expression was additionally correlated to measures of cardiac hypertrophy. Assessment of circulating CRIP1 (cystein-rich protein 1) levels as biomarkers showed a strong association with increased risk for incident stroke (hazard ratio, 1.06; 95% confidence interval, 1.03-1.09; =5.0×10). Our comprehensive analysis of global gene expression highlights 8 novel transcripts significantly associated with BP, providing a link between gene expression and BP. Translational approaches further established evidence for the potential use of CRIP1 as emerging disease-related biomarker.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.09458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997260PMC
October 2017

Genetic variants including markers from the exome chip and metabolite traits of type 2 diabetes.

Sci Rep 2017 07 20;7(1):6037. Epub 2017 Jul 20.

Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.

Diabetes-associated metabolites may aid the identification of new risk variants for type 2 diabetes. Using targeted metabolomics within a subsample of the German EPIC-Potsdam study (n = 2500), we tested previously published SNPs for their association with diabetes-associated metabolites and conducted an additional exploratory analysis using data from the exome chip including replication within 2,692 individuals from the German KORA F4 study. We identified a total of 16 loci associated with diabetes-related metabolite traits, including one novel association between rs499974 (MOGAT2) and a diacyl-phosphatidylcholine ratio (PC aa C40:5/PC aa C38:5). Gene-based tests on all exome chip variants revealed associations between GFRAL and PC aa C42:1/PC aa C42:0, BIN1 and SM (OH) C22:2/SM C18:0 and TFRC and SM (OH) C22:2/SM C16:1). Selecting variants for gene-based tests based on functional annotation identified one additional association between OR51Q1 and hexoses. Among single genetic variants consistently associated with diabetes-related metabolites, two (rs174550 (FADS1), rs3204953 (REV3L)) were significantly associated with type 2 diabetes in large-scale meta-analysis for type 2 diabetes. In conclusion, we identified a novel metabolite locus in single variant analyses and four genes within gene-based tests and confirmed two previously known mGWAS loci which might be relevant for the risk of type 2 diabetes.
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http://dx.doi.org/10.1038/s41598-017-06158-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519666PMC
July 2017

Attention, cognitive control and motivation in ADHD: Linking event-related brain potentials and DNA methylation patterns in boys at early school age.

Sci Rep 2017 06 19;7(1):3823. Epub 2017 Jun 19.

Dept. of Child & Adolescent Mental Health, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.

In order to better understand the underpinnings of attention-deficit/hyperactivity disorder (ADHD), we targeted the relationship of attentional, cognitive control and motivational processes with DNA methylation patterns of 60 candidate genes in boys at early school age. Participants (6 to 8 years; N = 82) were selected from a German longitudinal cohort (FRANCES). ADHD-related behaviour was assessed via maternal ratings. Performance and event-related potential measures (inter alia Cue-P3 and Nogo-P3), which were recorded in a motivational go/nogo task, indicated diminished attentional orienting, reduced inhibitory response control and a larger motivational effect on performance in ADHD already at this relatively young age. Methylation patterns were analysed in buccal cell DNA with the Illumina HumanMethylation 450K array. For CpG sites at genes of the dopaminergic (COMT, ANKK1) and the neurotrophic (BDNF, NGFR) system, associations with the Nogo-P3 as well as ADHD symptom severity were found suggesting that these systems are involved in response control deficits in ADHD. Methylation effects related to both functional aspects and ADHD behaviour were also observed for DPP10 and TPH2. Epigenetic mechanisms may play a role in ADHD-associated deficits but findings need to be replicated in larger samples and are limited by the fact that only peripheral methylation could be considered.
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http://dx.doi.org/10.1038/s41598-017-03326-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476641PMC
June 2017

Ultra-sensitive troponin I is an independent predictor of incident coronary heart disease in the general population.

Eur J Epidemiol 2017 07 5;32(7):583-591. Epub 2017 Jun 5.

Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636, Munich, Germany.

Troponins are sensitive markers of myocardial injury and predictive of cardiovascular events, but conventional assays fail to detect slightly elevated troponins in a considerable proportion of the general population. Using a novel ultrasensitive assay, we explored the relationship of troponin levels with the incidence of coronary heart disease (CHD) in a case-cohort sample (mean age 52.5 ± 0.2 years, 51.5% women) comprising 803 CHD cases and 1942 non-cases. Ultrasensitive troponin I was detectable in 99.9% of available case-cohort samples. In an age- and sex-adjusted model, individuals in the highest quartile of the troponin distribution had a more than threefold increased risk for CHD events compared to those in the bottom quartile [hazard ratio, HR, 3.11; 95% confidence interval (CI) 2.15-4.49]. In a model adjusting for cardiovascular risk factors including C-reactive protein, cystatin C and N-terminal pro brain natriuretic peptide, individuals in the highest troponin I quartile still showed a hazard ratio of 2.58 (95% CI 1.66-4.00) for incident CHD as compared to those in the lowest quartile. Ultrasensitive troponin I was detectable in almost all individuals of a study sample reflecting middle-aged to elderly European general population. Ultrasensitive troponin concentrations exhibit an independent, graded, positive relation with incident CHD.
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http://dx.doi.org/10.1007/s10654-017-0266-7DOI Listing
July 2017

Anxiety Associated Increased CpG Methylation in the Promoter of Asb1: A Translational Approach Evidenced by Epidemiological and Clinical Studies and a Murine Model.

Neuropsychopharmacology 2018 Jan 25;43(2):342-353. Epub 2017 May 25.

Institute of Epidemiology II, Helmholtz Zentrum München-German Research Centre for Environmental Health, Neuherberg, Germany.

Epigenetic regulation in anxiety is suggested, but evidence from large studies is needed. We conducted an epigenome-wide association study (EWAS) on anxiety in a population-based cohort and validated our finding in a clinical cohort as well as a murine model. In the KORA cohort, participants (n=1522, age 32-72 years) were administered the Generalized Anxiety Disorder (GAD-7) instrument, whole blood DNA methylation was measured (Illumina 450K BeadChip), and circulating levels of hs-CRP and IL-18 were assessed in the association between anxiety and methylation. DNA methylation was measured using the same instrument in a study of patients with anxiety disorders recruited at the Max Planck Institute of Psychiatry (MPIP, 131 non-medicated cases and 169 controls). To expand our mechanistic understanding, these findings were reverse translated in a mouse model of acute social defeat stress. In the KORA study, participants were classified according to mild, moderate, or severe levels of anxiety (29.4%/6.0%/1.5%, respectively). Severe anxiety was associated with 48.5% increased methylation at a single CpG site (cg12701571) located in the promoter of the gene encoding Asb1 (β-coefficient=0.56 standard error (SE)=0.10, p (Bonferroni)=0.005), a protein hypothetically involved in regulation of cytokine signaling. An interaction between IL-18 and severe anxiety with methylation of this CpG cite showed a tendency towards significance in the total population (p=0.083) and a significant interaction among women (p=0.014). Methylation of the same CpG was positively associated with Panic and Agoraphobia scale (PAS) scores (β=0.005, SE=0.002, p=0.021, n=131) among cases in the MPIP study. In a murine model of acute social defeat stress, Asb1 gene expression was significantly upregulated in a tissue-specific manner (p=0.006), which correlated with upregulation of the neuroimmunomodulating cytokine interleukin 1 beta. Our findings suggest epigenetic regulation of the stress-responsive Asb1 gene in anxiety-related phenotypes. Further studies are necessary to elucidate the causal direction of this association and the potential role of Asb1-mediated immune dysregulation in anxiety disorders.
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http://dx.doi.org/10.1038/npp.2017.102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729551PMC
January 2018

Circulating Levels of Interleukin 1-Receptor Antagonist and Risk of Cardiovascular Disease: Meta-Analysis of Six Population-Based Cohorts.

Arterioscler Thromb Vasc Biol 2017 06 20;37(6):1222-1227. Epub 2017 Apr 20.

From the Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany (C. Herder, M.C.-K., M.R.); German Center for Diabetes Research (DZD), München-Neuherberg, Germany (C. Herder, M.C.-K., A. Peters, M.R., B.T.); Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (T.d.l.H.G., C. Huth, A.Z., S.W., C.M., A. Peters, B.T.); German Center for Cardiovascular Research (DZHK), Partner site Munich Heart Alliance, Germany (T.d.l.H.G., W.K.); Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (S.W.); Tethys Bioscience, Emeryville, CA (J.S.-K., D.P.); National Institute for Health and Welfare, Helsinki, Finland (K.K., A. Pietilä, V.S.); Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands (S.L., A.D., M.A.I.); Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany (B.W.C.B.); Department of Biostatistics and Epidemiology, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, United Kingdom (A.D.); National Institute for Health and Welfare, Turku, Finland (A.J.); Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Institute of Clinical Science B, Queen's University Belfast, United Kingdom (F.K.); UKCRC Centre of Excellence for Public Health (Northern Ireland), Queen's University Belfast, United Kingdom (F.K.); Dalla Lana School of Public Health, University of Toronto, Ontario, Canada (O.S.); Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Germany (T.Z., S.B.); German Center for Cardiovascular Research (DZHK), Partner site Hamburg, Lübeck, Kiel, Germany (T.Z., S.B.); Department of Endocrinology and Diabetology, Medical Faculty, University Hospital Düsseldorf, Germany (M.R.); Deutsches Herzzentrum München, Technische Universität München, Germany (W.K.); and Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Germany (W.K.).

Objective: Interleukin (IL)-1β represents a key cytokine in the development of cardiovascular disease (CVD). IL-1β is counter-regulated by IL-1 receptor antagonist (IL-1RA), an endogenous inhibitor. This study aimed to identify population-based studies on circulating IL-1RA and incident CVD in a systematic review, estimate the association between IL-1RA and incident CVD in a meta-analysis, and to test whether the association between IL-1RA and incident CVD is explained by other inflammation-related biomarkers in the MONICA/KORA Augsburg case-cohort study (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease/Cooperative Health Research in the Region of Augsburg).

Approach And Results: We performed a systematic literature search and identified 5 cohort studies on IL-1RA and incident CVD in addition to the MONICA/KORA Augsburg case-cohort study for a meta-analysis based on a total of 1855 CVD cases and 18 745 noncases with follow-up times between 5 and 16 years. The pooled standardized hazard ratio (95% confidence interval) for incident CVD was 1.11 (1.06-1.17) after adjustment for age, sex, anthropometric, metabolic, and lifestyle factors (<0.0001). There was no heterogeneity in effect sizes (I=0%; =0.88). More detailed analyses in the MONICA/KORA study showed that the excess risk for CVD was attenuated by ≥10% after additional separate adjustment for serum levels of high-sensitivity C-reactive protein, IL-6, myeloperoxidase, soluble E-selectin, or soluble intercellular adhesion molecule-1.

Conclusions: Serum IL-1RA levels were positively associated with risk of CVD after adjustment for multiple confounders in a meta-analysis of 6 population-based cohorts. This association may at least partially reflect a response to triggers inducing subclinical inflammation, oxidative stress, and endothelial activation.
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http://dx.doi.org/10.1161/ATVBAHA.117.309307DOI Listing
June 2017

Allele-specific quantitative proteomics unravels molecular mechanisms modulated by cis-regulatory PPARG locus variation.

Nucleic Acids Res 2017 04;45(6):3266-3279

Else Kroener-Fresenius-Center for Nutritional Medicine, Chair of Nutritional Medicine, Technische Universität München, 85354 Freising-Weihenstephan, Germany.

Genome-wide association studies identified numerous disease risk loci. Delineating molecular mechanisms influenced by cis-regulatory variants is essential to understand gene regulation and ultimately disease pathophysiology. Combining bioinformatics and public domain chromatin information with quantitative proteomics supports prediction of cis-regulatory variants and enabled identification of allele-dependent binding of both, transcription factors and coregulators at the type 2 diabetes associated PPARG locus. We found rs7647481A nonrisk allele binding of Yin Yang 1 (YY1), confirmed by allele-specific chromatin immunoprecipitation in primary adipocytes. Quantitative proteomics also found the coregulator RING1 and YY1 binding protein (RYBP) whose mRNA levels correlate with improved insulin sensitivity in primary adipose cells carrying the rs7647481A nonrisk allele. Our findings support a concept with diverse cis-regulatory variants contributing to disease pathophysiology at one locus. Proteome-wide identification of both, transcription factors and coregulators, can profoundly improve understanding of mechanisms underlying genetic associations.
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http://dx.doi.org/10.1093/nar/gkx105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389726PMC
April 2017
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