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Pechlaner R.,Innsbruck Medical University | Willeit P.,Innsbruck Medical University | Willeit P.,University of Cambridge | Summerer M.,Molecular and Clinical Pharmacology | And 20 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2015

Objective: The enzyme heme oxygenase-1 (HO-1) exerts cytoprotective effects in response to various cellular stressors. A variable number tandem repeat polymorphism in the HO-1 gene promoter region has previously been linked to cardiovascular disease. We examined this association prospectively in the general population.Approach and Results: Incidence of stroke, myocardial infarction, or vascular death was registered between 1995 and 2010 in 812 participants of the Bruneck Study aged 45 to 84 years (49.4% males). Carotid atherosclerosis progression was quantified by high-resolution ultrasound. HO-1 variable number tandem repeat length was determined by polymerase chain reaction. Subjects with 32 tandem repeats on both HO-1 alleles compared with the rest of the population (recessive trait) featured substantially increased cardiovascular disease risk (hazard ratio [95% confidence interval], 5.45 [2.39, 12.42]; P<0.0001), enhanced atherosclerosis progression (median difference in atherosclerosis score [interquartile range], 2.1 [0.8, 5.6] versus 0.0 [0.0, 2.2] mm; P=0.0012), and a trend toward higher levels of oxidized phospholipids on apolipoprotein B-100 (median oxidized phospholipids/apolipoprotein B level [interquartile range], 11364 [4160, 18330] versus 4844 [3174, 12284] relative light units; P=0.0554). Increased cardiovascular disease risk in those homozygous for 32 repeats was also detected in a pooled analysis of 7848 participants of the Bruneck, SAPHIR, and KORA prospective studies (hazard ratio [95% confidence interval], 3.26 [1.50, 7.33]; P=0.0043).Conclusions: This study found a strong association between the HO-1 variable number tandem repeat polymorphism and cardiovascular disease risk confined to subjects with a high number of repeats on both HO-1 alleles and provides evidence for accelerated atherogenesis and decreased antioxidant defense in this vascular high-risk group. © 2014 American Heart Association, Inc.

Fischer A.,University of Kiel | Schmid B.,University of Kiel | Ellinghaus D.,University of Kiel | Nothnagel M.,University of Kiel | And 22 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2012

Rationale: Sarcoidosis is a complex inflammatory disease with a heterogeneous clinical picture. Among others, an acute and chronic clinical course can be distinguished, for which specific genetic risk factors are known. Objectives: To identify additional risk loci for sarcoidosis and its acute and chronic subforms, we analyzed imputed data from a genomewide association scan for these phenotypes. Methods: After quality control, the genome-wide association scan comprised nearly 1.3 million imputed single-nucleotide polymorphisms based on an Affymetrix 6.0 Gene Chip dataset of 564 German sarcoidosis cases, including 176 acute and 354 chronic cases and 1,575 control subjects. Measurements and Main Results:We identified chromosome 11q13.1 (rs479777) as a novel locus influencing susceptibility to sarcoidosis with genome-wide significance. The marker was significantly associated in three distinct German case-control populations and in an additional German family sample with odds ratios ranging from 0.67 to 0.77. This finding was further replicated in two independent European case-control populations from the Czech Republic (odds ratio, 0.75) and from Sweden (odds ratio, 0.79). In a meta-analysis of the included European case-control samples the marker yielded a P value of 2.68 3 10-18. The locus was previously reported to be associated with Crohn disease, psoriasis, alopecia areata, and leprosy. For sarcoidosis, fine-mapping and expression analysis suggest KCNK4, PRDX5, PCLB3, and most promising CCDC88B as candidates for the underlying risk gene in the associated region. Conclusions: This study provides striking evidence for association of chromosome 11q13.1 with sarcoidosis in Europeans, and thus identified a further genetic risk locus sharedby sarcoidosis, Crohndisease and psoriasis. Copyright © 2012 by the American Thoracic Society.

PubMed | University of Nottingham, St George's, University of London, MRC Human Genetics Unit, Swiss Tropical and Public Health Institute and 33 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2015

Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10s role in influencing lungs susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.

News Article | February 16, 2017
Site: www.eurekalert.org

The Helmholtz Zentrum München has published results of the largest genome-wide association study on proteomics to date. An international team of scientists reports 539 associations between protein levels and genetic variants in 'Nature Communications'. These associations overlap with risk genes for 42 complex diseases. Genome-wide association studies (GWAS) provide an opportunity to associate concentration changes in certain proteins or metabolic products with gene loci. Knowledge of these genes makes it possible to establish connections to complex diseases. Scientists utilize the fact that to date, hundreds of associations between genetic variants and complex diseases have been demonstrated. These associations are immensely important because they do help uncover the underlying molecular mechanisms. "In the world's largest proteomics GWAS to date, we worked with colleagues* to examine blood samples from 1,000 participants in the KORA study**," reports Dr. Gabi Kastenmüller. She is acting director and head of the Metabolomics Group at the Institute of Bioinformatics and Systems Biology (IBIS) at the Helmholtz Zentrum München. The team quantified a total of 1,100 proteins. Dr. Christian Gieger, head of the Molecular Epidemiology Research Unit (AME) at the Helmholtz Zentrum München, adds: "We found 539 independent associations between protein levels and genetic variants." These overlap with genetic risk variants for 42 complex conditions, such as cardiovascular diseases and Alzheimer's disease. "Our results provide new insights into the biological processes that are influenced by a very wide range of complex diseases and that can be used as a basis for the development of new strategies to predict and prevent these diseases," Gieger states. The team is now planning to investigate the exact mechanisms behind the new gene-protein associations. * Participants from the Helmholtz Zentrum München were: The Molecular Epidemiology Research Unit (AME), the Institute of Epidemiology 2 (EPI2), the Institute of Bioinformatics and Systems Biology (IBIS), and the Institute of Genetic Epidemiology (IGE). External partners were the German Center for Diabetes Research (DZD), the German Center for Cardiovascular Disease (DZHK), and Weill Cornell Medicine, Qatar and Doha, Qatar. ** KORA study: The "Kooperative Gesundheitsforschung in der Region Augsburg" (Cooperative Health Research in the Augsburg Region) study has been investigating the health of thousands of people living in the Greater Augsburg area for 30 years. The objective is to understand the effects of environmental factors, lifestyle and genes. Key topics of the KORA studies are issues involving the genesis and progress of chronic diseases, particularly cardiac infarction and diabetes mellitus. Risk factors from the area of health-related behaviour (such as smoking, nutrition, and physical activity), environmental factors (including air and noise pollution), and genetics are explored for this purpose. Issues regarding the utilization and costs of healthcare are examined from the point of view of healthcare research. http://www. Original publication: Karsten Suhre et al. (2017): Connecting genetic risk to disease endpoints through the human blood plasma proteome, Nature Communications, DOI: 10.1038/ncomms14357. The Helmholtz Zentrum München, as the German Research Center for Environmental Health, pursues the objective of developing personalized medicine for the diagnosis, therapy, and prevention of widespread diseases such as diabetes mellitus and lung diseases. To this end, it investigates the interactions of genetics, environmental factors, and lifestyle. The Zentrum's headquarters is located in Neuherberg in the north of Munich. The Helmholtz Zentrum München employs around 2,300 people and is a member of the Helmholtz Association, which has 18 scientific-technical and biological-medical research centres with around 37,000 employees. http://www. The Institute of Bioinformatics and Systems Biology (IBIS) concentrates on the analysis and interpretation of large, high-dimensional biological data sets in order to extract from them information on the molecular basis of complex diseases. In this framework, the institute systematically examines genetic variants, expression patterns, and protein and metabolite profiles and their associations. IBIS develops new bioinformatic and systems biology methods and resources that make it possible to model and visualize high throughput data and the results gained from them. http://www. The Molecular Epidemiology Research Unit (AME) analyses population-based cohorts and case studies for certain diseases with the help of genomics, epigenomics, transcriptomics, proteomics, metabolomics, and functional analyses. The objective is to explain the molecular mechanisms in complex diseases such as type 2 diabetes and obesity. The unit runs the epidemiology biosample bank and handles sample administration and storage for national and international projects. http://www.

PubMed | Hannover Medical School, Institute of Epidemiology I and Institute of Medical Informatics, Ludwig Maximilians University of Munich, Institute of Computational Biology and 5 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2014

Availability of standardized metabolite panels and genome-wide single-nucleotide polymorphism data endorse the comprehensive analysis of gene-metabolite association. Currently, many studies use genome-wide association analysis to investigate the genetic effects on single metabolites (mGWAS) separately. Such studies have identified several loci that are associated not only with one but with multiple metabolites, facilitated by the fact that metabolite panels often include metabolites of the same or related pathways. Strategies that analyse several phenotypes in a combined way were shown to be able to detect additional genetic loci. One of those methods is the phenotype set enrichment analysis (PSEA) that tests sets of metabolites for enrichment at genes. Here we applied PSEA on two different panels of serum metabolites together with genome-wide data. All analyses were performed as a two-step identification-validation approach, using data from the population-based KORA cohort and the TwinsUK study. In addition to confirming genes that were already known from mGWAS, we were able to identify and validate 12 new genes. Knowledge about gene function was supported by the enriched metabolite sets. For loci with unknown gene functions, the results suggest a function that is interrelated with the metabolites, and hint at the underlying pathways.

News Article | December 22, 2016
Site: www.eurekalert.org

The extra pounds you gain during the holidays will not only show up on your hips but will also affect your DNA. This is the result of a large-scale international study coordinated by Helmholtz Zentrum München, a partner in the German Center for Diabetes Research, which has now been published in 'Nature'. The study shows that a high BMI leads to epigenetic changes at nearly 200 loci of the genome - with effects on gene expression. While our genes do not change in the course of life, our lifestyle can directly influence their surroundings. Scientists speak here of the epigenome (Greek epi: over, outside of, around), which refers to everything that happens on or around the genes. Up to now there has not been much research on how the epigenome is altered as a result of being overweight. "This issue is particularly relevant because an estimated one and a half billion people throughout the world are overweight," said first author Dr. Simone Wahl of the Research Unit Molecular Epidemiology (AME) at Helmholtz Zentrum München, "especially considering that being overweight can have adverse consequences and lead to diabetes and diseases of the cardiovascular and metabolic systems." For this reason, the international research team led by Dr. Christian Gieger and Dr. Harald Grallert of the AME (as well as Jaspal Kooner and John Chambers of Imperial College London) examined possible correlations between body mass index (BMI) and epigenetic changes.* Using state-of-the-art technology, the team carried out the world's largest study so far on the subject. The scientists examined the blood samples of over 10,000 women and men from Europe. A large proportion of these were inhabitants of London of Indian ancestry, who according to the authors are at high risk for obesity and metabolic diseases. In a first step with 5,387 samples **, the research team identified 207 gene loci that were epigenetically altered dependent on the BMI. They then tested these candidate loci in blood samples of an additional 4,874 subjects and were able to confirm 187 of these***. Further studies and long-term observations also indicated that the changes were predominantly a consequence of being overweight - not the cause. "In particular, significant changes were found in the expression of genes responsible for lipid metabolism and substrate transport, but inflammation-related gene loci were also affected," said group leader Harald Grallert. From the data, the team was also able to identify epigenetic markers that could predict the risk of type 2 diabetes. "Our results allow new insights into which signaling pathways are influenced by obesity", said Christian Gieger, head of the AME. "We hope that this will lead to new strategies for predicting and possibly preventing type 2 diabetes and other consequences of being overweight." Next, within the framework of translational research in the German Center for Diabetes Research, the researchers want to investigate in detail how the epigenetic changes affect the expression of the underlying genes. * Specifically, the team investigated the methylation patterns, i.e. the presence or absence of methyl groups on the DNA. By means of high-throughput measurements, these methylation patterns can now be investigated relatively quickly and on a large scale. ** Among others from the Augsburg KORA study, the London LOLIPOP study and a part of the EPICOR study population from Italy *** Some of these have also been confirmed in adipose tissue, indicating that changes in gene regulation in disease-relevant tissues are also visible in the blood. Helmholtz Zentrum München has extensive expertise in the field of genetic and epigenetic causal research on metabolic diseases: As recently as July 2016, the researchers were involved in the world's largest genetic study on type 2 diabetes, which was likewise published in the renowned journal Nature. Link to press release: https:/ Furthermore, already in March 2016 scientists of Helmholtz München showed that diet-induced obesity and diabetes can be passed on epigenetically to the offspring via both oocytes and sperm. Link to related press release: https:/ Wahl, S. et al. (2016): Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature, doi:10.1038/nature20784 http://www. The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. http://www. The Research Unit of Molecular Epidemiology (AME) analyses population-based cohorts and case studies for specific diseases, using genomics, epigenomics, transcriptomics, proteomics, metabolomics and functional analyses. The aim of this research unit is to decipher the molecular mechanisms of complex diseases like type 2 diabetes or obesity. The unit administers the biological specimen repository of the Department of Epidemiology and stores the samples for national and international projects. http://www. The Institute of Epidemiology II (EPI II) focuses on the assessment of environmental and lifestyle risk factors which jointly affect major chronic diseases such as diabetes, heart disease and mental health. Research builds on the unique resources of the KORA cohort, the KORA myocardial infarction registry, and the KORA aerosol measurement station. Aging-related phenotypes have been added to the KORA research portfolio within the frame of the Research Consortium KORA-Age. The institute's contributions are specifically relevant for the population as modifiable personal risk factors are being researched that could be influenced by the individual or by improving legislation for the protection of public health. http://www. Research at the Institute of Genetic Epidemiology (IGE) focuses on planning, realization and analysis of projects regarding the identification of genetic factors responsible for complex traits. This involves application, further development and implementation of a variety of statistical methods to address specific aspects such as rare genetic variants, mitochondrial DNA, gene-gene and gene-environment interactions, family studies, and the handling of population structures. The elucidation of disease-relevant genetic factors as well as their inclusion into models of disease risk provides the basis of individualized approaches to treatment or prevention. http://www. The Institute of Human Genetics (IHG) at the Helmholtz Zentrum München and the Technical University of Munich: The Institute is concerned with identifying genes associated with disease and characterizing their functions. The main aim of the research projects is to develop disease-related genetic variation in humans and mice as well as to develop chromosome analysis techniques and new methods for dealing with specific issues in the sphere of pre- and post-natal diagnostics and tumor cytogenetics. http://www. The German Center for Diabetes Research (DZD) is a national association that brings together experts in the field of diabetes research and combines basic research, translational research, epidemiology and clinical applications. The aim is to develop novel strategies for personalized prevention and treatment of diabetes. Members are Helmholtz Zentrum München - German Research Center for Environmental Health, the German Diabetes Center in Düsseldorf, the German Institute of Human Nutrition in Potsdam-Rehbrücke, the Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Medical Center Carl Gustav Carus of the TU Dresden and the Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the Eberhard-Karls-University of Tuebingen together with associated partners at the Universities in Heidelberg, Cologne, Leipzig, Lübeck and Munich. http://www.

Petersen A.-K.,Institute of Genetic Epidemiology | Zeilinger S.,Research Unit of Molecular Epidemiology | Kastenmuller G.,Institute of Bioinformatics and Systems Biology | Werner R.-M.,Institute of Bioinformatics and Systems Biology | And 20 more authors.
Human Molecular Genetics | Year: 2014

Previously,we reported strong influences of genetic variants on metabolic phenotypes, some of them with clinical relevance. Here, we hypothesize that DNA methylation may have an important and potentially independent effect on human metabolism. Totest this hypothesis,we conducted what is to the best of our knowledge the first epigenome-wide association study (EWAS) between DNA methylation and metabolic traits (metabotypes) in human blood. We assess 649 blood metabolic traits from 1814 participants of the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) population study for association with methylation of 457 004 CpG sites, determined on the Infinium Human Methylation 450 Bead Chip platform. Using the EWAS approach, we identified two types of methylome-metabotype associations. One type is driven by an underlying genetic effect; the other type is independent of genetic variation and potentially driven by common environmental and life-style-dependent factors. We report eight CpG loci atgenome-wide significance that have a genetic variant as confounder (P = 3.9 × 10-20 to 2.0 × 10-108, r2 = 0.036 to 0.221).Seven loci display CpG site-specific associations to metabotypes ,but do not exhibit any underlying genetic signals (P = 9.2 × 10-14 to 2.7 × 10-27, r2 = 0.008 to 0.107). We further identify several groups of CpG loci that associate with a same metabotype, such as 4-vinylphenol sulfate and 4-androsten-3-beta,17-beta-diol disulfate. In these cases, the association between CpG-methylation and metabotype is likely the result of a common external environmental factor, including smoking. Our study shows that analysis of EWAS with large numbers of metabolic traits in large population cohorts are, in principle, feasible. Taken together, our data suggest that DNA methylation plays an important role in regulating human metabolism. © The Author 2013. Published by Oxford University Press.

Zech M.,Klinikum rechts der IsarTechnical University MunchenMunich Germany | Castrop F.,Neurologische Klinik und Poliklinik | Schormair B.,Klinikum rechts der IsarTechnical Universityt MunchenMunich Germany | Jochim A.,Neurologische Klinik und Poliklinik | And 10 more authors.
Movement Disorders | Year: 2014

Recessive DYT16 dystonia associated with mutations in PRKRA has until now been reported only in seven Brazilian patients. The aim of this study was to elucidate the genetic cause underlying disease in a Polish family with autosomal-recessive, early-onset generalized dystonia and slight parkinsonism, and to explore further the role of PRKRA in a dystonia series of European ancestry. We employed whole-exome sequencing in two affected siblings of the Polish family and filtered for rare homozygous and compound heterozygous variants shared by both exomes. Validation of the identified variants as well as homozygosity screening and copy number variation analysis was carried out in the two affected individuals and their healthy siblings. PRKRA was analyzed in 339 German patients with various forms of dystonia and 376 population-based controls by direct sequencing or high-resolution melting. The previously described homozygous p.Pro222Leu mutation in PRKRA was found to segregate with the disease in the studied family, contained in a 1.2 Mb homozygous region identical by state with all Brazilian patients in chromosome 2q31.2. The clinical presentation with young-onset, progressive generalized dystonia and mild parkinsonism resembled the phenotype of the original DYT16 cases. PRKRA mutational screening in additional dystonia samples revealed three novel heterozygous changes (p.Thr34Ser, p.Asn102Ser, c.-14A>G), each in a single subject with focal/segmental dystonia. Our study provides the first independent replication of the DYT16 locus at 2q31.2 and strongly confirms the causal contribution of the PRKRA gene to DYT16. Our data suggest worldwide involvement of PRKRA in dystonia. © 2014 International Parkinson and Movement Disorder Society.

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