Highlights Genetics and Epidemiology

Structure of SXL-UNR translation regulatory complex
Structure of SXL-UNR translation regulatory complex

Largest Worldwide Study on Atopic Eczema

The development of atopic eczema, or atopic dermatitis, is favorably influenced by gene variants associated with autoimmune diseases. This has been shown by the largest genome-wide association study on atopic eczema to date. The study, which involved 40 centers located in 14 countries, increases the number of known risk genes to 31. The data of more than 350 000 participants revealed ten regions in the human genome in which mutations increase the disease risk.

Lavinia Paternoster, Marie Standl et al.: Multi-Ancestry Genome-Wide Association Study of 21,000 Cases and 95,000 Controls Identifies New Risk Loci for Atopic Dermatitis. Nature Genetics 47 (2015) | doi: 10.1038/ng.3424

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Large number of Gene Functions Discovered

The European EUMODIC consortium has made a major advancement towards elucidating the function of disease-relevant genes. Using newly developed statistical techniques, 160 previously unknown genes could be assigned functions, among others in the areas of metabolic processes and neurology. A total of 320 genes were investigated. The gained insights have been made available to the scientific community on the website of the International Mouse Phenotyping Consortium (IMPC).

Martin Hrabé de Angelis et al.: Deciphering Mammalian Gene Function Through Broad Based Phenotypic Screens Across a Consortium of Mouse Clinics. Nature Genetics 47 (2015) | doi: 10.1038/ng.3360

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Exposure to Ultrafine Particles Influences Cardiac Function

Inhalable particles include all particulate matter with a diameter smaller than 10 micrometers (PM10). In this group a distinction is made between even finer particles smaller than 2.5 micrometers (PM2.5) in diameter, which can deeply enter the lung, and ultrafine particles with diameters less than 0.1 micrometers (100 nanometers), which can also enter the blood stream. The adverse health effects caused by fine particles have been known for some time. In addition, ultrafine particles appear to play a significant role in cardiac function – even if an individual is exposed to these for only a few minutes.

Annette Peters et al.: Elevated Particle Number Concentrations Induce Immediate Changes in Heart Rate Variability: a Panel Study in Individuals with Impaired Glucose Metabolism or Diabetes. Particle and Fibre Toxicology 12 (2015) | doi: 10.1186/s12989-015-0083-7

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Changes in Body Weight and Metabolism

More and more people are overweight, leading to a rapid increase in the incidence of cardiovascular disease, disturbances of the lipid metabolism and diabetes. Now the effects of long-term changes in body weight on the metabolism have been investigated. Techniques such as metabolomics and transcriptomics allow the simultaneous determination of a variety of low molecular weight metabolites or gene activities. Thus insights could be obtained into the molecular mechanisms that are affected by weight gain, for example changes in lipid and amino acid metabolism and insulin sensitivity.

Simone Wahl et al.: Multi-omic Signature of Body Weight Change: Results from a Population-based Cohort Study. BMC Medicine 13 (2015) | doi:10.1186/s12916-015-0282-y

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Mitochondrial Gene Defect Causes Heart and Brain Diseases

Rare diseases observed to have a higher incidence in families suggest that a genetic defect is the cause. Scientists have now identified such a disease gene through genome-wide sequencing analyses of the genetic material. Patients with mutations of the mitochondrial gene GTPBP3 had a thickening of the heart muscle and hyperacidity of the blood – both signs of a disturbance of the muscle metabolism. In addition, the individuals suffered from neurological symptoms.

Robert Kopajtich et al.: Mutations in GTPBP3 Cause a Mitochondrial Translation Defect Associated with Hypertrophic Cardiomyopathy, Lactic Acidosis, and Encephalopathy. American Journal of Human Genetics 95 (2014) | doi: 10.1016/j.ajhg.2014.10.017

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Genetic Defect Causes Diabetes and Neurodegeneration

Diabetes mellitus and neurodegenerative diseases may have one and the same cause. This is the result of a study conducted within the scope of a genetic research project. In two families, the researchers identified a genetic defect that leads to a lack of an important protein. This protein is crucial for the correct folding of proteins and for the degradation of misfolded proteins in the cells of the pancreas and the brain. In the future, the rare genetic defect shall serve as a model for the study of the common causes of diabetes and neurodegeneration.

Matthis Synofzik et al.: Absence of BiP Co-chaperone DNAJC3 Causes Diabetes Mellitus and Multisystemic Neurodegeneration. American Journal of Human Genetics 96 (2014) | doi 10.1016/j.ajhg.2014.10.013

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Model Mechanism of Gene Regulation Elucidated

Cellular proteins that specifically bind to the RNA regulate the expression of genetic information on the level of messenger RNA (mRNA). By elucidating the structure of an RNA protein complex that controls the sex-specific gene expression of the fruit fly, the researchers showed how this regulatory process takes place on the molecular level. The decrypted mechanism reveals how the cooperation of two RNA-binding proteins enables the specific recognition of mRNA. Thus, by combining different RNA-binding proteins, many different processes in the cell can be regulated although only a limited number of RNA-binding proteins exist.

Janosch Hennig et al.: Structural Basis for the Assembly of the SXL-UNR Translation Regulatory Complex. Nature 515 (2014) | doi: 10.1038/nature13693

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Gene Mutation for Eye Malformation

For the first time, a mutation in the peroxidasin gene of the mouse has been identified that leads to serious, recessively inherited eye diseases. Among other functions, the gene regulates the development of the eye. The discovery can now serve as a model for corresponding human diseases.

Xiaohe Yan et al.: Peroxidasin is Essential for Eye Development in the Mouse. Human Molecular Genetics 23 (2014) | doi:10.1093/hmg/ddu274

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More Cardiovascular Deaths during Cold and Hot Temperatures

For the period between 1990 and 2006 approximately 188,000 deaths due to cardiovascular disease were analyzed in three Bavarian cities. Both with a rise in temperature from 20°C to 25°C and with a temperature drop from -1°C to -8°C the number of deaths due to cardiovascular diseases increased significantly by 9.5 percent and 7.9 percent respectively. Older individuals were most affected. These effects were particularly significant for the mortality rate due to heart failure, arrhythmias and stroke.

Susanne Breitner et al.: Short-term Effects of Air Temperature on Cause-specific Cardiovascular Mortality in Bavaria, Germany. Heart, 0:1–9 (2014) | doi:10.1136/heartjnl-2014-305578

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Air Pollutants: Genes Determine Extent of Inflammatory Response

Genetic predisposition is a key factor in determining how individuals respond to ambient air pollutants. Air pollutants can induce oxidative stress in the human body, resulting in a systemic inflammatory response which affects the entire body. Scientists at Helmholtz Zentrum München analyzed inflammatory parameters in a total of 1,765 blood samples and determined that individuals with specific gene variants have a stronger inflammatory response than people who do not have this genetic predisposition.

Regina Rückerl et al.: Associations between Ambient Air Pollution and Blood Markers of Inflammation and Coagulation/Fibrinolysis in Susceptible Populations. Environment International 70 (2014) | doi: 10.1016/j.envint.2014.05.013

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Drugs That Lower Blood Pressure and Blood Fat Levels Have Complex Effects on Metabolism

The variation of 295 serum metabolites for 1,762 participants of the KORA cohort was analyzed in connection with the ingestion of antihypertensive and lipid-level-lowering drugs. Overall, the authors found 41 significant associations between medication and serum metabolite variation: 11 for beta-blockers, 4 for ACE inhibitors, 7 for diuretics, 10 for statins and 9 for fibrates. The aim was to contribute to the mechanistic understanding of the effects and side effects of these drugs.

Elisabeth Altmaier et al.: Metabolomics Approach Reveals Effects of Antihypertensives and Lipid-lowering Drugs on the Human Metabolism. European Journal of Epidemiology 29 (2014) | doi: 10.1007/s10654-014-9910-7

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How Genes Determine Metabolism

Within the framework of an international cooperation, the first comprehensive atlas has been created of genetic variants which influence the metabolite concentrations in the blood. Based on genome-wide data and blood analyses of 7,824 adults in the English TwinUK and HMGU KORA cohorts, significant - in part unknown - associations and biochemical connections between 145 gene loci and more than 400 blood metabolites could be identified. Data on expression and inheritance of already known genes in the respective context and their correlation to specific diseases were integrated into the comparative analysis. The resulting atlas of molecular signatures makes it possible to categorize previously unknown gene-metabolite associations and to make gene loci metabolites accessible for analysis based on their molecular and genetic context. Such validated networks can be studied to systematically search for gene variants with heightened risk for specific diseases, but also to search for potential biomarkers and pharmacological targets for individualized diagnostic or therapeutic methods. With its underlying, functional annotations and disease associations, the atlas is accessible online for the international scientific community.

So-Youn Shin et al.: An Atlas of Genetic Influences on Human Blood Metabolites. Nature Genetics 46 (2014) | doi: 10.1038/ng.2982

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DNA Variants That Influence Gene Activity Identifiable in Blood

Blood samples provide suitable investigative material to study the molecular mechanisms of complex diseases with a genetic background. In one study, researchers succeeded in identifying several thousand DNA variants that play a significant role in the regulation of gene expression (eQTLs, expression quantitative trait loci). Despite many confounding factors, the influence of these DNA variants appeared to be very robust. Blood is therefore suitable to investigate the regulatory influence of disease-related DNA variants, even if the disease primarily affects other tissue.

Katharina Schramm et al.: Mapping the Genetic Architecture of Gene Regulation in Whole Blood. PLOS ONE 9 (2014) | doi: 10.1371/journal.pone.0093844

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Restless Legs: Early Cause – Late Effect

The restless legs syndrome is characterized by unpleasant sensations in people’s legs at night and the constant urge to move. The disorder has a genetic basis. Now for the first time, the functional relevance of a specific gene variant in the MEIS1 locus has been identified which plays an important role in the development of the central nervous system already during the embryonic stage. The gene variant of MEIS1 discovered in the region of the forebrain, which is responsible for movement, leads to reduced gene expression of MEIS1 during embryonic development. As a result, the pathogenesis of restless legs syndrome could be associated for the first time with a specific brain region. Scientists presume that the developmental disorder elicited by changes in the forebrain predisposes individuals for this syndrome, which does not appear until old age.

Derek Spieler, Maria Kaffe, Franziska Knauf: Restless Legs Syndrome-associated Intronic Common Variant in Meis1 Alters Enhancer Function in the Developing Telencephalon. Genome Research (2014) | doi: 10.1101/gr.166751.113

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Frailty in Old Age Linked to Stress Hormone

Frailty in old age is closely linked to a disturbed regulation of cortisol levels: The levels are lower in the morning and higher in the evening instead of vice versa. Frailty is characterized by unintentional weight loss, feelings of exhaustion and fatigue, physical inactivity, slow gait speed and low grip strength. In the study the data of 745 participants between the ages of 65 and 90 years were evaluated.

Hamimatunnisa Johar et al.: Blunted Diurnal Cortisol Pattern is Associated with Frailty: A Cross-Sectional Study of 745 Participants Aged 65 to 90 Years. JCEM (2014) | doi: 10.1210/jc.2013

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Particulate Matter Increases the Risk of Heart Attack

Long-term exposure to particulate matter is associated with increased risk of heart attack. This can already be observed at levels of exposure below current limit values. These are the results of a European research team led by scientists of Helmholtz Zentrum München, which were evaluating the data of more than 100,000 participants. The study therefore supports the demand to lower the current particulate limits.

Giulia Cesaroni et al.: Long-term Exposure to Ambient Air Pollution and Incidence of Acute Coronary Events: Prospective Cohort Study and Meta-analysis in 11 European Cohorts from the ESCAPE Project. The British Medical Journal 348 (2014) | doi: dx.doi.org/10.1136/bmj.f7412

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