Osteosarcoma (OS), the most common primary malignant bone tumor, has a peak incidence during the ... more Osteosarcoma (OS), the most common primary malignant bone tumor, has a peak incidence during the pubertal growth spurt. OS occurs at increased frequency in several inherited cancer syndromes (e.g., Li-Fraumeni and Rothmund Thomson syndromes). A limited number of common SNPs associated with OS have been identified in biologically plausible pathways (e.g., growth or DNA repair). We developed an international, multi-institutional study in order to conduct the first genome-wide association study (GWAS) of OS. Participating subjects provided informed consent through local IRBs. Control subjects were cancer free adults derived from large studies in prior GWAS at the NCI. Genotyping of all cases was conducted using the Illumina OmniExpress SNP microarray chip platform in 2 phases. The first phase analyzed 910 osteosarcoma cases. After quality control filtering and assessment of population substructure, 596 cases of European (EUR) ancestry were advanced to the primary GWAS analysis (Phase 1...
<jats:p>Cardiac QT interval represents both ventricular depolarization and repolarization e... more <jats:p>Cardiac QT interval represents both ventricular depolarization and repolarization events. Previous studies suggested significant genetic contribution to the normal QT interval length variation. In a candidate gene approach, we sought to identify novel genetic determinants of the normal QT interval length within the Ankyrin-2 (Ank-2) gene.</jats:p> <jats:p>Population and Methods: The study population consisted of 1492 participants of the WHO MONICA population survey. A standard measurement of the QT interval from the 12-lead ECG was available in 1212 individuals. The QT interval was corrected for covariates using different general and population specific formulas (QTc). Altogether, 22 SNPs within the Ank-2 gene were genotyped using the TaqMan technology. Statistical analyses included ANOVA and linear regression based trend test for comparisons of the QTc means.</jats:p> <jats:p>Results: In the promotor region of the alternative splicing Ank-2 variant, several SNPs and haplotypes were highly significantly associated with the QTc interval length. Specifically, a SNP rs1979086 (minor allele frequency f=0.44) was associated with the QTc length in the whole population (P=0.004 for ANOVA and P&lt;0.001 for the trend test). The QTc difference between the genotype groups was 2.87 ms (95%CI 1.18 – 4.56) and more pronounced in men where the QTc difference between the genotype groups was 4.65 ms (95% CI 2.18 – 7.12; P=0.0006 for ANOVA and P=0.0004 for the trend test). The results remained robust when QTc extreme quartiles and quintiles, respectively, were tested in a case-control pattern. Highly significant association results were obtained for all genetic models used (OR 1.58; P=0.00009; trend test for extreme QTc quartiles). A frequent haplotype (f=0.28) spanning approximately 20 kb in this region was highly significantly associated with the QTc length in the whole study population (QTc difference vs. most prevalent haplotype 3.66 ms, 95%CI 3.14 – 4.17, P&lt;0.0001).</jats:p> <jats:p>Conclusion: A small genomic region in the promotor of the Ank-2 gene contains SNPs and haplotypes that significantly influence the QTc interval in the normal population of German descent. A gender-specific effect with greater influence in male participants requires further evaluation.</jats:p>
Next generation sequencing (NGS) allows whole exome or whole genome sequencing for a given patien... more Next generation sequencing (NGS) allows whole exome or whole genome sequencing for a given patient to be performed timely and at reasonable cost. This diagnostic quantum leap not only has various legal, ethical and economical aspects but will naturally also impact upon patient care. Currently, however, the wide-spread introduction of NGS into routine diagnostics is facing many obstacles. In particular, it is to be expected that NGS will identify a large number of rare variants in a given patient that are of (yet) unknown clinical significance. As a first step towards solving this problem, we introduce the concept of a database that will systematically integrate genotypic and phenotypic information from the German health care context. Not only will this resource be of great scientific value, but the database shall also provide human geneticists with the evidence base necessary for the reliable evaluation of their patient-related sequencing data.
Potentially life threatening ventricular arrhythmias may occur as a consequence of genetic varian... more Potentially life threatening ventricular arrhythmias may occur as a consequence of genetic variants affecting key proteins that directly or indirectly alter myocardial electrical properties. Diseases such as Long-QT-Syndrome, Brugada Syndrome, catecholaminergic polymorphic ventricular tachycardia in structurally normal hearts and hypertrophic, dilated, and right ventricular cardiomyopathy in structurally abnormal hearts are the best known examples of monogenic conditions causing ventricular arrhythmias and sudden cardiac death (SCD).
Abstract presented in the XV International Symposium on Atherosclerosis, 2009, Boston, USA, 14–18... more Abstract presented in the XV International Symposium on Atherosclerosis, 2009, Boston, USA, 14–18 Jun
Introduction A serious side-effect of antiarrhythmic and many other agents is drug-induced long Q... more Introduction A serious side-effect of antiarrhythmic and many other agents is drug-induced long QT syndrome (diLQTS) with torsades de pointes. To test the role of common genetic variation in diLQTS...
This study compared metabolite shifts induced by training for, participation in, and recovery fro... more This study compared metabolite shifts induced by training for, participation in, and recovery from a marathon race competition among athletes divided into three groups based on fitness (relative maximum oxygen uptake (VO2max)) and performance levels (net running time). Plasma samples from 76 male runners participating in the Munich Marathon were analyzed for metabolite shifts using a targeted metabolomics panel. For the entire cohort of runners, pronounced increases were measured immediately after the race for plasma concentrations of acylcarnitines (AC), the ratio (palmitoylcarnitine + stearoylcarnitine)/free carnitine that is used as a proxy for the activity of the mitochondrial enzyme carnitine palmitoyltransferase, and arginine-related metabolites, with decreases in most amino acids (AA) and phospholipids. Plasma levels of AA and phospholipids were strongly increased 24 and 72 h post-race. Post-race plasma concentrations of AC and arginine-related metabolites were higher in the ...
Heritability studies have estimated the genetically attributable part of body mass index variance... more Heritability studies have estimated the genetically attributable part of body mass index variance to be in the range of 30-70 %. Rs7566650 (G>C) single-nucleotide polymorphism (SNP) near the promoter of the INSIG2 gene has been identified as associated with body mass index. The gene product of INSIG2 is involved in regulation of fatty acid and cholesterol synthesis. In order to replicate this association we have analysed 2,559 unrelated individuals of Slavonic Caucasian origin from the populationbased Czech MONICA 3-year cohort. Body mass index, waist-hip ratio and plasma lipids (total-cholesterol, HDL-cholesterol, triglycerides) were measured at two independent examinations within three years. We could not detect any association between the SNP rs7566605 and body mass index, waist-hip ratio or lipid parameters, both with or without adjusting for age and gender. Neither the body mass index change nor lipid changes were significantly affected by the INSIG2 gene variant. Our result...
Osteosarcoma (OS), the most common primary malignant bone tumor, has a peak incidence during the ... more Osteosarcoma (OS), the most common primary malignant bone tumor, has a peak incidence during the pubertal growth spurt. OS occurs at increased frequency in several inherited cancer syndromes (e.g., Li-Fraumeni and Rothmund Thomson syndromes). A limited number of common SNPs associated with OS have been identified in biologically plausible pathways (e.g., growth or DNA repair). We developed an international, multi-institutional study in order to conduct the first genome-wide association study (GWAS) of OS. Participating subjects provided informed consent through local IRBs. Control subjects were cancer free adults derived from large studies in prior GWAS at the NCI. Genotyping of all cases was conducted using the Illumina OmniExpress SNP microarray chip platform in 2 phases. The first phase analyzed 910 osteosarcoma cases. After quality control filtering and assessment of population substructure, 596 cases of European (EUR) ancestry were advanced to the primary GWAS analysis (Phase 1...
<jats:p>Cardiac QT interval represents both ventricular depolarization and repolarization e... more <jats:p>Cardiac QT interval represents both ventricular depolarization and repolarization events. Previous studies suggested significant genetic contribution to the normal QT interval length variation. In a candidate gene approach, we sought to identify novel genetic determinants of the normal QT interval length within the Ankyrin-2 (Ank-2) gene.</jats:p> <jats:p>Population and Methods: The study population consisted of 1492 participants of the WHO MONICA population survey. A standard measurement of the QT interval from the 12-lead ECG was available in 1212 individuals. The QT interval was corrected for covariates using different general and population specific formulas (QTc). Altogether, 22 SNPs within the Ank-2 gene were genotyped using the TaqMan technology. Statistical analyses included ANOVA and linear regression based trend test for comparisons of the QTc means.</jats:p> <jats:p>Results: In the promotor region of the alternative splicing Ank-2 variant, several SNPs and haplotypes were highly significantly associated with the QTc interval length. Specifically, a SNP rs1979086 (minor allele frequency f=0.44) was associated with the QTc length in the whole population (P=0.004 for ANOVA and P&lt;0.001 for the trend test). The QTc difference between the genotype groups was 2.87 ms (95%CI 1.18 – 4.56) and more pronounced in men where the QTc difference between the genotype groups was 4.65 ms (95% CI 2.18 – 7.12; P=0.0006 for ANOVA and P=0.0004 for the trend test). The results remained robust when QTc extreme quartiles and quintiles, respectively, were tested in a case-control pattern. Highly significant association results were obtained for all genetic models used (OR 1.58; P=0.00009; trend test for extreme QTc quartiles). A frequent haplotype (f=0.28) spanning approximately 20 kb in this region was highly significantly associated with the QTc length in the whole study population (QTc difference vs. most prevalent haplotype 3.66 ms, 95%CI 3.14 – 4.17, P&lt;0.0001).</jats:p> <jats:p>Conclusion: A small genomic region in the promotor of the Ank-2 gene contains SNPs and haplotypes that significantly influence the QTc interval in the normal population of German descent. A gender-specific effect with greater influence in male participants requires further evaluation.</jats:p>
Next generation sequencing (NGS) allows whole exome or whole genome sequencing for a given patien... more Next generation sequencing (NGS) allows whole exome or whole genome sequencing for a given patient to be performed timely and at reasonable cost. This diagnostic quantum leap not only has various legal, ethical and economical aspects but will naturally also impact upon patient care. Currently, however, the wide-spread introduction of NGS into routine diagnostics is facing many obstacles. In particular, it is to be expected that NGS will identify a large number of rare variants in a given patient that are of (yet) unknown clinical significance. As a first step towards solving this problem, we introduce the concept of a database that will systematically integrate genotypic and phenotypic information from the German health care context. Not only will this resource be of great scientific value, but the database shall also provide human geneticists with the evidence base necessary for the reliable evaluation of their patient-related sequencing data.
Potentially life threatening ventricular arrhythmias may occur as a consequence of genetic varian... more Potentially life threatening ventricular arrhythmias may occur as a consequence of genetic variants affecting key proteins that directly or indirectly alter myocardial electrical properties. Diseases such as Long-QT-Syndrome, Brugada Syndrome, catecholaminergic polymorphic ventricular tachycardia in structurally normal hearts and hypertrophic, dilated, and right ventricular cardiomyopathy in structurally abnormal hearts are the best known examples of monogenic conditions causing ventricular arrhythmias and sudden cardiac death (SCD).
Abstract presented in the XV International Symposium on Atherosclerosis, 2009, Boston, USA, 14–18... more Abstract presented in the XV International Symposium on Atherosclerosis, 2009, Boston, USA, 14–18 Jun
Introduction A serious side-effect of antiarrhythmic and many other agents is drug-induced long Q... more Introduction A serious side-effect of antiarrhythmic and many other agents is drug-induced long QT syndrome (diLQTS) with torsades de pointes. To test the role of common genetic variation in diLQTS...
This study compared metabolite shifts induced by training for, participation in, and recovery fro... more This study compared metabolite shifts induced by training for, participation in, and recovery from a marathon race competition among athletes divided into three groups based on fitness (relative maximum oxygen uptake (VO2max)) and performance levels (net running time). Plasma samples from 76 male runners participating in the Munich Marathon were analyzed for metabolite shifts using a targeted metabolomics panel. For the entire cohort of runners, pronounced increases were measured immediately after the race for plasma concentrations of acylcarnitines (AC), the ratio (palmitoylcarnitine + stearoylcarnitine)/free carnitine that is used as a proxy for the activity of the mitochondrial enzyme carnitine palmitoyltransferase, and arginine-related metabolites, with decreases in most amino acids (AA) and phospholipids. Plasma levels of AA and phospholipids were strongly increased 24 and 72 h post-race. Post-race plasma concentrations of AC and arginine-related metabolites were higher in the ...
Heritability studies have estimated the genetically attributable part of body mass index variance... more Heritability studies have estimated the genetically attributable part of body mass index variance to be in the range of 30-70 %. Rs7566650 (G>C) single-nucleotide polymorphism (SNP) near the promoter of the INSIG2 gene has been identified as associated with body mass index. The gene product of INSIG2 is involved in regulation of fatty acid and cholesterol synthesis. In order to replicate this association we have analysed 2,559 unrelated individuals of Slavonic Caucasian origin from the populationbased Czech MONICA 3-year cohort. Body mass index, waist-hip ratio and plasma lipids (total-cholesterol, HDL-cholesterol, triglycerides) were measured at two independent examinations within three years. We could not detect any association between the SNP rs7566605 and body mass index, waist-hip ratio or lipid parameters, both with or without adjusting for age and gender. Neither the body mass index change nor lipid changes were significantly affected by the INSIG2 gene variant. Our result...
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