130 research outputs found
Identification of a new gene (OLFML2B) and characterization of its variants in patients with disturbance of the cardiac repolarization and sudden infant death syndrome (SIDS)
No full textDurch eine genomweite Assoziationsstudie wurde die Region Chr. 1q23.3 als der stärkste quantitative Trait-Locus (QTL) in Bezug auf zwei Gene, das bereits bekanntere NOS1AP- und das bisher noch wenig erforschte OLFML2B-Gen, beschrieben. Knockout-Untersuchungen im Zebrafisch bestätigten, dass der Verlust eines jeden der beiden Gene zu Störungen der kardialen Repolarisation und zu kardialer Dilatation führen kann.
Aufgrund dieser Erkenntnisse wurde in dieser Dissertation bei Patienten mit Veranlagung zu Herzrhythmusstörungen durch Long-QT Syndrom (LQT), medikamenteninduziertem Long-QT Syndrom (drug induced LQT bzw. diLQT), plötzlichem Herztod (sudden cardiac death, SCD) oder plötzlichem Kindstod (sudden infant death syndrome, SIDS) das OLML2B-Gen auf seltene Mutationen untersucht, die diese Erkrankungen verursachen bzw. begünstigen können. Im Rahmen dieser Arbeit wurden bei den untersuchten Patienten insgesamt 14 potentiell krankheitsauslösende heterozygote Missense-Mutationen innerhalb dieses Gens identifiziert aus insgesamt 86 aufgefundenen Varianten in allen Kollektiven einschließlich der Kontrollen. Diese Mutationen wurden vier- bis zwölfmal häufiger in den Patientenkollektiven als in den Kontrollkollektiven gesehen. Insbesondere wurden drei heterozygote Missense-Varianten bei Kindern mit SIDS gefunden. In Zusammenschau dieser Daten mit funktionellen Untersuchungen einer weiteren Dissertation kann angenommen werden, dass die aufgefundenen Varianten die Repolarisationsreserve im menschlichen Herzen reduzieren, was wiederum zu einer Prädisposition für plötzlichen Kindstod (SIDS), LQTS und diLQT führen und ein bisher unbekannter Pathomechanismus für kardiale Arrhythmien gefunden werden kann. Dadurch könnten sich mittelfristig potentiell neue diagnostische und therapeutische Implikationen ergeben.Chromosome 1q23.3 has been identified as the most prominent quantitative trait locus (QTL) related to the electrocardiographic measurement of QT-interval by genome-wide association studies. In this chromosomal region, two genes, the already known NOS1P-gene and the so far little explored OLFML2B-gene have been identified. Knockout studies in zebrafish confirmed that the loss of any of the two genes can lead to disturbance of the cardiac repolarization and cardiac dilatation.
Based on these findings, patients with predisposition to arrhythmia (long QT syndrome, drug induced LQT), sudden cardiac death (SCD) and sudden infant death syndrome (SIDS) were investigated in this thesis for the presence of rare mutations of the OLFML2B-gene associated with the disease or its predisposition. In my work, 14 of 86 identified variants within this gene were found in patients within the defined groups with potential high relevance for phenotype changes. These mutations could be found four to twelve times more frequent in the patient groups than in the general population control group. In particular there were three heterozygous missense-mutations found in children with SIDS. Taken together with extended functional studies from another thesis, it can be assumed that the described mutations in this gene can cause a diminishment of the repolarization reserve in cardiac cells leading to SIDS, long QT syndrome and drug induced QT syndrome. The findings show that, by means of GWAS, an entirely new pathomechanism for complex polygenic diseases can be identified with potential implications for diagnosis and therapy
A novel mutation in Lamin A/C (LMNA-R377C) causes Dilated Cardiomyopathy of the CMD1A Subtype
No full textIn der vorliegenden Arbeit wurde die bislang weltweit größte molekular untersuchte Familie mit einer Lamin-Kardiomyopathie (Mutation Arg377Cys, Exon 6 des Lamin-Gens) molekulargenetisch und klinisch untersucht. Das Alter der klinischen Erstmanifestation lag im Durchschnitt bei 40,2 Jahren. 40 % der Betroffenen erhielten einen Schrittmacher oder einen implantierbaren Kardioverter-Defibrillator. Die mittlere Lebenserwartung lag bei 59,5 Jahren, Haupttodesursache war Folgen eines Apoplexes (66%). Bei der Untersuchung häufiger Polymorphismen in FII, FV und MTHFR konnte kein Hinweis auf eine familiäre Thrombophilie gefunden werden, insbesondere nicht bei den Schlaganfallpatienten. Als verlässlichster klinisch-diagnostischer Parameter der CMD1A erwies sich die Verlängerung der PQ-Zeit im Standard-EKG. Für Betroffene ergeben sich durch eine molekulargenetische Analyse neue Möglichkeiten der Prävention und frühzeitigen Therapie der Erkrankung.We describe a large Austrian family in which a novel mutation R377C (Arg377Cys) in exon 6 caused the condition. We studied 36 members of the family of whom 21 were affected. All 15 affected family members with DNA available carried the mutation. These data make this the largest CMD1A kinship so far examined at the molecular level.In addition to the cardiac phenotype 4 of 15 neurologicaly examined mutation carriers (26 %) showed recurrent myalgia and 2 (13 %) suffered from obstucive sleep apnoea syndrome. Remarkably, among the 7 patients who had undergone a pacemaker (PM) implantation, 4 experienced a stroke afterwards. No thrombembolic events were noted in patients without a PM. The high risk of stroke after PM implantation had so far not been described in CMD1A. In two patients with early onset conduction disease who had received an intrathoracal cardioverter/defibrillator (ICD), episodes of severe ventricular tachycardia (VT) were recorded and terminated within the first two years after implantation. These data suggest that for patients with lamin-cardiomyopathy who require PM implantation due to conduction disease, an ICD should be considered, even if no major episodes of VT/VF have yet been documented. For all patients with PM or ICD implants, a stringent regimen for prevention of thromboembolic events should be implemented
Genetics of the ECG: QT or not QT- A genetic analysis of a complex electrophysiological trait confirms several previously detected associations
No full textGenetik komplexer Herzerkrankungen und den mit ihnen korrelierten EKG-Veränderungen
No full textKardiale Arrhythmien und quantitative EKG-Merkmale unterliegen zum Teil starken genetischen Einflüssen. Dieses oft als hohe Heritabilität bezeichnete Phänomen ist nur zum Teil durch Mutationen mit Mendelschen Erbgängen erklärbar. In dieser Habilitationsschrift wird der Beitrag häufiger genetischer Varianten und multifaktorieller Erkrankungsmodelle zu elektrophysiologischen Phänotypen mit Hilfe genomweiter Assoziationsstudien (GWAS) untersucht. GWAS zum QT-Intervall und zum PQ-Intervall wurden in Normal-Bevölkerungskollektiven von über 15.000 Personen durchgeführt, GWAS zum Vorhofflimmern in über 1.000 Patienten und Kontrollen. Für das QT-Intervall wurden zehn und für das PQ-Intervall neun Genorte identifiziert, in denen Varianten die Intervalldauern um wenige Millisekunden verlängern oder verkürzen. In den QT-Intervall modifizierenden Genorten befinden sich vier bekannte repolarisationsrelevante Krankheitsgene für monogenes Long QT-Syndrom. Die PQ-Intervall modifizierenden Genorte kodieren in der Mehrzahl für atriale Transkriptionsfaktoren und in nur zwei Fällen für Ionenkanäle. Bei den Assoziationen zum Vorhofflimmern, das mit einer Prävalenz von ca. 1% die häufigste Arrhythmie ist, wurden in bis zu 3.413 Patienten zusätzlich zu der bekannten Genregion nahe PITX2 auch Varianten in den Genen ZFHX3 und KCNN3 sowie fünf der neun PQ-Intervall assoziierten Varianten als Risikofaktoren für Vorhofflimmern identifiziert. Diese Ergebnisse erweitern das Verständnis von kardialer Elektrophysiologie und von Arrhythmien, identifizieren neue Targetproteine für antiarrhythmetische Medikamente und ermöglichen prädiktive Risikomodelle für Vorhofflimmern
A multimetric approach to analysis of genome-wide association by single markers and composite likelihood
No full textTwo case/control studies with different phenotypes, marker densities, and microarrays were examined for the most significant single markers in defined regions. They show a pronounced bias toward exaggerated significance that increases with the number of observed markers and would increase further with imputed markers. This bias is eliminated by Bonferroni adjustment, thereby allowing combination by principal component analysis with a Malecot model composite likelihood evaluated by a permutation procedure to allow for multiple dependent markers. This intermediate value identifies the only demonstrated causal locus as most significant even in the preliminary analysis and clearly recognizes the strongest candidate in the other sample. Because the three metrics (most significant single marker, composite likelihood, and their principal component) are correlated, choice of the n smallest P values by each test gives <3n regions for follow-up in the next stage. In this way, methods with different response to marker selection and density are given approximately equal weight and economically compared, without expressing an untested prejudice or sacrificing the most significant results for any of them. Large numbers of cases, controls, and markers are by themselves insufficient to control type 1 and 2 errors, and so efficient use of multiple metrics with Bonferroni adjustment promises to be valuable in identifying causal variants and optimal design simultaneously
Functional characterization and pathophysiological evaluation of the Olfactomedin-like 2B gene
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Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders
Get PDFElevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets
The association of a SNP upstream of INSIG2 with body mass index is reproduced in several but not all cohorts
Get PDFA SNP upstream of the INSIG2 gene, rs7566605, was recently found to be associated with obesity as measured by body mass index (BMI) by Herbert and colleagues. The association between increased BMI and homozygosity for the minor allele was first observed in data from a genome-wide association scan of 86,604 SNPs in 923 related individuals from the Framingham Heart Study offspring cohort. The association was reproduced in four additional cohorts, but was not seen in a fifth cohort. To further assess the general reproducibility of this association, we genotyped rs7566605 in nine large cohorts from eight populations across multiple ethnicities (total n = 16,969). We tested this variant for association with BMI in each sample under a recessive model using family-based, population-based, and case-control designs. We observed a significant (p < 0.05) association in five cohorts but saw no association in three other cohorts. There was variability in the strength of association evidence across examination cycles in longitudinal data from unrelated individuals in the Framingham Heart Study Offspring cohort. A combined analysis revealed significant independent validation of this association in both unrelated (p = 0.046) and family-based (p = 0.004) samples. The estimated risk conferred by this allele is small, and could easily be masked by small sample size, population stratification, or other confounders. These validation studies suggest that the original association is less likely to be spurious, but the failure to observe an association in every data set suggests that the effect of SNP rs7566605 on BMI may be heterogeneous across population samples
Differential modulation of human immunoglobulin isotype production by the neuropeptides substance P, NKA and NKB1Dedicated to the 60th birthday of Professor Eckart Köttgen.1
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