Herz-Kreislauf-Erkrankungen als Folge arteriosklerotischer Prozesse sind die häufigste Todesursache weltweit. Lipidstoffwechselstörungen sind ein wichtiger Risikofaktor für die Pathogenese der Arteriosklerose. Komplexe Phänotypen, wie z.B. der Lipidstoffwechsel, werden durch eine Vielzahl von genetischen und Umweltfaktoren beeinflusst. Obwohl der Lipidstoffwechsel biochemisch gut charakterisiert ist und viele Gene, die für Proteine innerhalb des Lipidstoffwechsels kodieren bekannt sind, sind die spezifischen genetischen Faktoren, die die Variabilität des Lipidstoffwechsels beeinflussen, weitgehend unbekannt. Die vorgelegten Studien zeigen verschiedene Ansätze, wie genetische Faktoren, die die Variabilität des Lipidstoffwechsels beeinflussen, identifiziert und quantifiziert werden können. Dabei wird ein besonderer Schwerpunkt auf die Untersuchung der Variabilität im nicht-pathologischen Bereich des Stoffwechsels gelegt. Im Rahmen der durchgeführten Arbeiten wurden: 1. modifizierende Genorte bei familiären Hyperlipidämien identifiziert. Dieser Ansatz wurde am Beispiel von zwei Familien mit familiärer Hypercholesterinämie aus Israel und Syrien illustriert. Mit Hilfe der Familie aus Israel wurde ein Genort, der für einen Cholesterin-senkenden Effekt verantwortlich ist, kartiert. Mit Hilfe der Familie aus Syrien wurde ein Gen für die Ausprägung von Xanthomen postuliert. 1. der Einfluß von Genen und Genorten auf die Variabilität des Lipidstoffwechsels in einer Zwillingspopulation nachgewiesen. Dieser Anstz wurde anhand von Genorten auf Chromosom 13q (Cholesterin-senkender Genort), auf Chromosom 8 (Lipioprotein Lipase und Makrophagen Scavenger Rezeptor) und dem PPAR?-Gen auf Chromosom 3 illsutriert. 3. der Einfluß einzelner genetischer Varianten in sechs Kandidatengenen des Lipidstoffwechsels in einer familienbasierten Stichprobe quantifiziert. 4. ein mathematisches Modell des Lipidstoffwechsels entwickelt, mit dem Ziel, sich der Komplexität des Stoffwechsels sowohl von experimenteller als auch von theoretischer Seite her zu nähern. / Cardiovascular disease resultung from atherosclerotic processes are the most commonest cause of death worldwide. Lipid disturbances are a major risk factor in the pathogenesis of atherosclerosis. Complex phenotypes, e.g. lipid metabolism, are influenced by a variety of genetic and environmental factors. Although lipid metabolism is well characterized biochemically and many genes, coding for proteins of lipid metabolism are known, the specific genetic variants, influencing the variability of lipid metabolism are largely unknown. The studies presented show different approaches to the identification of genetic factors contributing quantitatively and qualitatively to the variability of lipid metabolism. This work puts an emphasis on the variability in the non-pathological range of lipid concentrations. The following issues are addressed in the context of this work: 1. Identification of modifying genes of familial lipid disorders. This approach is illustrated for two families with familial hypercholesterolemia from Israel and Syria. The family from Israel allowed the mapping and identification of a cholesterol-lowering gene locus. The family from Syria helped postulating a giant xanthoma gene. 2. The influence of genes and gene loci on the variability of lipid metabolism using a twin cohort. This approach was illustrated for gene loci on chromosome 13q (cholesterol-lowering gene locus), chromosome 8 (Lipoprotein lipase and macrophage scavenger receptor gene locus), and the PPAR?-gene on chromosome 3. 3. The influence of single nucleotide polymorphisms in six lipid metabolism relevant genes using a family based association approach. 5. A mathematical model of lipid metabolism was developed. The goal was to approach the complexity of lipid metabolism experimentally as well as theoretically.

Background: We aimed to increase the knowledge regarding the familial arrhythmogenic disorder Long QT Syndrome (LQTS) and its recessive variant Jervell and Lange-Nielsen Syndrome (JLNS) in Sweden, including prevalences and clinical phenotypes. A specific focus was directed towards two KCNQ1 mutations –p.Y111C and p.R518X- commonly identified in Swedish LQTS index cases. Methods: Cases and families with LQTS (p.Y111C or p.R518X) and JLNS were recruited via regional clinical practices, national referrals to the Clinical Genetics laboratory, Umeå University Hospital, and a national inventory. Molecular genetics methods were used for case ascertainment. Clinical data was obtained via medical records, a questionnaire, and/or an interview. Electrocardiograms were manually assessed. In p.R518X heterozygotes intra-familial phenotypic variability (QTc and cardiac events) was assessed by analysis of sequence variants (modifier genes). The origins of the mutations p.Y111C and p.R518X were investigated using genealogical and haplotype analysis (microsatellite markers). In families sharing a common haplotype mutation age and associated prevalence was analyzed using ESTIAGE and DMLE computer software. Results: We identified p.Y111C (170 mutation-carriers) and p.R518X (101 mutation-carriers) as two major causes of LQTS/JLNS in Sweden. LQTS phenotype was revealed to be relatively benign in p.Y111C and p.R518X (annual incidence of life-threatening cardiac events, before therapy 0.05% and 0.04%, respectively). Gender-specific effects of genetic modifiers on phenotypic expression were seen. A founder origin, approximately 600-700 years ago in two northern river valleys was established for p.Y111C and p.R518X, and a high prevalence of LQTS founder descendants suggested. A minimum JLNS prevalence of 1:200 000 in preadolescent Swedish children was revealed. JLNS phenotype was mainly severe, with a cumulative incidence of life-threatening cardiac events of 53% (annual incidence rate before therapy 5%) and four sudden deaths. Possible founder effects regarding four KCNQ1 mutations; p.Y111C (8%), p.R518X (50%), c.572_576del (17%) and p.Q530X (8%) together explained 83% of the JLNS mutation-spectrum in Sweden, consisting of 8 KCNQ1 mutations. Conclusion: The high prevalence of p.Y111C- and p.R518X-related LQTS as well as JLNS revealed in Sweden could be explained by the combination of mild clinical phenotypes in heterozygotes and strong founder effects present during the population development of northern Sweden. Increased knowledge regarding the occurrence of LQTS and JLNS as well as mutation- and/or genotype-specific data constitute prerequisites for possible improvement of patient management.

<p>The goal of this thesis is to algorithmically identify candidate modifiers for <i>retinitis pigmentosa</i> (RP) to help improve therapy and predictions for this genetic disorder that may lead to a complete loss of vision. A current research by (Chow et al., 2016) focused on the genetic contributors to RP by trying to recognize a correlation between genetic modifiers and phenotypic variation in female <i>Drosophila melanogaster</i>, or fruit flies. In comparison to the genome-wide association analysis carried out in Chow et al.’s research, this study proposes using a K-Means clustering algorithm on RNA expression data to better understand which genes best exhibit characteristics of the RP degenerative model. Validating this algorithm’s effectiveness in identifying suspected genes takes priority over their classification.</p><p>This study investigates the linear relationship between <i>Drosophila </i>eye size and genetic expression to gather statistically significant, strongly correlated genes from the clusters with abnormally high or low eye sizes. The clustering algorithm is implemented in the R scripting language, and supplemental information details the steps of this computational process. Running the mean eye size and genetic expression data of 18,140 female <i>Drosophila</i> genes and 171 strains through the proposed algorithm in its four variations helped identify 140 suspected candidate modifiers for retinal degeneration. Although none of the top candidate genes found in this study matched Chow’s candidates, they were all statistically significant and strongly correlated, with several showing links to RP. These results may continue to improve as more of the 140 suspected genes are annotated using identical or comparative approaches.</p>

<p>  </p> <p>Inhalation is a primary route of environmental and occupational exposures. Inhalation toxicology studies have thoroughly demonstrated the efficacy and adverse effects of a large number of chemicals, metals, pharmaceuticals, and agrochemicals. With the rapid development of new technologies and emergence of prominent subpopulations, some emerging exposure issues have arisen. To better protect public health, it is necessary to address these numerous emerging issues related to inhalation toxicology including 1) exposures to complex and unknown chemical emissions generated as we resolve infrastructure needs, 2) real-world exposure scenarios such as nanoparticle (NP) mixtures that may induce unique toxicity, and 3) variations in toxicity responses that occur in vulnerable and prevalent subpopulations following exposures. We designed three aims 1) to characterize differential representative composite manufacturing emissions (CMEs) and toxicity assessment of inhalation exposure to CMEs, 2) to examine the contribution of variable iron and manganese NP components in welding fumes to pulmonary toxicity, and 3) to evaluate metabolic syndrome (MetS)-induced variations in NP-Biocorona (NP-BC) composition following inhalation and modulation of pulmonary toxicity. Overall, this proposal aimed to characterize the emerging and complex exposures occurring in the real world and elucidate the mechanisms of differential pulmonary toxicity and susceptibility associated with CMEs, different metal NP components in welding fumes, and underlying diseases such as MetS. The conclusions from this project can help to improve the application of water infrastructure repairing technology and the utilization of welding and understand the mechanism of susceptibility to NP exposure among individuals with underlying diseases. Furthermore, the findings from these evaluations have supported and improved worldwide regulation, which promotes a safer utilization of novel materials, newly developed medicines, and complex chemicals.</p>