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Title
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A multi-omics approach to elucidate risk factors for obesity and associated liver pathology
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Author
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Abstract
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| Obesity is a highly prevalent condition in which excess body fat has accumulated as a result of the chronic imbalance in energy homeostasis. The disorder is characterized by a heterogeneous phenotype that represents itself in many different isolated forms as well as with varying cardiovascular and metabolic manifestations. Ectopic fat accumulation in the liver as a consequence of weight gain is present in up to 90% of patients and is referred to as non-alcoholic fatty liver disease. The high incidence of fatty liver disease in patients with obesity indicates an interconnection between both conditions. Research into their pathogenesis denoted a multifactorial aetiology with eating behaviour, lifestyle, environment, and genetics as the main contributing factors. Although successful efforts already identified numerous variants, the disease’s onset and the development of metabolic alterations leading to its comorbidities later in life are still incompletely understood. Further unravelling the genetic landscape of obesity is thus essential as it will provide insights into its pathogenesis. The general aim of this thesis was therefore to investigate the genetic architecture of complex obesity phenotypes by examining the role of structural variation in non-syndromic forms of obesity and the combined effect of (epi)genetics in the development of obesity and associated liver pathology. In a first part, fine-mapping and exploration of the 11q11 region in a traditional case-control study indicated an increased prevalence of a ± 80 kb deletion covering OR4C11, OR4P4, and OR4S2. The functional impact of these three olfactory receptor genes was assessed by expression profiling in metabolic relevant tissues and postulates that gene disruption will negatively influence energy metabolism with fat accumulation and obesity as outcome. In a second part, a targeted multi-omics approach investigating the influence of common polymorphisms and DNA methylation variation on PON1 status and the hepatometabolic phenotype exposed a significant relationship for (i) regulatory polymorphism rs705379:C>T with waist-to-hip ratio and indicative features of liver pathology and (ii) coding polymorphism rs854560:A>T with the expression of circadian clock gene ARNTL. These findings demonstrate the promising use of vertical data-integration methods to gain novel mechanistic insights that can improve our understanding of complex disease pathogenesis. |
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Language
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English
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Publication
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Antwerpen
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Universiteit Antwerpen, Faculteit Farmaceutische, Biomedische en Diergeneeskundige Wetenschappen, Departement Biomedische Wetenschappen
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2020
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Volume/pages
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238 p.
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Note
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Van Hul, Wim [Supervisor]
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Vanden Berghe, Wim [Supervisor]
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Full text (publisher's version - intranet only)
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