<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Unraveling Gene Networks of Human Cholesterol Homeostasis and Their Roles in Cardiovascular Disease"^^ . "It is well established that elevated plasma cholesterol is a major risk factor for\r\natherosclerosis, the cause of cardiovascular disease (CVD), which is most often\r\nmanifested as coronary artery disease (CAD) and myocardial infarction (MI). The\r\nidentification through GWAS of genes associated with lipids and CVD has only to a\r\nminor extent explained the genetic architecture of CVD and dyslipidemias. In an\r\neffort to identify genes affecting cholesterol regulation, an RNAi-based functional\r\nprofiling of GWAS-derived loci, which were associated with lipid traits, CAD and/or\r\nMI was previously performed in our lab (Blattmann et al. 2013). This study resulted\r\nin the identification of 55 genes that had an effect on LDL internalization and/ or\r\ncellular cholesterol levels. However, most of the screen hits did not have a strong\r\neffect, suggesting that the combinatorial -rather than the individual- function of\r\nthese genes might regulate cholesterol homeostasis and subsequently CVD. This\r\nreasoning is supported by the fact that CVD is a complex disease, which is assumed\r\nto arise from the synergistic effect of genes.\r\nIn the present study, a combinatorial RNAi screen was performed in order to identify\r\ninteractions between genes identified in the aforementioned study, after\r\njuxtaposing them with the results of an Exome Chip of more than 70,000 individuals,\r\ngenotyped for lipid traits (LDL, HDL, TG, TC) (Peloso et al. 2014). For this purpose, the\r\neffect on LDL uptake of all pairwise combinations between 30 candidate genes was\r\ntested, and 21 pairs were confirmed as genetic interactors. A gene interaction model\r\nnetwork was constructed, based on the results of the screen, connecting known\r\ncholesterol regulators, as well as genes without a previously reported lipidregulatory\r\nfunction. Secondary screens were performed to measure the effect of the\r\ngene interactions on LDLR mRNA and protein, as well as on SREBF1 and SREBF2\r\nmRNA levels. The results from secondary experiments provided further valuable\r\ninformation for the mechanistic interpretation of the interactions. The one occurring\r\nbetween LDLR, which encodes for the receptor of LDL and HAVCR1, which encodes\r\nfor a membrane receptor for hepatitis A virus was followed up. Furthermore,\r\nhypotheses were generated for the sub-network of LDLR-MLXIPL-HAVCR1 on the\r\nmechanism of interaction influencing cholesterol homeostasis. Hypotheses were\r\nmade also for a few other interesting interactions, which correlated with cellular\r\nLDLR mRNA and/or protein levels, as well as with SREBF mRNA levels. For HAVCR1,\r\nmutation screening was performed, whereby the overexpression of 18 out of 19\r\nmutations had a significant inhibitory effect on LDL uptake, further supporting a so\r\nfar undescribed role for HAVCR1 in cholesterol endocytosis. In parallel, in\r\ncollaboration with Heiko Runz (Merck Research Laboratories), all lead SNPs of the\r\ngenes tested with co-RNAi were examined for co-occurrence and SNP-SNP\r\ninteractions in a cohort of more than 4000 individuals (Muntendam et al. 2010).\r\nWith this analysis, an additive effect was demonstrated for three pairs of SNPs that\r\ncorresponded to gene interactions identified with the co-RNAi screen (LPL+CELSR2,\r\nAPOB+HMGCR, LDLR+NCAN).\r\nIn summary, the study in hand identified combinatorial effects of genes on\r\ncholesterol homeostasis, through systematic identification of genetic interactions\r\nbetween GWAS-derived genes. Altogether, this research demonstrates the potential\r\nof the scalable strategy employed using quantitative cell-based assays, to uncover\r\nthe genetic networks underlying common disorders and diseases. Further\r\ncharacterization of these networks would lead to a better understanding of CVD\r\ninheritance and provide valuable insight for the generation of novel treatments."^^ . "2018" . . . . . . . "Anthi"^^ . "Trasta"^^ . "Anthi Trasta"^^ . . . . . . "Unraveling Gene Networks of Human Cholesterol Homeostasis and Their Roles in Cardiovascular Disease (Other)"^^ . . . . . . "Unraveling Gene Networks of Human Cholesterol Homeostasis and Their Roles in Cardiovascular Disease (Other)"^^ . . . . . . "Unraveling Gene Networks of Human Cholesterol Homeostasis and Their Roles in Cardiovascular Disease (Other)"^^ . . . . . . "Unraveling Gene Networks of Human Cholesterol Homeostasis and Their Roles in Cardiovascular Disease (Other)"^^ . . . . . . "Unraveling Gene Networks of Human Cholesterol Homeostasis and Their Roles in Cardiovascular Disease (Other)"^^ . . . . . . "Unraveling Gene Networks of Human Cholesterol Homeostasis and Their Roles in Cardiovascular Disease (PDF)"^^ . . . "Anthi Trasta_PhD Thesis.pdf"^^ . . "HTML Summary of #23205 \n\nUnraveling Gene Networks of Human Cholesterol Homeostasis and Their Roles in Cardiovascular Disease\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .