Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/28017
Title: Analysis of genetic variation within urotensin-II system in regulation of blood pressure and renal function
Authors: Debiec, Radoslaw Marek
Supervisors: Tomaszewski, Maciej
Lambert, David
Award date: 1-Jun-2013
Presented at: University of Leicester
Abstract: Elevated blood pressure (BP) and reduced glomerular filtration rate (GFR) are risk factors for cardiovascular disease. BP and GFR are influenced by heritable factors. Only small proportion of this heritability has been explained so far. This project aimed to identify genetic loci contributing to population variation in BP or GFR through application of candidate gene and large scale genotyping approaches. The candidate gene approach utilised tagging single nucleotide polymorphisms (SNP) in genes of the urotensin-II (U-II) pathway in a sample of white European subjects (3 family collections and 5 unrelated subject studies – altogether 10,748 subjects). This was followed by gene expression studies in 2 collections of human kidneys and phylogenetic analysis of the system to examine its evolutionary conservation from fish to human. The large scale genotyping project utilised data from 50K IBC genotyping array in a cohort of families (520 pedigrees) from general population of UK. None of the 28 SNPs in U-II pathway genes was associated with BP or GFR. Gene expression levels of UTS2 and UTS2R were strongly correlated (r=0.83, p<0.0001) but renal expression was not associated with human hypertension. The phylogenetic analysis showed that strong purifying selection acting on this system in lower vertebrates was lost in primates. The large scale genotyping approach showed strong signal of association in the 5,10-methylenetetrahydrofolate reductase (NAD(P)H) gene (MTHFR) locus with clinic diastolic BP. Each minor copy (G) of rs17037388 was associated with 2.03mmHg reduction in clinic diastolic BP (p=3.01x10[superscript -06]). Gene candidate and large scale genotyping approaches performed in parallel provide useful information about genetic architecture of complex traits. The data from genetic association in candidate U-II system genes did not provide evidence on its association with BP or GFR. Large scale genotyping experiment led to identification of genuine association signal with clinic diastolic BP.
Links: http://hdl.handle.net/2381/28017
Type: Thesis
Level: Doctoral
Qualification: PhD
Rights: Copyright © the author. All rights reserved.
Appears in Collections:Theses, Dept. of Cardiovascular Sciences
Leicester Theses

Files in This Item:
File Description SizeFormat 
2013DebiecRPhD2.pdf2.65 MBAdobe PDFView/Open


Items in LRA are protected by copyright, with all rights reserved, unless otherwise indicated.