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The Genetics of Coronary Heart Disease across Ethnicities and in those with Type 2 Diabetes

Beaney, KE; (2016) The Genetics of Coronary Heart Disease across Ethnicities and in those with Type 2 Diabetes. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Coronary heart disease (CHD) is the most common cause of the death worldwide, presenting a considerable burden to both individual and public health. The genetics of CHD was investigated in two contexts in this thesis - risk prediction and the identification of functional mechanisms through which associated loci affect CHD pathophysiology. The use of a 19 single nucleotide polymorphism (SNP) CHD gene score (GS) was assessed in three ethnic groups (European, South Asian and Afro-Caribbean), but there was no strong evidence of clinical utility. A systematic literature search identified all variants robustly associated with CHD. Most of these variants were from the meta-analysis performed by the CARDIoGRAMplusC4D consortium. The GS was updated using effect sizes from this meta-analysis, resulting in improved performance. Overall, there was evidence of potential clinical utility in the European and Afro-Caribbean groups and in those with type 2 diabetes (T2D) (all p<0.05). However, results from the Pakistani cohorts were inconsistent. T2D-specific GSs were also assessed and were associated with CHD in the T2D group only (p<0.05). Functional analysis of two risk loci was performed. Firstly, rs10911021, previously associated with CHD in T2D and this result was supported by the findings of this thesis. Counterintuitively, the CHD “protective” allele was associated with lower high density lipoprotein (HDL) cholesterol (p=5x10-4) and lower large HDL traits (false discovery rate adjusted p-values p<0.05) in T2D only, indicating a complex relationship between CHD, T2D and HDL. Secondly, the CHD risk locus on chromosome 21q22 (lead SNP rs9982601) was not associated with any CHD risk factors. Using bioinformatics tools and in vitro functional assays, a candidate functional SNP - rs28451064 - was identified (which showed allele-specific protein binding and the minor allele had 12 % higher expression p=4.82x10-3). Further investigation is required to define the underlying molecular pathways.

Type: Thesis (Doctoral)
Title: The Genetics of Coronary Heart Disease across Ethnicities and in those with Type 2 Diabetes
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Inst of Clinical Trials and Methodology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL
URI: http://discovery.ucl.ac.uk/id/eprint/1522245
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