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Functional analysis of novel genetic markers of coronary artery disease identified by genome-wide association studies

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posted on 2015-02-04, 16:12 authored by Peter Stuart Braund
Coronary artery disease (CAD) is the commonest cause of death worldwide. It is a multifactorial disease caused by interplay between genes and environment. Defining genes that affect CAD risk and understanding their mechanisms may help to improve its prevention and treatment. Recent genome-wide association studies have identified several novel loci associated with CAD. In this thesis I examined two of these loci. The first was a locus on chromosome 1p13.3. I showed that this locus was also associated with LDL-cholesterol. Fine-mapping of the locus and in silico analyses suggested that SNP rs12740374, where the risk allele disrupts binding of a liver-specific transcription factor, is probably the causal variant at the locus. Finally, I showed that the lipid-lowering effect of statin is independent of this locus, suggesting that targeting the mechanism by which this locus affects LDL-cholesterol may provide additional therapeutic benefit. The second locus was on chromosome 13q34 located near the COL4A1 and COL4A2 genes which code for collagen Type 4, a key component of the arterial wall. In silico analyses identified an intronic 4-SNP haplotype within a bidirectional promoter that was likely to include the causal variant(s). A putative kidney expression QTL was identified with the CAD risk allele associated with lower expression of COL4A1 and COL4A2. Functional experiments showed DNA-protein binding to the SNPs in the haploblock. However, there were no differences in level of DNA-binding between the alleles or a differential impact on gene expression. In a clinical study, there was no difference between the 13q34 genotype groups in restenosis rates in patients undergoing percutaneous coronary angioplasty. In conclusion, the work on locus 1p13.3 shows that it is possible to identify a causal SNP from a GWA study signal, and elucidate its mechanism, but the studies on locus 13q34, indicates that this is a challenging process.

History

Supervisor(s)

Samani, Nilesh; Tomaszewski, Maciej

Date of award

2015-01-01

Author affiliation

Department of Cardiovascular Sciences

Awarding institution

University of Leicester

Qualification level

  • Doctoral

Qualification name

  • PhD

Language

en

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