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Title: Candidate genotypes in prediction of coronary heart disease
Author: Bolton, Jennifer Lynn
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2011
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Introduction There has been much discussion on personalised medicine; however use of genotype in risk prediction for coronary heart disease (CHD) has not resulted in appreciable improvements over non-genetic risk factors. The primary aim was to determine whether candidate single nucleotide polymorphisms (SNPs) identified from genome-wide association studies improved prediction of CHD over conventional risk factors (CRF). The secondary aim was to determine whether the use of apolipoproteins or lipoprotein(a) improved risk prediction of CHD. Methods Analyses used the Edinburgh Heart Disease Prevention Study (EHDPS), with 1592 men aged 30-59 and follow-up after 20 years; and the Edinburgh Artery Study (EAS), with 1592 men and women aged 54-75 and 15 years of follow-up. Candidate SNPs were identified by systematic literature reviews. CHD status was evaluated as severe (myocardial infarction or coronary revascularisation), and any (severe CHD, angina or non-specified ischaemic heart disease). Cox proportional hazards models were used to evaluate addition of candidate SNPs or lipids to models containing CRF. Results A group of genome-wide significant SNPs resulted in a non-significant improvement in C-index for severe CHD (0.038, p=0.082), and a significant improvement in C-index for any CHD (0.042, p=0.016); the associated net reclassification improvements (NRI) were 20.5% and 18.7%, respectively. Regression trees identified SNPs that were predictive of the remaining variance after adjusting for CRF; this resulted in a significant improvement in C-index for any CHD (0.031, p=0.008). The NRI were 11.0% and 9.6% for severe and any CHD, respectively. When compared with HDL cholesterol/total cholesterol, apolipoprotein AI/total cholesterol yielded a NRI of 3.3% for severe CHD. Lipoprotein(a) improved prediction of severe CHD, with a non-significant improvement in C-index (0.020, p=0.087), and NRI of 11.8%. Conclusion The results of this study indicate that a well selected group of candidate SNPs can improve risk prediction for CHD over-and-above CRF. The inclusion of lipoprotein(a), along with CRF, appeared to improve prediction of severe CHD, but not any CHD.
Supervisor: Anderson, Niall ; Price, Jackie ; Wilson, Jim Sponsor: Medical Research Council (MRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: genetics ; coronary heart disease ; CHD ; prediction ; risk ; lipoprotein(a) ; apolipoprotein