Evaluation of genetic and plasma markers of VEGF levels for prognosis in coronary heart disease : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Health Sciences at Massey University, Wellington, New Zealand
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2024-12-13
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Massey University
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Abstract
Cardiovascular disease (CVD) is the leading cause of death. CVD risk assessment is complicated by the multifactorial nature of disease onset and the lack of predictive biomarkers in patients. The vascular endothelial growth factor (VEGF-A), involved in blood vessel formation, could be considered a novel biomarker since increased levels have been observed in CVD aetiologies. Genetic variants, such as single nucleotide polymorphisms (SNPs), influence circulating VEGF-A levels and have been linked to CVD risk. SNPs are biomarkers that are independent of age that can be link to molecular mechanisms involved in CVD. The identification of clinically relevant SNPs will complement the existing CVD risk framework and further our understanding on the role of VEGF-A in CVD.
Imputed genotype data was obtained for 47 SNPs located at the VEGFA locus (human chromosome 6, n = 30), the VEGF receptor 2 (VEGFR2) locus (human chromosome 4, n = 13) and the very low-density lipoprotein receptor (VLDLR) locus (human chromosome 9, n = 4). Imputed genotype data for 1935 patients from the Coronary Disease Cohort Study (CDCS) and 1183 individuals from the Canterbury Healthy Volunteers Study (HVOL) was assessed. Association between genotype groups with cardiometabolic parameters was tested using one-way ANOVA tests. Association of genotypes with clinical endpoints was examined by Kaplan-Meir analyses and multivariate regression models. Candidate SNPs were selected from among all the imputed SNPs if data was p < 0.1 for any of the analyses. Manual genotyping, using predesigned TaqMan assays, was performed for SNPs with multiple significant associations (p < 0.05). Validation of imputed findings with manual genotyping data was possible for rs6921438, rs7767396, rs2305948 and rs1870377. VEGF-A levels for 227 HVOL participants were measured by an ELISA immunoassay to compare with previously reported levels from 549 CDCS patients.
SNPs identified that influence circulating VEGF-A levels included five at the VEGFA locus (rs6921438. rs7767396, rs45137773, rs7763440 and rs11757868), seven at the VEGFR2 locus (rs2305948, rs1870377, rs1870378, rs1870379, rs7677779, rs13136007 and rs10016064) and four at the VLDLR locus (rs7043199, rs10738760. rs7030781 and rs2375981). The homozygote minor allele genotypes for each SNP were associated with lower VEGF-A levels. Manual genotyped data for VEGFA locus variants rs6921438 and rs7767396 showed: a) rs6921438 AA was associated with increased all-cause death (p = 0.03), non ST-elevated myocardial infarction (NSTEMI, p = 0.0003), heart failure (HF, p = 0.035) and major adverse cardiovascular event (MACE, p = 0.032) risk b) rs7767396 GG was associated with increased NSTEMI (p = 0.001) HF (p = 0.023) risk c) rs6921438 AA (Hazard Ratio (HR) = 6.6 p = 0.016) and VEGF-A (HR = 2.64, p = 0.014) were independent HF admission risk predictors, along with established predictors. Manual genotyped data for VEGFR2 locus variants rs2305948 and rs1870377 showed a) rs2305948 CC was associated with higher all-cause mortality (p = 0.045) and shorter time to first cardiovascular readmission risk (p = 0.045) b) rs1870377 was an independent predictor for cardiovascular death when adjusting for NTproBNP, hypertension, creatinine, and beta blocker treatment (TT vs TA+AA, p = 0.048, HR = 1.125). Lastly, analyses showed that VLDLR locus variant rs10738760 AA genotype was associated with increased risk of cardiovascular death (p = 0.047, HR = 1.50).
The use of imputation data can facilitate the identification of clinically relevant SNPs by observing the amount and statistical significance of associations. In total, 11 imputed variants were identified as expression quantitative trait loci (eQTL) SNPs that affect circulating VEGF-A levels. Validation by genotyping confirmed that rs6921438 and rs7767396, at the VEGFA locus, are associated with VEGF-A levels and CVD risk. Additional data supported that VEGFR2 exonic variants rs2305948 and rs1870377 have an impact on increased outcome risk. Moreover, the VLDLR variant rs10738760 can interact with molecular mechanisms that exacerbate CVD risk. Overall, these five SNPs are promising genetic markers for CVD risk profiling assessments before outcome occurrence.
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Keywords
vascular endothelial growth factor A, single nucleotide polymorphisms, coronary heart disease, prognosis, genetic variants