Journal Articles

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Author: search.filters.author.Doughty RNSubject: search.filters.subject.Prognosis

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    VEGF-A cis-located SNPs on human chromosome 6 associated with VEGF-A plasma levels and survival in a coronary disease cohort
    (BioMed Central Ltd, 2025-12) Meza-Alvarado JC; Pilbrow AP; Frampton CM; Cameron VA; Richards AM; Troughton RW; Doughty RN; Page RA; Mallard B; Bromhead C; Palmer BR
    Background: Cardiovascular disease (CVD) is the leading cause of death worldwide. Risk stratification of CVD patients may be improved by predictive biomarkers, including genetic markers. Elevated circulating vascular endothelial growth factor A (VEGF-A) levels have been linked to CVD development. We explored whether single nucleotide polymorphisms (SNPs) at the VEGFA locus on human chromosome 6 were associated with VEGF-A levels and clinical outcomes in established CVD. VEGF-A levels were compared between coronary heart disease patients and heart healthy controls. Methods: Imputed genotypes of 30 SNPs from the VEGFA region for 1935 patients from the Coronary Disease Cohort Study (CDCS) and 1183 individuals from the Canterbury Healthy Volunteers Study (HVOL) were analysed for associations with cardiometabolic parameters. Association with clinical endpoints was assessed using Kaplan-Meier analysis and multivariate regression models. To validate the findings from imputed data, DNA samples of 2027 CDCS patients and 227 HVOL participants were manually genotyped for variants rs6921438 and rs7767396. Baseline plasma VEGF-A assayed by ELISA in 227 HVOL participants was compared with levels in 549 CDCS patients. Results: Manual genotyping showed rs6921438 AA and rs7767396 GG genotype groups had lower VEGF-A levels at baseline (CDCS: rs6921438 AA (27.7 pg/mL), AG (43.3 pg/mL), GG (63.2 pg/mL), p = 4.49 × 10− 22; rs7767396: GG (27.4 pg/mL), AG (42.8 pg/mL), AA (61.5 pg/mL) p = 3.47 × 10− 21; HVOL rs6921438 AA (12.8 pg/mL), GA (19.9 pg/mL), GG (26.4 pg/mL) p = 0.021; rs7767396 GG (12.6 pg/mL), AG (19.6 pg/mL), AA (25.9 pg/mL) p = 0.029). In the CDCS cohort rs6921438 AA was associated with increased risk of 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 events (p = 0.032); rs7767396 GG was associated with increased NSTEMI (p = 0.001) and HF (p = 0.023) risk; rs6921438 AA (Hazard Ratio (HR) = 6.55 p = 0.017), rs7767396 GG (HR = 0.149, p = 0.017) and VEGF-A (HR = 2.55, p = 0.018) were independent HF admission risk predictors. Conclusions: Variants rs6921438 and rs7767396 are associated with plasma VEGF-A levels. Both SNPs and VEGF-A may be useful in prognosis for HF after acute coronary events.
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    Plasma levels of soluble VEGF receptor isoforms, circulating pterins and VEGF system SNPs as prognostic biomarkers in patients with acute coronary syndromes
    (BioMed Central Ltd, 15/08/2018) Marks ECA; Wilkinson TM; Frampton CM; Skelton L; Pilbrow AP; Yandle TG; Pemberton CJ; Doughty RN; Whalley GA; Ellis CJ; Troughton RW; Owen MC; Pattinson NR; Cameron VA; Richards AM; Gieseg SP; Palmer BR
    BACKGROUND: Development of collateral circulation in coronary artery disease is cardio-protective. A key process in forming new blood vessels is attraction to occluded arteries of monocytes with their subsequent activation as macrophages. In patients from a prospectively recruited post-acute coronary syndromes cohort we investigated the prognostic performance of three products of activated macrophages, soluble vascular endothelial growth factor (VEGF) receptors (sFlt-1 and sKDR) and pterins, alongside genetic variants in VEGF receptor genes, VEGFR-1 and VEGFR-2. METHODS: Baseline levels of sFlt-1 (VEGFR1), sKDR (VEGFR2) and pterins were measured in plasma samples from subgroups (n = 513; 211; 144, respectively) of the Coronary Disease Cohort Study (CDCS, n = 2067). DNA samples from the cohort were genotyped for polymorphisms from the VEGFR-1 gene SNPs (rs748252 n = 2027, rs9513070 n = 2048) and VEGFR-2 gene SNPs (rs2071559 n = 2050, rs2305948 n = 2066, rs1870377 n = 2042). RESULTS: At baseline, levels of sFlt-1 were significantly correlated with age, alcohol consumption, NTproBNP, BNP and other covariates relevant to cardiovascular pathophysiology. Total neopterin levels were associated with alcohol consumption at baseline. 7,8 dihydroneopterin was associated with BMI. The A allele of VEGFR-2 variant rs1870377 was associated with higher plasma sFlt-1 and lower levels of sKDR at baseline. Baseline plasma sFlt-1 was univariately associated with all cause mortality with (p < 0.001) and in a Cox's proportional hazards regression model sFlt-1 and pterins were both associated with mortality independent of established predictors (p < 0.027). CONCLUSIONS: sFlt-1 and pterins may have potential as prognostic biomarkers in acute coronary syndromes patients. Genetic markers from VEGF system genes warrant further investigation as markers of levels of VEGF system components in these patients. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry. ACTRN12605000431628 . 16 September 2005, Retrospectively registered.