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Vascular Endothelial Growth Factor and Ischemic Heart Disease Risk: A Mendelian Randomization Study.

ABSTRACT: Vascular endothelial growth factor (VEGF) has angiogenic and possibly proatherosclerotic properties. Observationally it is positively associated with cardiovascular disease, although these observations could be confounded or due to reverse causation. We assessed ischemic heart disease (IHD) risk by genetically predicted VEGF, ie, using Mendelian randomization.Single nucleotide polymorphisms (SNPs) predicting VEGF level, at genome-wide significance, were applied to the CARDIoGRAMplusC4D 1000 Genomes-based genome-wide association study IHD case (n=60 801)-control (n=123 504) study. We obtained unconfounded estimates using instrumental variable analysis by combining the Wald estimates for each SNP using inverse variance weighting and Mendelian randomization-Egger regression. Based on 9 SNPs independently predicting VEGF (rs1740073 [C6orf223], rs2375981 [KCNV2], rs2639990 [ZADH2], rs4782371 [ZFPM1], rs6921438 [LOC100132354], rs7043199 [VLDLR-AS1], rs10761741 [JMJD1C], rs6993770 [ZFPM2], and rs114694170 [MEF2C]), VEGF was unrelated to IHD (odds ratio 0.99 per log-transformed pg/mL, 95%CI 0.96-1.02) using inverse variance weighting. However, Mendelian randomization-Egger regression suggested an inverse relation of VEGF with IHD (odds ratio 0.95, 95%CI 0.91-0.99), although the association was not evident after excluding the lead SNP (rs6921438) or additionally excluding the pleiotropic SNP (rs6993770).Our study does not provide strong evidence for a positive effect of VEGF on IHD but does not rule out the possibility that some specific types of VEGF, for which genetic predictors have not yet been identified, might play a role.

SUBMITTER: Au Yeung SL

PROVIDER: S-EPMC5586422 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Vascular Endothelial Growth Factor and Ischemic Heart Disease Risk: A Mendelian Randomization Study.

Au Yeung Shiu Lun SL Lam Hugh Simon Hung San HSHS Schooling C Mary CM

Journal of the American Heart Association 20170801 8

<h4>Background</h4>Vascular endothelial growth factor (VEGF) has angiogenic and possibly proatherosclerotic properties. Observationally it is positively associated with cardiovascular disease, although these observations could be confounded or due to reverse causation. We assessed ischemic heart disease (IHD) risk by genetically predicted VEGF, ie, using Mendelian randomization.<h4>Methods and results</h4>Single nucleotide polymorphisms (SNPs) predicting VEGF level, at genome-wide significance, ...[more]

PMID: 28765276

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Project description:ObjectiveThe relationship between vascular endothelial growth factor (VEGF) and the risk of malignant brain tumors has always been a concern in the medical field. However, the causal inferences from published observational studies on this issue may be affected by confounders, coinheritability and reverse causality. We aimed to investigate the causal relationship between VEGF and different types of malignant brain tumors.MethodsUsing publicly available summary data from genome-wide association studies (GWAS) of VEGF (n=16,112) and different types of malignant brain tumors (n=174,097-174,646), we adopted a standard two-sample bidirectional Mendelian randomization (MR) to estimate potential causal associations of circulating VEGF levels and the risk of malignant brain tumors. Inverse variance weighted (IVW) was used as the primary analysis method to estimate causality. MR-Egger regression, weighted median (WM), penalty weighted median (PWM), MR robust adjusted profile score (MR.RAPS) and causal analysis using summary effect estimates (CAUSE) methods were used in sensitivity analyses to verify the robustness of the findings. Meanwhile, we applied the MR pleiotropy residual sum and outlier (MR-PRESSO) test and PhenoScanner tool to identify and remove potential horizontal pleiotropic single nucleotide polymorphisms (SNPs). Additionally, linkage disequilibrium score regression (LDSC) analysis was conducted to assess the coinheritability of exposure and outcome.ResultsA total of 6 (VEGF), 12 (malignant brain tumor), 13 (brain glioblastoma) and 12 (malignant neoplasm of meninges) SNPs were identified as valid instrumental variables. No evidence supported a causal relationship between circulating VEGF levels and the risk of malignant brain tumors (forwards: odds ratio (OR) = 1.277, 95% confidence interval (CI), 0.812~2.009; reversed: β = 0.005, 95% CI, -0.029~0.038), brain glioblastoma (forwards: OR (95% CI) = 1.278(0.463~3.528); reversed: β = 0.010, 95% CI, -0.002~0.022) and malignant neoplasm of meninges (forwards: OR (95% CI) = 0.831(0.486~1.421); reversed: β = 0.010, 95% CI, -0.030~0.050) using the main IVW method. Outliers and pleiotropy bias were not detected by sensitivity analyses and pleiotropy-robust methods in any estimates. LDSC failed to identify genetic correlations between VEGF and different types of malignant brain tumors.ConclusionsOur findings reported no coinheritability and failed to provide evidence for causal associations between VEGF and the risk of different types of malignant brain tumors. However, certain subtypes of VEGF for which genetic predictors have not been identified may play a role and need to be further investigated.

Project description:BackgroundThe role of n-6 polyunsaturated fatty acids (PUFAs) in ischemic heart disease (IHD) is controversial, and dietary guidelines vary. Observationally, lower saturated fat intake and higher intake of vegetable oils rich in linoleic acid (LA), the main n-6 PUFA, is associated with lower IHD and diabetes; however, randomized controlled trials have not fully corroborated these benefits. We assessed how genetically predicted LA affected IHD and its risk factors, including diabetes, lipids, and blood pressure. We also assessed the role of LA in reticulocyte count, the red blood cell precursor, which has recently been identified as a possible causal factor in IHD.MethodsTwo-sample instrumental variable analysis with genetic instruments, i.e., Mendelian randomization, was used to obtain unconfounded estimates using genetic variants strongly (p value < 5 × 10-8) and solely associated with LA, applied to an IHD case (n ≤ 76,014)-control (n ≤ 264,785) study (mainly based on the meta-analysis of CARDIoGRAMplusC4D 1000 Genomes and UK Biobank CAD SOFT GWAS), the DIAbetes Genetics Replication And Meta-analysis diabetes case (n = 26,676)-control (n = 132,532) study, lipids from the Global Lipids Genetics Consortium Results (n = 196,475), and reticulocyte count and blood pressure from the UK Biobank (n ≤ 361,194). A weighted median and Mendelian randomization Egger were used for sensitivity analysis.ResultsGenetically predicted LA was not associated with IHD or systolic blood pressure. Genetically predicted higher serum LA was associated with lower diabetes (odds ratio (OR) 0.97 per percentage in total fatty acid increase in LA, 95% confidence interval (CI) 0.96 to 0.99) and lower lipids (low-density lipoprotein, high-density lipoprotein, and total cholesterol), but may be associated with higher diastolic blood pressure. The findings were robust to different single nucleotide polymorphism (SNP) selections, analytic methods, and correction for multiple testing.ConclusionsOur novel study suggests a benefit of LA for diabetes and lipids but no benefit for IHD, blood pressure, or reticulocyte count. Explicating these paradoxical findings would facilitate identification of effective new interventions for diabetes and IHD.

Dataset Information

Vascular Endothelial Growth Factor and Ischemic Heart Disease Risk: A Mendelian Randomization Study.

Publications

Vascular Endothelial Growth Factor and Ischemic Heart Disease Risk: A Mendelian Randomization Study.

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