The association of functional polymorphisms in genes encoding growth factors for endothelial cells and smooth muscle cells with the severity of coronary artery disease

Abstract

BackgroundDespite the important roles of vascular smooth muscle cells and endothelial cells in atherosclerotic lesion formation, data regarding the associations of functional polymorphisms in the genes encoding growth factors with the severity of coronary artery disease (CAD) are lacking. The aim of the present study is to analyze the relationships between functional polymorphisms in genes encoding basic fibroblast growth factor (bFGF, FGF2), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), platelet derived growth factor-B (PDGFB), transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor A (VEGF-A) and the severity of coronary atherosclerosis in patients with stable CAD undergoing their first coronary angiography.MethodsIn total, 319 patients with stable CAD who underwent their first coronary angiography at the Silesian Centre for Heart Diseases in Zabrze, Poland were included in the analysis. CAD burden was assessed using the Gensini score. The TaqMan method was used for genotyping of selected functional polymorphisms in the FGF2, PDGFB, TGFB1, IGF1 and VEGFA genes, while rs4444903 in the EGF gene was genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The associations between the selected polymorphisms and the Gensini were calculated both for the whole cohort and for a subgroup of patients without previous myocardial infarction (MI).ResultsThere were no differences in the distribution of the Gensini score between the genotypes of the analyzed polymorphisms in FGF2, EGF, IGF1, PDFGB, and TGFB1 in the whole cohort and in the subgroup of patients without previous MI. The Gensini score for VEGFA rs699947 single-nucleotide polymorphism (SNP) in patients without previous myocardial infarction, after correction for multiple testing, was highest in patients with the A/A genotype, lower in heterozygotes and lowest in patients with the C/C genotype, (p value for trend = 0.013, false discovery rate (FDR) = 0.02). After adjustment for clinical variables, and correction for multiple comparisons the association between the VEGFA genotype and Gensini score remained only nominally significant (p = 0.04, FDR = 0.19) under the dominant genetic model in patients without previous MI.ConclusionsWe were unable to find strong association between analyzed polymorphisms in growth factors and the severity of coronary artery disease, although there was a trend toward association between rs699947 and the severity of CAD in patients without previous MI.Electronic supplementary materialThe online version of this article (doi:10.1186/s12872-016-0402-4) contains supplementary material, which is available to authorized users.

The Relationship between VEGFA and TGFB1 Polymorphisms and Target Lesion Revascularization after Elective Percutaneous Coronary Intervention

“…They found that allele T is associated with higher CAD burden assessed using the Gensini Score [ 11 ]. On the other hand, a study conducted at our center did not confirm these findings in the population of Polish patients [ 17 ]. TGFB1 polymorphism (rs1800470) has been also studied in the context of ISR.…”

“…Fragoso et al reported, for the first time, that rs1800470 polymorphism could be involved in the risk of developing ISR in the Mestizo population undergoing PCI with drug-eluting stent or BMS implantation [ 42 ]. In our previous study, we showed that the TGFB1 polymorphism (rs1800470) allele T is associated with decreased neointima formation in patients with CAD receiving BMS [ 10 ]. Any discrepancy with our previous study can be explained by the use of different inclusion criteria and the different endpoints of both studies.…”

“…Therefore, the A/A genotype is a risk factor for atherosclerosis, and the C/C genotype is protective [ 12 ]. Our previous study evaluating the Gensini Score as a marker of atherosclerotic burden relative to SNPs revealed that the A/A genotype was more frequently observed than the C/C genotype in patients with the highest Gensini Score [ 17 ]. Results of the meta-analysis of seven case-control studies indicated that rs699947 may be associated with the risk of CAD development, and A allele carriers have higher CAD susceptibility in comparison with the C allele carriers [ 47 ].…”

“…DNA was extracted from blood samples using the GeneMATRIX Quick Blood DNA Purification Kit (EURX, Poland) according to the manufacturer's instructions. Similar to our previously used methods [ 10 , 17 ], we identified single-nucleotide polymorphisms (SNPs) in the TGFB1 and VEGFA genes using TaqMan genotyping assays on the 7300 Real-Time PCR System and the SDS 1.4 Allelic Discrimination software (Applied Biosystems, USA). Samples that were initially identified as homozygous and heterozygous were sequenced, and after genotype confirmation, they were used as positive controls.…”

“…We chose rs699947 and rs1800470 as previous studies confirmed that they are functional polymorphisms and affect both gene expression and VEGF-A and TGF- β 1 serum levels [ 8 , 9 ]. Moreover, we previously reported that rs699947 and rs1800470 polymorphisms in the genes encoding VEGF-A and TGF- β 1, respectively, are associated with late lumen loss (LLL) in patients with stable coronary artery disease (CAD) who received elective PCI with BMS implantation [ 10 ]. Additionally, these polymorphisms have been studied in the context of other cardiovascular disorders and have been proven to affect, inter alia, the angiographic severity of CAD [ 11 , 12 ] and the risk of myocardial infarction [ 13 , 14 ].…”