The VEGF +405 CC Promoter Polymorphism is Associated With an Impaired Prognosis in Patients With Chronic Heart Failure: A MERIT-HF Substudy

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Background A common polymorphism positioned at +405 of the vascular endothelial growth factor (VEGF) gene is known to influence VEGF protein production. In contrast, a second polymorphism, positioned at −460 polymorphism, has no reported functional effects. VEGF is linked to angiogenesis and might directly influence the clinical outcome of patients with chronic heart failure (CHF). We investigated the association between two VEGF polymorphisms and morbidity and mortality in patients with CHF. Methods and Results VEGF promoter polymorphisms +405 and −460 were examined in 596 CHF patients enrolled in the Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF) study and in 187 healthy controls. In CHF patients, a risk ratio for each genotype was calculated using the combined endpoint of all-cause mortality or hospitalization. The allele frequencies of the +405 and −460 polymorphisms for the CHF cohort and for 187 healthy controls were not significantly different. However, the presence of the +405 CC genotype (frequency 0.14) was independently associated with an adverse outcome as described by the MERIT study combined endpoint compared with the +405 GG genotype (risk ratio 1.65; 95%CI 1.03–2.64; P = .039). The −460 polymorphism was not associated with an altered prognosis ( P = .60). Conclusion Our results indicate that the VEGF +405 CC genotype is associated with an adverse clinical outcome in patients with CHF. This genotype has been associated with lower plasma VEGF levels, suggesting a possible mechanism of action for the gene variant. This belief is further supported by the fact that the VEGF −460 polymorphism, which does not affect plasma VEGF levels, did not adversely affect the prognosis.