Aims: Our objective was to investigate the association of common variants in the coding region of advanced glycosylation end-product specific receptor (RAGE) and the prognosis of heart failure (HF).
Methods and results: A total of 3394 HF patients were continuously enrolled from January 2009 to August 2018 with a median follow-up of 20.4 months. Additionally, 2861 healthy subjects also participated in the study. By sequencing these two groups, we identified a common functional missense variant rs2070600 in the coding region of RAGE, which showed a significant association with the prognosis of HF [hazard ratio = 0.53, 95%, confidence interval (CI) = 0.30-0.94, P = 0.03], but no association with the risk of HF (odds ratio = 0.52, 95%, CI = 0.66-1.04, P = 0.106). A series of functional assays revealed that rs2070600-A, but not -G allele, suppressed the expression of RAGE protein by facilitating the binding of miR-125a-3p. Furthermore, the RAGE messenger RNA levels of human peripheral blood lymphocytes were reduced in subjects with the rs2070600-AA genotype compared with subjects with the rs2070600-GG or -AG genotypes. Additionally, our Western blot results from human heart tissue showed increased RAGE expression in HF samples compared with that in healthy donors.
Conclusions: Our results demonstrate that the common missense variant rs2070600-A allele is associated with a reduced risk of cardiovascular death and cardiac transplantation by facilitating the binding of miR-125a-3p.
Keywords: Genetics; Heart failure; Prognosis; RAGE; miR-125a-3p.
© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.