The association between osteoprotegerin and arterial stiffness in a 10-year longitudinal study of patients with type 2 diabetes

Introduction: Osteoprotegerin (OPG) inhibits vascular calcification which is central to pathogenesis of arterial stiffness. However, it promotes inflammation by upregulating expression of vascular cell adhesion molecule-1(VCAM-1), thereby contributing to arterial stiffness. We investigated longitudinal association between OPG and arterial stiffness in type 2 diabetes (T2D), causality of the association and mediation by VCAM-1. Methods: This was a prospective cohort study of T2D patients (N = 1877, mean age 57.0 ± 10.8) with 10 years’ follow-up. Baseline plasma OPG was measured using immunoassay. Pulse wave velocity (PWV) was assessed using applanation tonometry. We examined association between OPG and follow-up PWV using linear mixed model. One-sample Mendelian Randomization (MR) was conducted with rs1385492 as OPG-associated single nucleotide polymorphism (SNP). Results: Baseline natural log (Ln)-transformed OPG was positively associated with baseline and follow-up PWV with adjusted coefficients 0.43 (95%CI 0.05, 0.80; p = .026) and 0.51 (95%CI 0.06 to 0.97; p = .028) respectively. Genetically-predicted higher levels of plasma OPG was associated with higher last follow-up PWV with coefficient 10.81 (95%CI 2.97, 18.65; p = .007) per unit increase in LnOPG. Higher VCAM-1 accounted for 10.2% of association between LnOPG and follow-up PWV. Discussion: Baseline plasma OPG was associated with higher follow-up PWV in patients with T2D, with genetic evidence from MR. This association may be mediated, at least in part, by VCAM-1.