Association of RANK/RANKL/OPG gene polymorphisms with risk of peripheral arterial disease (PAD) and critical limb ischemia in the general Italian population

BackgroundPeripheral arterial disease (PAD) is an important determinant of the excessive morbidity and mortality in atherosclerotic patients, especially in patients with critical limb ischemia (CLI). Several studies recently conducted have demonstrated that the RANK/RANKL/OPG system plays an important role in the metabolism of the bone and in vascular pathology, including atherogenesis and arterial calcification and is involved in plaque instability and rupture by inducing plaque calcification.Aim and methodsThe aim of the present study to evaluate whether the rs3134069, the rs2073617, and the rs2073618 polymorphisms of the OPG gene, the rs9533156 and the rs2277438 gene variants of the RANKL gene and the rs1805034 gene polymorphism of the RANK gene are associated with presence and severity of PAD in general Italian population. Our study included 1221 patients (523 with PAD and 698 controls without PAD).ResultsWe found that the rs3134069, the rs2073617, and the rs2073618 polymorphisms of the OPG gene, the rs9533156 gene variants of the RANKL gene and the rs1805034 gene polymorphism of the RANK gene were significantly and independently associated with PAD. We also found that these five polymorphisms act synergistically in patients with PAD and are associated with different levels of risk for PAD and CLI, depending on the number of high-risk genotypes carried concomitantly by a given individual.DiscussionGenetic variations of rs3134069, rs2073617, and rs2073618 on the OPG gene, rs9533156 on the RANKL gene and rs1805034 on the RANK gene are associated with the risk to develop PAD and these five gene polymorphisms act synergistically in patients with PAD and are associated with different risk for PAD.