Abstract 1808: Genetic Variation at the Quaking Locus Associates with Clinical Restenosis after Percutaneous Coronary Intervention and Induces Vascular Smooth Muscle Cell Dysfunction
The mRNA binding protein Quaking (Qk) has been implicated in embryonic vasculogenesis, which is primarily dependent on vascular smooth muscle cell (VSMC) differentiation, but a role in adulthood remains elusive. Restenosis is a frequent complication of percutaneous coronary intervention (PCI) and is mainly dependent on VSMC proliferation and migration. Therefore, we hypothesized that single nucleotide polymorphisms (SNPs) in the Qk gene could have profound impact on VSMC mediated restenosis in humans and may serve as markers for risk stratification. The GENetic DEterminants of Restenosis (GENDER) project is a multicenter, prospective study design that enrolled 3,104 consecutive patients after successful PCI. We set out to characterize the role of Qk in instent restenosis by analysis for association of 12 SNPs throughout the Qk gene and the risk of restenosis. As many as seven SNPs were found to significantly associate with the risk for target vessel revascularization (TVR). The strongest associations were found close to the transcription start site (2786 T/C: HR: 2.3, 95%CI: 1.3–3.9, P=0.002) and in intron 3 (57896 A/G: HR: 0.7, 95%CI: 0.6 – 0.9, P=0.005 and 65752 A/G: HR: 1.5, 95%CI: 1.1–1.9, P=0.006). Ten percent of patients carried the 65752G risk allele but lacked the protective 57896G allele. Importantly, these patients were at high risk to develop restenosis (HR: 1.8, 95%CI: 1.3–2.5, p<0.001). To establish a causal involvement of Qk in vascular remodelling we focussed on phenotype and functionality of primary VSMCs from aortas of Qk viable mutant (QKv) mice versus wild type littermates. VSMCs derived from Qkv mice were characterized by a stellate morphology, and displayed a decreased capacity to deal with serum withdrawal-induced stress. We are first to identify the link of Qk with the risk for instent restenosis after PCI. As altered VMSC differentiation in Qk deficient VSMCs suggests a causal relationship, Qk may serve as a marker for TVR risk prediction and a therapeutic target.