A functional polymorphism in ADAMTS7 3′-UTR abrogates miR-654-5p-mediated ADAMTS7 expression suppression and increases the incidence, short-term outcome, and recurrence of large artery atherosclerotic stroke among southern Chinese population

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A Disintegrin and Metalloproteinase with Thrombospondin motifs 7 (ADAMTS7) plays a critical role in atherosclerosis by degrading the extracellular matrix and modulating smooth muscle cell (SMC) proliferation, migration, and phenotypic transformation. This study investigated the association between the ADAMTS7 single-nucleotide polymorphism (SNP) rs1045130 and large artery atherosclerotic (LAA) stroke. Genotyping analyses were conducted on two independent case-control cohorts comprising 1,027 LAA patients and 1,043 age-matched controls, followed by the quantification of ADAMTS7 expression and its downstream molecular effects. ADAMTS7 was highly expressed in endothelial cells, SMCs, and macrophage-derived foam cells of vulnerable human aortic plaques. Furthermore, individuals carrying the rs1045130 A allele or GA/AA genotype had a significantly higher susceptibility to LAA stroke, poorer short-term outcomes, and an increased risk of one-month recurrence. Mechanistically, the G > A mutation disrupts the ADAMTS7-miR-654-5p interaction, leading to elevated ADAMTS7 expression and subsequent promotion of foamed vascular SMCs (VSMCs) proliferation and migration. The rs1045130 G > A variant is associated with increased LAA stroke incidence and worse prognosis. The mutation promotes the proliferation and migration of foamed VSMCs by disrupting the miR-654-5p/ADAMTS7 axis, potentially accounting for the higher disease risk and poorer prognosis observed in affected individuals.

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