Variants in matrix metalloproteinase-9 gene are associated with hemorrhagic transformation in acute ischemic stroke patients with atherothrombosis, small artery disease, and cardioembolic stroke

Objective The potential effect of matrix metalloproteinase-9 (MMP-9) variants and these variants interactions on hemorrhagic transformation (HT) risk after ischemic stroke (IS) remain unclear. The aims of present study were to investigate the associations of six variants in MMP-9 with HT, and these variants interactions whether related to increased HT risk. Method A total of 705 patients with IS who were admitted to the participating hospitals within 48 hr of symptom onset were consecutively enrolled between March 2014 and December 2016. HT was confirmed by brain computed tomography (CT) scan during 14 days from stroke onset. Six variants of MMP-9 gene were measured by mass spectrometry. Interactions of gene variant-gene variant were assessed through generalized multifactor dimensionality reduction method (GMDR). Results HT occurred in 104 (14.8%) patients. There were no differences in genotypes for the six variants between patients with and without HT using univariate analysis (all p > 0.05). GMDR analysis revealed that there was a synergistic effect of gene variant-gene variant interactions between rs3918242 and rs3787268 in MMP-9 gene. Cox regression analysis showed that high-risk interactions of rs3918242 and rs3787268 were associated with increased risk of HT after adjusting for covariates (hazard ratio: 2.08; 95% confidence interval: 1.34-7.85; p = 0.016). Conclusion Incidence of HT is common in acute IS in Chinese population. The mechanisms leading to HT are most likely multifactorial. Two-loci interactions of rs3918242 and rs3787268 in MMP-9 gene may confer a higher risk for HT.