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

Xingyang Yi,Ju Zhou,Guo Sui,Qiang Zhou,Chun Wang,Zhenxiao Chai,Jing Lin

doi:10.1002/brb3.1294

Abstract

ObjectiveThe 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.MethodA 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).ResultsHT 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).ConclusionIncidence 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.

Highlights

Hemorrhagic transformation (HT) is the most feared complication in patient with acute ischemic stroke (IS)
The risk factors for HT conferred by high‐risk interactive variable was analyzed by Cox proportional‐hazards model to adjust confounding variables, which were significantly associated with HT (p < 0.05) on univariate analysis, and were reported as hazard ratio (HR) with 95% confidence interval (CI)
The results showed that the high‐risk interactive genotype of rs3918242 and rs3787268 was independent predictors for the HT risk after ad‐ justment for the covariates (HR: 2.08; 95% CI: 1.34–7.85; p = 0.016, Table 5)

Summary

| BACKGROUND

Hemorrhagic transformation (HT) is the most feared complication in patient with acute ischemic stroke (IS). MMP‐9 single nucleotide polymorphisms (SNPs) encode and reg‐ ulate the transcription of MMP‐9 protein, and are associated with plasma MMP‐9 levels (Blankenberg et al, 2003). It has been known MMP‐9 SNPs are associated with carotid atherosclerosis and increased IS incidence (Lin et al, 2012; Nie, Wang, & Tang, 2014; Yuan et al, 2013). One study in a Mediterranean population did not show the associations of MMP‐9 SNPs with HT (Montaner et al, 2003) These inconsistent results revealed that the genetic etiologies for HT may be complex, and common limitation of these studies is that these trials only assessed single gene polymorphisms without consideration of interactions between gene variant–gene variant.

| MATERIALS AND METHODS

| DISCUSSION

Findings

| CONCLUSION