Polymorphisms in the Promoters of the MMP-2 and TIMP-2 Genes Are Associated with Spontaneous Deep Intracerebral Hemorrhage in the Taiwan Population

Abstract

BackgroundSpontaneous intracerebral hemorrhage (ICH) is a devastating stroke subtype. Matrix metalloproteinases (MMPs) function in the degradation of extracellular matrix and the activities of MMPs are modulated by their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs). This study aimed to discuss relationship of MMP-2 and TIMP-2 to spontaneous deep ICH (SDICH) susceptibility and hematoma size.MethodsAssociations were tested by logistic regression and general linear models (GLM) where appropriate, adjusting with covariables of age, sex, hypertension, diabetes mellitus, smoking, and alcohol consumption. Association analyses were performed first by stratification of genders and then by the age of 65 years old (y/o). Elder population was defined as subjects who were older than 65 y/o.ResultsThere were 396 SDICH patients and 376 control subjects in this study. In the elder group, rs7503607 C>A variant in TIMP-2 was associated with SDICH in male and overall patients (OR = 3.49, 95% CI 1.45 to 8.40, P = 0.005 and OR = 2.45, 95% CI 1.37 to 4.38, P = 0.003, respectively) in additive genetic model. In recessive genetic model, rs2285053 TT genotype in MMP-2 was correlated to SDICH in male patients and overall elder group (OR = 7.30, 95% CI 1.3 to 40, P = 0.02 and OR = 2.91, 95% CI 1.02 to 8.31, P = 0.046, respectively), and rs7503726 AA genotype in TIMP-2 was associated with SDICH in female patients (OR = 0.29, 95% CI 0.1 to 0.84, P = 0.02). In younger male and overall younger patients, SDICH patients who had supratentorial hemorrhage had significantly lower frequency of AA genotypes in rs7503726 than those with infratentorial hemorrhage (OR = 0.36, 95% CI 0.17 to 0.75, P = 0.006 and OR = 0.43, 95% CI 0.22 to 0.84, P = 0.014, respectively). Hemorrhage size increased by 9.7 (95% CI 2.1 to 43, P = 0.004) cm3 per minor allele (A) of the rs7503607 variant in the elder female patients and increased by 4.3 (95% CI 1.4 to 12.9, P = 0.009) cm3 per minor allele (A) in all elder patients. In younger patients, the hemorrhage size decreased by 3.3 (95% CI 1.2 to 9.5, P = 0.03) cm3 per minor allele of the s7503726 variant in the female patients.ConclusionsThis study showed a significant association between the variants of MMP-2 and TIMP-2 promoters and SDICH susceptibility with significant age and gender differences. Hemorrhage location and size might be affected by TIMP-2 promoter variants in the SDICH patients.

Common matrix metalloproteinase-2 gene variants and altered susceptibility to breast cancer and associated features in Tunisian women

“…By disrupting Sp1 binding site, 37 the C-to-T transition at position 2735 and 21306 in MMP2 promoter region induces low MMP2 enzyme expression in stromal and neoplastic cells. 31 This explains, in part, the beneficial effect of lower expression of T allele in reducing excessive degradation of fibrillation collagen 29 and other ECM components and thus development of breast cancer. 34,38 Neither rs243864 (-790 G/A) nor rs243866 (-1575 G/A) MMP2 variants was associated with breast cancer in Tunisians, as MAF distribution of both variants was comparable between breast cancer cases and control women.…”

“…Several studies proposed that genetic polymorphism in MMP2 promoter region control MMP2 expression 23,31 and that sustained increased MMP2 levels might render the carriers more susceptible and aggressive to tumorigenesis. In this context, we examined the relationship between breast cancer susceptibility and the presence of MMP2 (promoter) variants: rs243864 (2790 G/T), rs243865 (21306 C/T), rs243866 (21575 G/A), and rs2285053 (2735 C/T) as potential risk biomarkers of breast cancer.…”

Polymorphism in dural arteriovenous fistula: matrix metalloproteinase‐2‐1306 C/T as a potential risk factor for sinus thrombosis

“…TIMP‐2, the main endogenous inhibitor of MMP‐2, is responsible for regulating the functions of MMPs . The MMP‐2/TIMP‐2 expression ratio is an important factor in certain nervous and vascular disorders . In our study, the TIMP‐2 (rs2277698) gene polymorphism was shown to be weakly associated with DAVF patients subgrouped by CVR grading ( P = 0.026; OR 3.0 [95% CI 1.1–8.2]).…”

Genetic Polymorphisms Associated with Spontaneous Intracerebral Hemorrhage

“…Further, while an intronic polymorphism of TIMP-1 rs2070584 C allele is associated with ICH in Chinese male patients [34], C allele of rs4898 provides a protective effect on DICH risk in the elderly male group [13]. Additionally, although the TIMP-2 AA rs7503726 genotype increased the risk of developing ICH in a genetic recessive model conducted on the German population [35], it was considered a protective factor against DICH in elderly Taiwanese females [14]. The disparity between the two reports may be due to different minor allele frequency (MAF) (39.14% in the former and 49.7% in the latter), heterogeneity of phenotypes, and stratification of subgroups in the latter report.…”

“…Further, men have younger age of ICH than women among Asians [12]. Differences in the exposure to causal factors, the control of hypertension and cholesterol, and the anticoagulant and antiplatelet treatment for stroke between countries and genders explain an important portion of the variance observed in ICH incidence between ethnicities [10] and genders [13,14,15,16]. However, a significant part of this variation remains unexplained.…”