title: Polymorphisms in the Promoters of the MMP-2 and TIMP-2 Genes Are Associated with Spontaneous Deep Intracerebral Hemorrhage in the Taiwan Population.
abstract: BACKGROUND
  Spontaneous 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.
  
  
  METHODS
  Associations 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.
  
  
  RESULTS
  There 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.
  
  
  CONCLUSIONS
  This 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.
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital Linkou Medical Center and College of Medicine, Chang-Gung University, Taoyuan, Taiwan.
authors.forename: Yi Chun
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital Linkou Medical Center and College of Medicine, Chang-Gung University, Taoyuan, Taiwan.
authors.forename: Wei Min
authors.initials: WM
authors.lastname: Ho
authors.affiliation: Department of Biotechnology, Ming Chuan University, Taoyuan, Taiwan.|Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Yun Shien
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital Linkou Medical Center and College of Medicine, Chang-Gung University, Taoyuan, Taiwan.
authors.forename: Huei Wen
authors.initials: HW
authors.lastname: Chen
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital Linkou Medical Center and College of Medicine, Chang-Gung University, Taoyuan, Taiwan.
authors.forename: Chiung-Mei
authors.initials: CM
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002543:Cerebral Hemorrhage / Q000235:genetics* / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006406:Hematoma / Q000235:genetics / Q000473:pathology; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D013624:Taiwan; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics*
chemical_list: C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2