found in one study, TIMP-1 variation was associated with 2 / 13 MMP-9, TIMP-1 and Hemorrhagic Stroke ICH in male population in another study. To date, there is no report addressing interactions between MMP-9 and TIMP-1 on SDICH susceptibility. Given the a priori evidence of association between SDICH susceptibility and MMP and TIMP pathway, the purpose of this study is to evaluate whether polymorphisms of MMP-9 and TIMP-1 would predispose to SDICH risk in the Taiwan population. To account for the effects of heterogeneity of the ICH mechanisms, this study focused on the phenotype of SDICH. Methods Subjects Subjects were recruited from the Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center. Patients with SDICH were diagnosed based on both clinical presentations and computed tomography and were enrolled if a patient or the legal representative was willing to provide written informed consent. Patients with a traumatic hemorrhage or secondary ICH were excluded. When a SDICH patient had compromised capacity to consent because of alteration of consciousness and mentality caused by neurological or medical conditions, the written informed consent was provided by his/her legal representative based on the laws and regulations of Taiwan. Participants of the control group were recruited from subjects with no history of neurodegenerative diseases, inflammatory diseases, and stroke. This study was approved 
by the Institutional Review Board of CGMH. Clinical information Anthropometric data and 12-hour fasting blood samples were collected from all participants. Hypertension was diagnosed when blood pressure repeatedly exceeded 140 mm Hg and/or 90 mm Hg or when a subject was taking antihypertensive medication to control hypertension. For SDICH cases without prior diagnosis of hypertension, patients were considered to have hypertension when BP measured after the acute phase of SDICH repeatedly >140 mm Hg and/or 90 mm Hg. Body mass index was calculated by weight in kilograms divided by squared height in meters. Diabetes mellitus was defined based on World Health Organization criteria. Alcohol use was defined as drinking 210 g per week. Smoking was defined as former or current smoking . Selection of SNP and Genotyping The cytogenetic location of MMP-9 was at 20q13.12. In the promoter variant of MMP-9, we examined rs3918242 which has been shown to influence expression and a subsequent increase in MMP-9 transcription. In addition, we selected tagSNPs to identify genetic variation and association to phenotypes without the need of genotyping every SNP in MMP-9 gene region. The tagSNP is a representative PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19783938 SNP in a region with high linkage disequilibrium represents a group of SNPs called a haplotype. Based on international HapMap data on NCBI Build 36 assembly for Asian population, 3 tagSNPs were selected to tag major haplotypes with criteria of minor allele frequency >0.05 and r2 value >0.8 by Haploview version 4.2, including rs17576, rs3787268, and rs2250889. It is worth 3 / 13 MMP-9, TIMP-1 and Hemorrhagic Stroke MMP-9 rs17576 MMP-9 PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19784385 rs3787268 MMP-9 rs2250889 TIMP-1 rs4898 F: forward primer; R: reverse primer; MSP: Mini-sequencing MedChemExpress Seliciclib primer doi:10.1371/journal.pone.0125397.t001 mentioning that according to dbSNP, there is a wide range of variation in rs17576 genotypes frequency among ethnicities, in which G allele could range from 0.22 to 1.0 . For TIMP-1 gene, we selected rs4898 which is a strong tag SNP for population CHB and has been dis
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