enesis and the compensation of MMP-2 and MMP-3 expression in response to low MMP-9 deficiency knock-out mice has been demonstrated, suggesting a complexity of the MMPs-TIMPs pathway. In our genetic approach, we found that C allele of rs4898 indeed provides a protective effect on SDICH risk in the elderly male group, but not in the young. Age and gender difference LY-411575 chemical information should be considered in any future study addressing the MMPsTIMPs pathway. A prior study showed that variation of TIMP-1 rs2070584 but not rs4898 was associated with ICH in the male population. However, age stratification was not performed in their report. Nevertheless, they demonstrated higher serum levels of TIMP-1 in ICH patients than in controls, even though no correlation between TIMP-1 levels and genotypes was found in their study. Furthermore, in our subjects <65 y/o, carriers of rs4898 minor allele and Hap3 had lower SDICH risk than non-carrier, suggesting a gene-gene interaction of protective effect of these genetic variations. Therefore, rs4898 minor allele and Hap3 may have a significant additive protective effect from SDICH susceptibility. This study included a homogenous disease entity in a same ethnic background, which may limit the confounding effect from multiple phenotypes and ethnicities. This is the first study proposing PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19786681 MMP-9 and TIMP-1 genotypes and their interactions to the SDICH susceptibility with age difference. However, because the number of female cases is relatively small, genetic effect that was less than 1.5 may not be identified in this study. Further replicated study is needed to confirm the results herein, especially for the female population to avoid a false negative result. In the present study, female patients with SDICH were older than female controls and the entire male group. Our group previously reported that female gender may be a protective factor of SDICH. Estrogen was related to nitric oxide production and nuclear factor kappa B pathway, which may be influenced by MMP-9. In addition, protective effect of estrogen on intracranial aneurysm rupture has been shown in animal model. Future study addressing the interaction between estrogen effect and 
MMP-9 and TIMP-1 in the SDICH risk is needed. It is worth mentioning that the SNPs we studied may not pose a specific risk factor for SDICH, given that these SNPs could be a risk factor for numerous conditions. Although the 10 / 13 MMP-9, TIMP-1 and Hemorrhagic Stroke effect sizes are moderate in certain subgroups, the study needs to be replicated before these SNPs can be viewed as independent risk factors for SDICH. Another limitation of this study is that we did PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19783938 not measure serum levels of MMP-9 and TIMP-1, which may otherwise provide additional functional information to support our hypothesis. Also, except for anticoagulants, we did not record information of medications, which may also be a study limitation. Conclusions This study showed a modest to moderate effects of MMP-9 and TIMP-1 polymorphisms on SDICH risks with significant age differences. There was interaction between MMP-9 haplotypes and TIMP-1 polymorphisms on SDICH susceptibility in male subjects younger than 65 years old. When young males exposed to alcohol, Hap3 was a protective factor of SDICH. In contrast, when young males exposed to smoke, Hap2 carriers had increased risk of SDICH. ~~ Melanin is a heterogenous and polymeric pigment found in many Prokaryote and Eukaryote organisms. Melanin production has been considered to be
