Association of Peroxisome Proliferator-Activated Receptors, Ppar-Mediated Genes and Ischemic Stroke

Stroke is the third leading cause of death and an important source of disability in Taiwan. The majority of stroke is ischemic stroke. Accumulated data showed the association of ischemic stroke and inflammation, cell adhesion, thrombosis, functional disturbance of lipid metabolism, and platelet function. The peroxisome proliferator-activated receptors alpha and gamma (PPARα, γ) evolve to be the biological sensors of altered lipid metabolism. They can also act as a negative regulator of pro-inflammatory genes via antagonism of the various inflammatory transcription factors. PPAR was shown to prevent post-ischemic inflammation and neuronal damage in animal studies. It may serve as potential targets for treating ischemic stroke. A total of 2000 ischemic stroke cases confirmed with computerized tomographic (CT) scan and/or magnetic resonance imaging (MRI) will be recruited from seven participant hospitals (NTUH, SKH, CMMC, TSGH, TMUH, SHH and WFH) which are the members of Taiwan Stroke Registry. A total of 1000 healthy controls will be frequency-matched by age and sex with cases and recruited from the health examination of these seven participant hospitals. The information of life style and environmental risk factors and disease histories will be collected from all study subjects through a structured questionnaire. The NIH Stroke Scale will be used to determine the stroke severity at admission and discharge in cases. All cases will also be followed up at 1-, 3-, 6-month and 1-year after stroke onset and their functional status will be assessed by modified Rankin Scale and Barthel Index. Genotyping of PPAR (α, γ) and their target genes (platelet-derived growth factor, iNOS, eNOS, AMP-activated protein kinase, liver X receptor α, long-chain acyl-CoA synthetase, lectin-like oxidized LDL receptor-1, CD36, NF-kB, VCAM1, CCR2, regulated upon activation normal T-cell expressed and secreted, TLR4) will be determined by the methods of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or real-time polymerase chain reaction (RT-PCR). The phenotype of interested genes will be assayed by ELISA kits. Because only few studies explore the relationship between the PPAR-mediated genes and ischemic stroke in humans, this three-year project aims to 1) evaluate the association of the risk of ischemic stroke and PPAR genes and their upstream (platelet-derived growth factor) and downstream genes which related to antioxidant (RAGE, iNOS and eNOS), lipid metabolism (AMP-activated protein kinase, liver X receptor α, long-chain acyl-CoA synthetase, lectin-like oxidized LDL receptor-1, CD36), and anti-inflammatory (NF-kB, VCAM1, CCR2, regulated upon activation normal T-cell expressed and secreted, TLR4); 2) to investigate the correlation between the genes belong to the PPAR pathway and stroke severity at admission and discharge; 3) to explore the relationship between the genes belong to the PPAR pathway and stroke outcomes (functional status, recurrence, and mortality) at 1-, 3- ,6- month and 1-year after stroke onset.