Tính đa hình gen thụ thể phosholipase a2 tác động lên chức năng và nguy cơ dày nội mạc động mạch cảnh

Phospholipase A2 Receptor Gene Polymorphisms Alter its Functions and Present a Genetic Risk of an Increased Intima-Media Thickness of the Carotid Artery NGUYEN VAN SI MD PhD University of Medicine and Pharmacy - Ho Chi Minh city Gia Dinh People’s Hospital Content • • • • • • Introduction Hypothesis Method Results Discussion Conclusion INTRODUCTION Inflammation and PLA2R Inflammation and PLA2R • Phospholipase A2 family – Highly related to inflammation via arachidonic acid pathway – Failure of PLA2 inhibitor in clinical trials (Darapladib) • Phospholipase A2 receptor – Specific receptor of PLA2 – Important roles • Inflammatory reduction • Cell behaviors Inflammation and PLA2R • Hanasaki K et al 2002 PLA2R: a regulator of biological functions of phospholipase A2 • Mishina et al 2014 Cardiac rupture after myocardial infarction – Lack of PLA2R: Less proliferation and migration SNPs of PLA2R gene • SNP: Single nucleotide polymorphism – Variation in a single nucleotide – May affect the function of the related protein • Two SNPs of PLA2R are completely linked Carotid Intima-media thickness (IMT) • Related to atherosclerosis • Measured by echography • Important marker in high risk patients HYPOTHESIS Hypothesis • The effects of PLA2R polymorphisms in the development of IMT • PLA2R polymorphisms may alter cell behaviors Method • Clinical arm: Case-control study – 925 Japanese patients were genotyped for PLA2R SNPs at T/C rs3749117 and G/C rs35771982 – Mendelian inheritance models were used to check the relationship between PLA2R SNPs and increased IMT • Laboratory arm – HEK293 cell-line was transfected with PLA2R genes (wild type and double-mutated type) – Cell behaviors were compared RESULTS Baseline characteristics PLA2R-CC and increased IMT in males Case: 315 cases Control: 265 cases PLA2R-CC and increased IMT in males PLA2R SNPs in HEK293 cells A: Migration assay B: Proliferation assay DISCUSSION PLA2R-CC and increased IMT PLA2R SNPs -Reduce migration -Reduce proliferation Reduce endothelial repair PLA2R-CC and effects in male patients • Men have more risk factors of endothelial injury • Hormonal protection in women PLA2R-CC and effects in male patients CONCLUSION Conclusion • PLA2R SNPs at rs3749117 and rs35771982 are risk factors of increased IMT (CC genotype): OR = 1.93, p < 0.01 • The relationship can be explained by the alteration in cell behaviors: reduced migration and proliferation Conclusion Male patients More risk factors Injury Endothelial layer Increased IMT Less repair PLA2R SNPs Reduced migration Reduced proliferation THANK YOU FOR LISTENING ... INTRODUCTION Inflammation and PLA2R Inflammation and PLA2R • Phospholipase A2 family – Highly related to inflammation via arachidonic acid pathway – Failure of PLA2 inhibitor in clinical trials... (Darapladib) • Phospholipase A2 receptor – Specific receptor of PLA2 – Important roles • Inflammatory reduction • Cell behaviors Inflammation and PLA2R • Hanasaki K et al 2002 PLA2R: a regulator of biological... biological functions of phospholipase A2 • Mishina et al 2014 Cardiac rupture after myocardial infarction – Lack of PLA2R: Less proliferation and migration SNPs of PLA2R gene • SNP: Single nucleotide