Identification Of APOH Polymorphisms As Common Genetic Risk Factors For Venous Thrombosis And Arterial Thrombosis In The Chinese Population

BackgroundThrombosis including arterial thrombosis （cardiac ischaemia and ischaemia stroke） and venous thrombosis （deep vein thrombosis and Pulmonary embolism） is the most common disease throughout the world, and is one of the leading causes of morbidity and mortality. In order to identify individuals at high risk early, it is necessary to find more genetic risk factors. Nowadays, the studies on genetic factors of thrombosis are mainly focused on coagulation and anticoagulation factors. The exploration of other proteins involved in thrombosis and hemostasis may lead to a breakthrough. Beta2-Glycoprotein I （J32GPI） is a newfound anticoagulant protein that can inhibit the procoagulation activities of thrombin and suppress the von Willebrand factor （VWF）-dependent platelet coagulation and adhesion.ObjectivesWe used APOH as a candidate gene to investigate whether the existence of genetic variation that could increase the risk of thrombosis or not, and to explore the specific mechanisms of these genetic variations in APOH gene to cause hereditary β2GPI deficiency and thrombosis in Chinese population.Methods/ResultsA total of1,304individuals diagnosed with a first venous thrombosis,1,444diagnosed with arterial thrombosis and1,334age-and sex-matched healthy participants were enrolled in this study. In the current study, with a resequencing method followed by a case-control study, four polymorphisms （c.₃2C>A, c.422T>C, c.461G>A, and c.1004G>C） in APOH （encoding b2-glycoprotein Ⅰ） were found to be in high linkage disequilibrium, which could result in three haplotypes. The H2heterozygotes and H3homozygotes had approximately1.5-fold and seven-fold increased risks for VT, respectively. The minor allele frequency in the general population was～10%. In addition, H3individuals showed a significantly decreased level of b2-glycoprotein I, but an increased level of thrombin generation. However, it seems that the H2heterozygotes and H3homozygotes would never increase risks for Ischemic infarction. Functional tests indicated that the mutant b2-glycoprotein I had a significantly lower capacity to extend thrombin clotting time and increase thrombin generation potential.ConclusionsThis study revealed APOH as a new candidate gene associated with thrombosis. The inclusion of this variant in routine thrombophilic detection may improve the diagnosis and prevention of venous thrombosis. And further genetic research on this gene in patients in whom the cause of thrombophilia is unknown is therefore warranted.