Study F Genetic Abnormalities And Polymorphisms Of Human Platelet Membrane Glycoproteins

Study of genetic abnormaIities and poIymorphismsof human platelet membrane glycoproteinsPh.D Candidate: SHI JumeiSupervisor: RUAN ChanggengAbstractBemard-Soulier syndrome (BSS) is a rare congenital disorder ofplatelets, usually inherited as an autosomal recessive trait. The disorder isdue to defective adhesion of plateletS to the vessel wall caused byquanitative or functional abnormalities of the platelet glycoprotein (GP)Ib-IX-V complex. To identify mechanism of molecular pathogenesis andrelationship betWeen phenotype and genotyPe of BSS, 3 patients withinherited bleeding symptom and gian platelets were studied on the basis ofdiagnosis standard. The entire coding regions of GPIba, GPIb6 and GPIXwere amplified by polyInerase chain reaction (PCR) using primer pairs,respectively Direct sequence analysis of the entire coding region of PCR-amplified fragrnents was performed using ABI 377 DNA Sequencer. AhomoZygous G--+A transition was identified, resulting in an AIa l39(GCC)--+Thr (ACC) substitution in the transmembrane domain of GPIX.The Alal39-Thr mutation is considered a novel mutation according todatabase about the mutation of BSS and the polymorphism of GPIX in theintemet, which is the first rePort of a mutation of BSS in China. 'The newmutation will benefit the further stUdy of the structure and function of GPIX.Platelet membrane glycoproteins play a crucial role in platelet adhetionand aggregation. The GP IallIa complex is a major collagen receptor onplatelets and other cell tyPes. The polymorphisms C807T and G873A withinthe coding region of the GP Ia gene are linked to GPIa / IIa surfaceexPression. The GPIa T807 / A873 allele causes a higher receptor exPression,enhancing platelet binding to collagen. ThesepolyInorphisms could,therefore, present a genetic predisposition for the developmentof3thromboembolic comPlications. In the study, distributions of the 807 CirpolyTnorphism were investigated by genotyPing DNA by PCR,BglIIrestriCtion fragInent length polymorphism analysis, and sequencing. The807T allelic and genotyPic frequencies were sighficantly lower in theChinese than in Caucasians (P<0.05). The GPIa gene C807T polymorphismof the platelet collagen receptor in Chinese population was different fromthat observed in Caucasians.We did a case-cothel stUdy comParing l07 patientS with acUteischemic stroke (AIS), 98 patients with acute myocardial infarction (ns)and l2l healthy individuals with matched age and sex. The genotyPefrequency of the 807T homorygote was higher in the AJS patients than incontrols. A strong association was found betWeen the 807T homoZygote andthe risk ofAIS (n=l07; odds ratio, ll.2 [95% CI l.4-88.5]; P<0.0l). Thehigher odds rato was detected in patients whO were younger than the age of60 years (<60 years; n=62; odds ratio, l7.8 [95%CI 2.2-l45.7]; P<0.00l).In contrast, there was no increased risk of AMI associated with thehomoZygous 807T genotyPe (n=98, P>0.05), when age, sex, smoldng,hyPertension, diabetes, body-mass index, LDL-cholesterol and HDL-cholesteroI were matched betWeen patient and contrOl subjects. Our datesuggest that the 807ri genotyPe frequency was significanly lower in theChinese than in Caucasians. And the 807T homoZygote of the plateletglycoprotein Ia/IIa gene polymorphism, associated with high expression inswte collagen receptor density would be an inherited risk factor for thedevelopment of stroke, but not for the develoPment of AMI in the ChinesepoPulation. Our findings will have imPortan bolications in increasing theunderstanding of t he mechanisms of disease and thereby giving the realoppoMity for developing novel and selective drug-based theraPies for theprevention ofAIS in the Chinese population.The platelet GP Ib Q plays a key role in the initial formation ofthrOmbi.It was reported that GP Ib Q gene polymorphisms (VNTR and HPA-2) wereassociated wth increased risk of coronary heart disease (C...