Glycoprotein Polymorphisms Research Articles

Increased Prevalence of Glycoprotein IIb/IIIa Leu 33 Pro Polymorphism in End Stage Renal Disease Patients on Hemodialysis

Traditional atherosclerosis risk factors cannot elucidate the increased prevalence of cardiovascular events in end stage renal disease (ESRD) patients on hemodialysis. A previous study has indicated a strong association of the PIA1/A2 polymorphism with myocardial infarction, diabetes and renal allograft rejection. In this investigation, we determined the prevalence of the PIA1/A2 polymorphism of platelet glycoprotein (GP) IIb/IIIa in ESRD patients on hemodialysis in the Eastern Province of Saudi Arabia. The PIA1/A2 polymorphism was determined in 42 ESRD patients receiving hemodialysis and in 49 subjects without current or past history of renal disease. Genotypes were determined by a reverse-hybridization assay and were confirmed by restriction fragment length polymorphism procedures. The PIA2 allele frequency among the control sample was 28.6% (2 were homozygous for PIA2, 23 were homozygous for PIA1, and 24 were heterozygous PIA1/A2). The PIA2 allele frequency among the hemodialysis sample was 50% (2 were homozygous for PIA2, 2 were homozygous for PIA1 and 38 were heterozygous for PIA1/A2). The PIA2 allele frequency among the hemodialysis patients was significantly higher than that in the control group [Odds ratios 2.5 (1.35-4.61), p<0.003; Adjusted odds ratios of 2.21 (1.05-4.65), p<0.036 after adjustment for the presence of diabetes; Simultaneously adjusting the odds ratios for the presence of standard risk factors (diabetes and hypertension) gave an adjusted OR of 6.87 (1.54-30.71), p=0.064]. These results suggest that the PIA2 polymorphism may contribute toward the etiology of cardiovascular diseases in ESRD patients. A further study with a larger sample size is needed to confirm above results.

Pharmacogenetic Modulation of Platelet Inhibition

Blood platelets are the primary defence mechanism involved in physiological haemostasis. Their disorders constitute a crucial risk factor in arterial thrombosis. As arterial thrombi are predominantly composed of platelet aggregates formed under conditions of elevated shear stress at sites of atherosclerotic vascular injury, prevention of arterial thrombosis can be considered the main target of antiplatelet therapy. However, a large interindividual variability in the clinical response to aspirin, clopidogrel and GpIIb/IIIa inhibitors is widely acknowledged by physicians as a barrier for rational pharmacotherapy. Several case-control studies have indicated that various polymorphisms of different platelet glycoprotein and receptors might contribute to arterial thrombosis. Moreover, polymorphisms of hepatic cytocrome P450, which generate the active metabolites of clopidogrel, are likely to play a considerable role in determining the in vivo response to this prodrug. Functional studies have revealed widespread gene-gene interactions, as well as modulation by non-genetic factors. Thus, the response to anti-platelet drugs is a classic “complex” trait, and the available data require a great deal of caution to avoid misinterpretation. In this article, we review the role of these polymorphisms in modulating platelet function and platelet response to inhibitors. Keywords: Platelet Inhibition, Blood platelets, haemostasis, antiplatelet therapy, clopidogrel, aspirin, active metabolites, gene-gene interactions, polymorphisms

Polymorphisms in Platelet Glycoprotein 1bα and Factor VII and Risk of Ischemic Stroke

Platelets and components of the coagulation cascade are known to be instrumental in the pathogenesis of arterial occlusive disorders. The aim of this meta-analysis is to test the hypothesis that genetic variation in the platelet glycoprotein 1balpha and Factor VII genes influence the occurrence of ischemic stroke. All genetic association studies that examined the R353Q (rs6046) polymorphism of the Factor VII gene and 2 polymorphisms of the platelet glycoprotein (1balpha) gene (Thr/Met rs6065 and Kozak sequence -5 C/T rs2243093) in relation to ischemic stroke were examined. Electronic databases Embase, Medline, and HuGEnet were searched for all years up until June 2006 for all studies that evaluated any of these candidate genes and stroke. Pooled ORs were calculated with 95% CIs using both fixed and random effects models. Meta-analysis for Factor VII (R353Q) did not detect any effect on ischemic stroke risk. Further estimation resulted in pooled OR(1) QQ versus RR=0.9 (95% CI: 0.4 to 1.9) and pooled OR(2) for RQ versus RR=0.9 (95% CI: 0.6 to 1.4). These results were robust and homogeneous. Pooling ORs for the platelet glycoprotein 1balpha Kozak variant -5 T/C polymorphism showed extreme heterogeneity with differing effect directions across studies. Fisher's method of pooling was therefore used to calculate a combined probability value, which was highly significant (P<0.001). The pooled OR for platelet glycoprotein 1balpha Met/Met v Thr/Thr was 1.0 to 2.0, depending on the sensitivity analyses, and for Thr/Met versus Thr/Thr, the pooled OR was between 1.3 and 1.4. These results were consistent, reasonably robust, and implied a dominant genetic effect. This analysis provides strong evidence that the Factor VII R353Q gene polymorphism is not associated with ischemic stroke, that the Thr/Met polymorphism of GP1balpha is associated with ischemic stroke in a dominant genetic model, and that the Kozak sequence polymorphism of GP1balpha may be close to another causative locus that is associated with ischemic stroke.

Comparative Analyses of the 9 Glycoprotein Genes Found in Wild‐Type and Vaccine Strains of Varicella‐Zoster Virus

The complete DNA sequences of wild-type and vaccine strains of varicella-zoster virus have been published and listed in GenBank. In this comparative genomic analysis, the sequences of the 9 glycoprotein open reading frames (ORFs) were compared. They included gE (ORF68), gI (ORF 67), gC (ORF14), gH (ORF37), gL (ORF60), gB (ORF31), gK (ORF5), gM (ORF50), and gN (ORF8 or ORF9A). After realignment on the basis of newer data, the corrected gB sequence was lengthened to include 931 residues. The data showed that there were glycoprotein polymorphisms that differentiated North American/European strains from Japanese strains-for example, an additional ATG codon in the gL of all Oka strains. Also, there were a small number of coding single-nucleotide polymorphisms present only in glycoproteins of vaccine strains. Because these changes were highly conserved, the structure of the glycoprotein was unlikely to be altered.

Association of the platelet membrane glycoprotein I a C807T gene polymorphism with aspirin resistance

To explore the correlation between the C807T polymorphism of platelet membrane glycoprotein I a (GP I a) gene and aspirin resistance in Chinese people, 200 patients with high-risk of atherosclerosis took aspirin (100 mg/d) for 7 days. Platelet aggregation function was detected using adenosine diphosphate (ADP) and arachidonic acid (AA) before and after the administration of aspirin. Then the subjects were divided into three groups according to the results of platelet aggregation function: an aspirin resistant (AR) group, an aspirin semi-responder (ASR) group and an aspirin-sensitive (AS) group. Platelet GP I a gene 807CT polymorphism was examined by means of polymerase chain reaction-sequence specific primers (PCR-SSP). The results showed that T allelic frequency in AR group and ASR group were higher that of AS group (P<0.005), and the prevalence of genotypes (TT+TC) of these two groups was significantly higher than that in AS group (P<0.05). Platelet GP I a T allele was significantly associated with aspirin resistance as revealed by multiple logistic regression (OR=3.76, 95% CI: 2.87-9.58). The results suggest that inherited platelet GP I a variations may have an important impact on aspirin resistance and the presence of GP I a T allele may be a marker of genetic susceptibility to aspirin resistance.

Impact of Platelet Glycoprotein Polymorphisms upon Clinical Events in Essential Thrombocythaemia Patients Enrolled in the PT1 Trial.

Multiple factors are likely to contribute to the pathogenesis of thrombosis in Essential thrombocythaemia (ET) including platelet number, activation of platelets and leukocytes; the formation of platelet leucocyte aggregates, and circulating prothrombotic and endothelial factors. The normal functional activity of platelets depends on the presence of platelet glycoprotein complexes, which play an important role in platelet adhesion and aggregation. A number of polymorphisms in platelet glycoproteins have been correlated with thrombotic events in hematologically normal patients. Particular polymorphisms of interest include three within the glycoprotein Ibα gene: −5T/C (affecting a Kozak sequence), 1018C/T (T145M, encoding Human Platelet Antigen − 2), a variable number of tandem repeats (VNTR) in a region encoding the macroglycopeptide and one polymorphism C807T, within the glycoprotein Ia gene. To date whether there is a relationship between these platelet glycoprotein polymorphisms and the clinical features of ET has not been determined. In this study samples obtained from 797 ET patients recruited to the 3 large prospective PT–1 trials were genotyped for the polymorphisms of interest and the results were correlated with clinical events including haemorrhagic and arterial or venous thrombotic events in the year prior to diagnosis and following trial entry (median 30 months). The VNTR data were analysed using the sum of the number of repeats of both alleles and treated as a continuous variable using logistic regression for retrospective and a Cox survival model for prospective analyses; other polymorphisms were analysed using the Chi-squared test for the retrospective clinical events, and log-rank survival analysis for the prospective clinical events. Neither the C807T, −5T/C Kozak nor the T145M polymorphism was associated with clinical events in the ET patient cohort. Interestingly the number of VNTR repeats was inversely associated with (p=0.02) rate of arterial events after trial entry in this patient cohort, but not for events in the year prior to diagnosis or post trial entry venous thrombotic or haemorrhagic events. This analysis suggested that a decreasing sum of VNTR were associated with an increased risk of arterial thrombosis, the degree of increase in risk was 75% per repeat (95% confidence interval 1.0–2.9). After multivariate analysis of this data with correction for age, sex, JAK2V617F and MPLW515L/K status the effect of the number of VNTR repeats remained significant (p=0.048). These results suggest that the C807T, T145M and −5T/C Kozak polymorphisms do not correlate with clinical events in ET. However a reduction in the number of VNTR within the glycoprotein Ibα gene was progressively associated with arterial events post trial entry (p=0.024) and remained significant on multivariate analysis (p=0.048).

Double heterozygosity polymorphisms for platelet glycoproteins Ia/IIa and IIb/IIIa increases arterial thrombosis and arteriosclerosis in patients with the antiphospholipid syndrome or with systemic lupus erythematosus

Objective:We analysed the genetic polymorphisms in platelet glycoproteins (GP) Ib-α, Ia/IIa and IIb/IIIa and their correlation with the development of arterial thrombosis and preclinical arteriosclerosis in patients with antiphospholipid syndrome...

Enhancing Effect of Collagen Receptor Polymorphisms on In Vitro Platelet Reactivity to Aspirin in Healthy Subjects.

[Background]Aspirin (ASA) is widely used as an antiplatelet drug, and a large number of clinical trials with ASA demonstrated significant efficacies for prevention and treatment of athrothrombosis. Recently, accumulating evidences indicated that there are inter-individual variations in the platelet response to ASA. The subpopulation, called ASA resistance, has the inability of response to ASA on ex vivo or in vitro platelet function tests and the poor clinical outcomes, although the mechanism underlying the variability is largely unknown. To date, genetic factors were showed to have an impact on platelet reactivity to ASA, and the inter-individual variations in platelet response to ASA was also reported to be associated with platelet sensitivity to collagen. In this study, the association between collagen-induced platelet aggregation (CIPA) and genetic polymorphisms of collagen receptors, glycoprotein (GP) Ia and GPVI, was analyzed using platelets treated by ASA (ASA +/−). We also investigated the effect of these polymorphisms on platelet thromboxane (TXB2) levels, closely related to the final stages of the arachidonate pathway inhibited by ASA.[Methods]We recruited genetically unrelated Japanese males (n=172) at their regular checkups. The mean age was 46.7±5.1 years. The subjects had no apparent hematologic or vascular disease and were not taking any medications that affect platelet function. Written informed consent was obtained from all study subjects. Platelet-rich plasma (PRP) sample was incubated with ASA [final concentration (fc) 10μM] or vehicle for 30 min at 24 degree Centigrade, and CIPA (fc 2μg/ml) test was performed on each PRP sample. Subsequently, platelet TXB2 levels were measured in the supernatant after centrifugation of each sample of CIPA test. Genotypes of the 807TC, Glu534Lys, Asn927Ser polymorphisms of GPIa and the Ser219Pro, Lys237Glu, Thr249Ala, Gln317Leu, His322Asn polymorphisms of GPVI were determined using the single-nucleotide primer extension-based method.[Results]To examine the sensitivity of platelets to ASA in vitro, we analyzed CIPA and platelet TXB2 levels in ASA(+/−). The maximum platelet aggregation and TXB2 levels in ASA(+) were significantly lower than those in ASA(−) (paired t-test, p<0.0001 and p<0.0001, respectively). Next, we investigated the association between the collagen receptor polymorphisms and the maximum platelet aggregation in ASA (+/−). For ASA(−), all genotypes of GPIa and GPVI were not associated with the maximum platelet aggregation. For ASA(+), subjects with 807TT/TC of GPIa had higher aggregation compared to those with 807CC(P=0.0135) whereas no association was observed between other polymorphisms and the maximum platelet aggregation. Moreover, repeated measures ANOVA showed that the difference in this inhibitory effect of ASA was significant between the 807TT/TC and 807CC genotypes (p=0.0253); the 807CC genotype has higher inhibitory effect of ASA. There was no association between platelet TXB2 levels and the GPIa and GPVI polymorphisms both in ASA(+) and ASA(−).[Conclusion]The 807CC genotype of GPIa polymorphism is associated with higher sensitivity to ASA in CIPA.

Platelet glycoprotein polymorphisms: Risk, in vivo expression and severity of atherothrombotic stroke in Chinese

Background Polymorphisms in platelet glycoprotein (GP) receptors Ia, Ib and IIIa may be heritable risk factors for platelet-dependent thrombosis leading to death. The precipitation of stroke by occlusive thrombi has led to the investigation of the platelet surface GP receptors, that are involved in critical steps in the activation of platelets. Three polymorphisms in the GP Iba gene and one in each of GPIIIa, GP Ia were selected based on the evidence of functional effects on structure or expression as candidates for risk. We also determined whether these polymorphisms were associated with in vivo expression levels of platelet GP receptors and the severity of the neurological deficit. Methods A Chinese hospital-based case-control study was conducted with 119 cases of atherothrombotic stroke and 166 age and sex matched controls. Genotyping was performed on lymphocyte DNA by standard methods and platelet GP expression levels were measured by flow-cytometry. Results Allele and genotype frequencies of the GP receptor polymorphisms differ considerably between ethnic populations. We found the D allele of the GP Iba VNTR polymorphism was significantly associated with atherothrombotic stroke in our Chinese cohort, however we did not find a relationship among these polymorphisms, the expression levels of GP receptors and severity of the neurological deficit. Conclusions In our Chinese cohort the D allele of the GP Iba VNTR polymorphism is associated with atherothrombotic stroke. The number of VNTR repeats alters the length of amino acid sequence, which might affect the structure and function of this receptor.

Role of five platelet membrane glycoprotein polymorphisms in branch retinal vein occlusion

To determine whether polymorphisms of platelet surface glycoprotein associated with arterial thrombosis are risk factors for branch retinal vein occlusion. A case-control study in which 69 patients with branch retinal vein occlusion and 147 controls who attended the eye clinic for nonvascular complications participated. DNA was extracted from whole blood and analyzed for genotyping of platelet glycoprotein polymorphisms by polymerase chain reactions and specific restricted enzymes. No relationship was found between the four platelet glycoprotein polymorphisms i.e. GPIa C807T, VNTR and Kozak of glycoprotein Ibalpha, the HPA-1 of glycoprotein IIIa and the occurrence of branch retinal vein occlusion. The HPA-2 polymorphism was found in 18 out 60 (30%) patients with branch retinal vein occlusion in comparison with 27 out 142 (19%) of controls, with an estimated odds ratio of 1.8 (95% confidence interval, 0.91-3.65). The four platelet glycoprotein polymorphisms are not risk factors for branch retinal vein occlusion and therefore it seems unnecessary to screen those patients for it. A larger study is required, however, to determine whether HPA-2 is a novel risk factor for branch retinal vein occlusion.

The K121Q Polymorphism of the Plasma Cell Glycoprotein-1 Gene is not Associated with Diabetes Mellitus Type 2 in German Caucasians

The K121Q polymorphism of the human plasma cell membrane glycoprotein 1 (PC-1) gene is known to be associated with diabetes mellitus type 2 in some populations studied, with contradictory results. The purpose of the present study was to examine a possible association between the presence of diabetes and the PC-1 K121Q polymorphism in a German Caucasian population. Associations between the polymorphism and various metabolic and anthropometric parameters were also examined. The presence of the K121Q variant was investigated using polymerase chain reaction restriction fragment-length polymorphism in 402 subjects with diabetes (231 men, 171 women, age 63+/-11 yrs, body mass index 28.7+/-5.1 kg/m2) and in 432 age- and sex-matched controls (247 men, 185 women, age 64+/-7 yrs, BMI 26.5+/-3.7 kg/m2). Ninety-seven subjects were carriers of the K121Q polymorphism in the control and 110 in the diabetic group (allelic frequency 11.9% and 14.7%, respectively, P=0.25). The polymorphism had no significant influence on the presence of atherosclerotic disease, body mass index, and blood pressure, both, in diabetics and in non-diabetic controls. Our data suggest that the K121Q polymorphism of the PC-1 gene is not associated with diabetes, obesity, hypertension or atherosclerosis in a German Caucasian population.

Occurrence of linked cytomegalovirus glycoprotein polymorphisms in transplant patients and congenitally infected infants

Occurrence of linked cytomegalovirus glycoprotein polymorphisms in transplant patients and congenitally infected infants

Aspirin and clopidogrel resistance: an emerging clinical entity

Antiplatelet therapy is a cornerstone of cardiovascular medicine. Aspirin and clopidogrel have emerged as critical therapies in the treatment of cardiovascular disease. Despite their efficacy, patients on these medications continue to suffer complications. Millions of patients are currently on low-dose antiplatelet therapy but it is unknown how many of these patients are under-treated or on the wrong medication. Aspirin and clopidogrel resistance are emerging clinical entities with potentially severe consequences such as recurrent myocardial infarction, stroke, or death. The mechanism of resistance remains incompletely defined, but there are specific clinical, cellular, and genetic factors that influence therapeutic failure. These factors range from physicians who fail to prescribe these medications despite appropriate indications to polymorphisms of platelet membrane glycoproteins. Rapid and accurate diagnosis of antiplatelet resistance also remains an issue as new bedside tests are developed. By understanding the mechanism of therapeutic failure and by improving the diagnosis of this clinical entity, a new era of individualized antiplatelet therapy may arise with routine measurements of platelet activity in the same way that cholesterol, blood pressure, and blood sugar are followed, thus improving the care for millions of people.

Genetic association of alpha2-Heremans–Schmid glycoprotein polymorphism with late-onset Alzheimer's disease in Italians

Alpha2-Heremans–Schmid glycoprotein (AHSG), also known as fetuin-A, is a highly glycosylated protein which has been recently reported to be decreased in the cerebrospinal fluid of patients with Alzheimer's disease. AHSG is genetically polymorphic and two common alleles, AHSG*1 and AHSG*2, have been described. The purpose of this study was to investigate the distribution of AHSG gene polymorphism in 235 Caucasian Italian patients with late-onset Alzheimer's disease (LOAD) and 235 age- and gender-matched healthy controls. In patients with LOAD, the genotype distribution was 184 AHSG 1*1, 44 AHSG 1*2, 7 AHSG 2*2, and was significantly different from that observed in the 235 control subjects (117 AHSG 1*1, 103 AHSG 1*2, 15 AHSG 2*2) ( χ 2 = 41.50, P < 0.0001). After allowance for age, gender and APOE ɛ4 status, multivariate logistic regression analysis revealed that the adjusted odds ratio for the development of LOAD in AHSG 1*1 homozygotes was 3.90 (95% CI: 2.58–5.90, P < 0.0001). These results suggest that the AHSG gene polymorphism may be associated with LOAD in Italians. Additional studies are warranted to examine the biological relevance of AHSG in the pathophysiology of neurodegenerative disorders.

Genetic factors contribute to bleeding after cardiac surgery.

Postoperative bleeding remains a common, serious problem for cardiac surgery patients, with striking inter-patient variability poorly explained by clinical, procedural, and biological markers. We tested the hypothesis that genetic polymorphisms of coagulation proteins and platelet glycoproteins are associated with bleeding after cardiac surgery. Seven hundred and eighty patients undergoing aortocoronary surgery with cardiopulmonary bypass were studied. Clinical covariates previously associated with bleeding were recorded and DNA isolated from preoperative blood. Matrix Assisted Laser Desorption/Ionization, Time-Of-Flight (MALDI-TOF) mass spectroscopy or polymerase chain reaction were used for genotype analysis. Multivariable linear regression modeling, including all genetic main effects and two-way gene-gene interactions, related clinical and genetic predictors to bleeding from the thorax and mediastinum. Nineteen candidate polymorphisms were assessed; seven [GPIaIIa-52C>T and 807C>T, GPIb alpha 524C>T, tissue factor-603A>G, prothrombin 20210G>A, tissue factor pathway inhibitor-399C>T, and angiotensin converting enzyme (ACE) deletion/insertion] demonstrate significant association with bleeding (P < 0.01). Adding genetic to clinical predictors results improves the model, doubling overall ability to predict bleeding (P < 0.01). We identified seven genetic polymorphisms associated with bleeding after cardiac surgery. Genetic factors appear primarily independent of, and explain at least as much variation in bleeding as clinical covariates; combining genetic and clinical factors double our ability to predict bleeding after cardiac surgery. Accounting for genotype may be necessary when stratifying risk of bleeding after cardiac surgery.

Platelet glycoprotein I(b)alpha and integrin alpha2 beta1 polymorphisms: gene frequencies and linkage disequilibrium in a population diversity panel.

Genetic variants in the GP1BA and ITGA2 genes have been proposed as potential modifiers for arterial vascular disease and bleeding disorders. Since ancestry may play an important role in the prevalence of these variants, we sought to determine their allele frequency and linkage disequilibrium in a collection of 1064 DNA samples from 51 ethnic groups. We studied haplotypes of ITGA2 defined by single nucleotide substitutions at positions -52, 807, and 1648, and GP1BA variants defined by sequence changes in positions -5 (Kozak), 1018 (T145M, HPA-2) and 1285 (VNTR A, B, C and D). Frequency of haplotypes of ITGA2 showed considerable variation across the different groups, with a higher prevalence of the haplotype -52C or T/807C/1648A observed in African compared with caucasian and Asian populations. The haplotypes 52C/807T/1648A and -52T/807T/1648A were not observed in caucasians or South Americans. While relative frequencies of the GP1BA Kozak alleles were comparable across groups, the methionine allele (HPA-2b) showed a higher frequency in Africa (0.26) than in the other groups. We also observed a high prevalence of the VNTR B allele in the African and Israeli populations. Haplotype analysis revealed incomplete linkage disequilibrium between the HPA-2 and VNTR alleles. Incorporation of GP1BA variants into the set of SNPs already genotyped by the HapMap project disrupted the pre-existing haplotype block. These data provide a valuable resource for optimal selection of variants best tailored for association studies of vascular disease or bleeding disorders when examining individuals of different ancestral origins.

A part le fibrinogène, les facteurs/marqueurs d’hémostase ont-ils aussi une place pour évaluer le risque d’accident cardiovasculaire ischémique ?

Most cardiovascular events result from a thrombotic complication of atherosclerotic lesions. In arterial vessels such as the coronary bed, an interrelationship of haemostatic, coagulation and fibrinolytic factors is implicated. While it can be demonstrated that fibrinogen is a risk factor/marker, the role of other factors is not well established. Under arterial flow conditions, platelets are predominantly involved in the thrombotic reaction. Yet, apart from a large increase in the platelet count, the involvement of platelet parameters in cardiovascular risk is not clearly evident. The lack of definitive platelet markers is at least partly due to the difficulty of studying platelet function ex vivo. Several polymorphisms of platelet glycoproteins carrying a moderate increase in risk have been reported, but only in younger patients. One potentially important factor for coagulation is the fibrin structure, which is dependent on fibrinogen, the rate of thrombin generation, the activity of factor XIII and the interrelationship of the cells concerned, all of which act on its sensitivity to thrombosis. Coagulation factors largely affect the rate of thrombin generation. The activity of the fibrinolytic system (and principally any deficiency) has a role in the cardiovascular risk. General markers of cardiovascular risk such as D-dimers are potentially useful, but they increase with thrombin generation and are decreased by a deficiency in fibrinolysis. Furthermore, possibly because they are not indicative of the fibrin structure, they are poorly correlated with clinical events. The poor significance of the available haemostatic, coagulation and/or fibrinolytic parameters is probably due to their lack of representativeness, since haemostatic, coagulation and fibrinolytic systems are all involved in the thrombotic response (and some in atherogenesis itself). Atherogenesis is a multifactorial process and numerous moderate risk factors act in association. Better predictability of the haemostatic tests would probably result from both the design of more representative tests and the evaluation of multiple parameters, and would lead to the definition of a risk score. Technological advances will make this possible.

Gene Polymorphism of Platelet Glycoprotein I bα in Chinese Patients with Large- and Small-Artery Subtypes of Ischemic Stroke

The platelet surface glycoprotein (GP) I bα, an important part of the GP I b-IX-V complex, participates in the formation of thrombosis by initially mediating platelet adhesion under high shear stress. The purpose of present study was to investigate the association between gene polymorphism of GP I bα (human platelet antigen 2, HPA2) and ischemic stroke in a matched case-control study. One hundred patients and 100 matched controls were enrolled in the study. The cases were divided into large- and small-vessel subtypes of ischemic stroke according to Trial of Org10172 in Acute Stroke Treatment criteria. Genotyping for GP I bα polymorphism was documented by polymerase chain reaction amplification and restriction enzyme analysis.There were no statistically significant differences in the GP I bα HPA2 genotype distribution between ischemic stroke group, large-vessel subtype group, small-vessel subtype group and corresponding control groups. The heterozygote genotype of GP I bα HPA2 was more frequent in the large-vessel subtype group (16.1%) than in the small-vessel subtype group (10.1%), but the difference was not statistically significant.Ourresults suggest that the polymorphism of the GP I bα HPA2 genotype might not be a genetic risk factor of ischemic stroke.

Association of ?2-HS glycoprotein (AHSG, fetuin-A) polymorphism with AHSG and phosphate serum levels

Alpha2-HS glycoprotein (AHSG), also known as fetuin-A, is a plasma protein displaying high-affinity interaction with calcium phosphate, by which ectopic vascular calcification is prevented. This investigation has attempted to evaluate the relationship between AHSG polymorphism and serum levels of AHSG and calcium-related parameters. AHSG levels in unrelated individuals were measured by quantitative rocket immunoelectrophoresis and were 581+/-38, 542+/-31, and 494+/-23 mg/l for three major genotypes of AHSG1 homozygotes (n=99), heterozygotes (n=55), and AHSG2 homozygotes (n=22), respectively (differences were significant: P<0.001). The circulating AHSG level was therefore influenced by the genetic polymorphism with the additive reduction in the AHSG2 allele. Statistical analysis of simple and multiple regression models revealed no associations between AHSG levels and serum values of total calcium, albumin-corrected total calcium, and ionized calcium. However, the AHSG levels demonstrated a significant negative correlation with free phosphate levels (P<0.001), indicating that AHSG is a novel determinant of serum phosphate. The AHSG polymorphism is attributable to the hereditary variation of AHSG and phosphate serum levels, which may affect skeletal development and chronic disorders such as vascular calcification.

Association between human α 2-Heremans Schmidt glycoprotein (AHSG) polymorphism and endometriosis in Korean women

To evaluate the relationship between the alpha 2-Heremans Schmidt glycoprotein (AHSG) gene polymorphism and endometriosis. Case-control study. Department of Obstetrics and Gynecology, Seoul National University Hospital, Korea. Seventy-nine women with endometriosis and 105 women without endometriosis. Determination of AHSG gene polymorphism. Prevalence of AHSG genotypes or alleles. The allele frequencies of AHSG 1 and AHSG 2 were found to be 0.69 and 0.31, respectively. The proportion of noncarriers of the AHSG 2 allele was significantly higher in women with endometriosis than in women without (55.7% vs. 39.0%). Women not carrying the AHSG 2 allele were found to have twice the risk of endometriosis than those carrying at least one copy of this allele. No significant difference was noted in the distribution of the AHSG alleles or AHSG genotypes between early stage endometriosis and late stage endometriosis. Endometriosis is associated with the AHSG gene polymorphism in Korean women.