PlA2 Polymorphism Research Articles

PlA2 Polymorphism of Platelet Glycoprotein IIb/IIIa and C677T Polymorphism of Methylenetetrahydrofolate Reductase (MTHFR), but Not Factor V Leiden and Prothrombin G20210A Polymorphisms, Are Associated with More Severe Forms of Legg-Calvé-Perthes Disease.

The possible association of common polymorphic variants related to thrombophilia (the rs6025(A) allele encoding the Leiden mutation, rs1799963(A), i.e., the G20210A mutation of the prothrombin F2 gene, the rs1801133(T) variant of the methylenetetrahydrofolate reductase (MTHFR) gene that encodes an enzyme involved in folate metabolism, and rs5918(C), i.e., the ‘A2’ allele of the platelet-specific alloantigen system that increases platelet aggregation induced by agonists), with the risk of Legg–Calvé–Perthes disease (LCPD) and the degree of hip involvement (Catterall stages I to IV) was analyzed in a cohort study, including 41 children of ages 2 to 10.9 (mean 5.4, SD 2.2), on the basis of clinical and radiological criteria of LCPD. In 10 of the cases, hip involvement was bilateral; thus, a total of 51 hips were followed-up for a mean of 75.5 months. The distribution of genotypes among patients and 118 controls showed no significant differences, with a slightly increased risk for LCPD in rs6025(A) carriers (OR: 2.9, CI: 0.2–47.8). Regarding the severity of LCPD based on Catterall classification, the rs1801133(T) variant of the MTHFR gene and the rs5918(C) variant of the platelet glycoprotein IIb/IIIa were associated with more severe forms of Perthes disease (Catterall III–IV) (p < 0.05). The four children homozygous for mutated MTHFR had a severe form of the disease (Stage IV of Catterall) and a higher risk of non-favorable outcome (Stulberg IV–V).

Spontaneous and Induced Platelet Aggregation during Pregnancy and Labor

Objective: to evaluate changes in characteristics of spontaneous platelet (Pt) aggregation in patients with obstetric complications associated with hereditary thrombophilia. Materials and methods. Blood samples were taken from 52 recently confined women on the first day after labor; at that, ethic regulations for the preanalytical phase were followed. Determination of PlA1/ PlA2 polymorphism enotype was performed by means of amplificationrestriction analysis. Geometrical characteristics of patients' peripheral blood Pt aggregation were studied by means of AFM Integra Prima. The degree of confidence of the parameters under test was determined using the ttest, and the significance level was considered valid at P<0.05. Results . A statistical analysis of the findings demonstrated that the length of Pt aggregates in healthy pregnant women was significantly higher than that in healthy nonpregnant women at all study phases. Patients with the P1A1/P1A2 polymorphism in the GP IIb/IIIa Pt receptor gene demonstrated increased widthm height, and density of Pt aggregates. The changes were most significant during the incubation phase lasting for 15 and 30 minutes. The study of geometric parameters of different exposures demonstrated the following: the longer the incubation period, the greater the difference between geometric parameters of the aggregates (e.g. height, length, and width). Conclusion. The analysis of obtained data demonstrated that the presence of P1A1/P1A2 polymorphism in GP IIb/IIIa Pt gene receptor contributes to the decrease in the platelet response threshold and enhances the spontaneous Pt aggregation. The imaging of aggregates provides strong evidence for the accelerated growth of the aggregates in thrombotic complications of pregnancy.

Platelet glycoprotein IIIa Leu33Pro gene polymorphism and coronary artery disease: A meta-analysis of cohort studies

Great interest has been focused in the last year on genetic predictors of cardiovascular risk. Glycoprotein IIb/IIIa (GP IIb/IIIa), fibrinogen receptor, is the final common pathway for aggregation and a key point for atherothrombosis. A single nucleotide polymorphism of IIIa subunit (Leu33Pro-PlA1/PlA2 allele) has been suggested to increase aggregation and adhesion, however, contrasting reports have been reported so far on its effects on coronary artery disease (CAD). Aim of the current study was to perform a large meta-analysis including cohorts of patients undergoing coronary angiography in order to evaluate whether this polymorphism is associated with coronary artery disease. Literature archives (Pubmed, EMBASE, Cochrane) and main scientific sessions abstracts were scanned for data of consecutive cohorts of patients undergoing coronary angiography, where PlA genotype was assessed. Primary endpoint was the prevalence of CAD. Secondary endpoint was severity of CAD defined as prevalence of multivessel disease (≥2 vessels). Data from seven studies were extracted, including a final number of 6700 patients. Among them 1893 (28.3%) carried the PlA2 polymorphism, 163 of them in homozygosis. Angiographically defined CAD was present in 3573 (74.3%) PlA1/PlA1 patients and in 1430 (75.5%) PlA2 carriers. PlA2 polymorphism was not associated with an increased prevalence of coronary artery disease, (OR [95% CI] = 1.07 [0.95–1.21], p = 0.28, pheterogeneity = 0.39). Similar results were obtained for multivessel disease (OR [95% CI] = 1.07[0.95–1.20], p = 0.27, pheterogeneity = 0.12). Meta-regression analysis demonstrated a significant inverse relationship between the risk of CAD among the PlA2 carriers and ageing (r = −0.044, (−0.09, −0.0008), p = 0.046). Present meta-analysis demonstrates that 33Leu → Pro substitution of GPIIIa does not influence the prevalence and extent of angiographically defined coronary artery disease in general population, although apparently playing a role among younger patients.

The PlA1/A2 polymorphism of glycoprotein IIIa as a risk factor for myocardial infarction: a meta-analysis.

BackgroundThe PlA2 polymorphism of glycoprotein IIIa (GPIIIa) has been previously identified as being associated with myocardial infarction (MI), but whether this represents a true association is entirely unclear due to differences in findings from different studies. We performed a meta-analysis to evaluate whether this polymorphism is a risk factor for MI.MethodsElectronic databases (MEDLINE and EMBASE) were searched for all articles evaluating genetic polymorphisms of GPIIIa. For studies where acute coronary events were recorded in association with genetic analysis, pooled odds ratios (ORs) were calculated using fixed-effects and random-effects models. The primary outcome measure was MI, and a secondary analysis was also performed for acute coronary syndromes (ACS) more generally.Findings57 studies were eligible for statistical analysis and included 17,911 cases and 24,584 controls. Carriage of the PlA2 allele was significantly associated with MI (n = 40,692; OR 1.077, 95% CI 1.024–1.132; p = 0.004) but with significant publication bias (p = 0.040). The degree of association with MI increased with decreasing age of subjects (≤45 years old: n = 9,547; OR 1.205, 95% CI 1.067–1.360; p = 0.003) and with adjustment of data for conventional cardiovascular risk factors (n = 12,001; OR 1.240, 95% CI 1.117–1.376; p<0.001). There was a low probability of publication bias for these subgroup analyses (all p<0.05).ConclusionsThe presence of significant publication bias makes it unclear whether the association between carriage of the PlA2 allele and MI is true for the total population studied. However for younger subjects, the relative absence of conventional cardiovascular risk factors results in a significant association between carriage of the PlA2 allele and MI.

The PlA1/A2 polymorphism of glycoprotein IIIa as a risk factor for stroke: a systematic review and meta-analysis.

BackgroundThe PlA1/A2 polymorphism of glycoprotein IIIa (GPIIIa) has been reported to be associated with risk of stroke in some studies, although other studies suggest no such association. This meta-analysis and systematic review was conducted to investigate the hypothesis that carriage of the PlA2 allele is a risk factor for stroke.MethodsElectronic databases (MEDLINE and EMBASE) were searched for all articles evaluating carriage of the PlA2 allele and the incidence of stroke. Pooled odds ratios (ORs) were calculated using fixed-effect and random-effect models.FindingsA total of 35 articles were eligible for inclusion, of which 25 studies were suitable for statistical analysis. For carriage of the PlA2 allele, OR 1.12 (n = 11,873; 95% CI = 1.03–1.22; p = 0.011) was observed for the incidence of stroke in adults, with subgroup analyses identifying the association driven by stroke of an ischaemic (n = 10,494; OR = 1.15, 95% CI = 1.05–1.27; p = 0.003) but not haemorrhagic aetiology (n = 2,470; OR = 0.90, 95% CI = 0.71–1.14; p = 0.398). This association with ischaemic stroke was strongest in individuals homozygous for the PlA2 allele compared to those homozygous for wild-type PlA1 (n = 5,906; OR = 1.74, 95% CI = 1.34–2.26; p<0.001). Subgroup analysis of ischaemic stroke subtypes revealed an increased association with stroke of cardioembolic (n = 1,271; OR 1.56, 95% CI 1.14–2.12; p = 0.005) and large vessel (n = 1,394; OR = 1.76, 95% CI 1.34–2.31; p<0.001) aetiology, but not those of small vessel origin (n = 1,356; OR = 0.99, 95% CI 0.74–1.33; p = 0.950). Egger's regression test suggested a low probability of publication bias for all analyses (p>0.05).ConclusionsThe totality of published data supports the hypothesis that carriage of the PlA2 polymorphism of GPIIIa is a risk factor for ischaemic strokes, and specifically those of cardioembolic and large vessel origin.

THE PLA1/A2 POLYMORPHISM OF GLYCOPROTEIN IIIA AS AN AGE-DEPENDENT RISK FACTOR FOR MYOCARDIAL INFARCTION: A META-ANALYSIS

The PlA2 polymorphism of glycoprotein IIIa (GPIIIa) has been associated with myocardial infarction (MI), especially in younger subjects. The true nature of this association is unclear due to poor agreement between studies. We have therefore performed this meta-analysis to examine the strength of

PLA2 polymorphism of platelet glycoprotein IIb/IIIa but not Factor V Leiden and prothrombin G20210A polymorphisms is associated with venous thromboembolism and more recurrent events in central Iran

Inherited thrombophilic gene polymorphisms have been linked to the pathogenesis of venous thromboembolism (VTE). As there are very limited data of these polymorphisms in the Iranian population, we aimed to investigate the correlation between them and VTE in central Iran. Seventy-two unrelated VTE patients and 306 healthy control individuals were recruited for the study. Genotyping from venous blood with EDTA for the factor V Leiden (FVL), prothrombin (FII) G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T and PLA2 polymorphism of platelet glycoprotein IIb/IIIa were undertaken by PCR-restriction fragment length polymorphism (PCR-RFLP). A total of 57 investigated polymorphisms with a mean of 0.79 per individual and 151 with a mean of 0.49 were found in patients and controls, respectively (P<0.001). FVL and FII G20210A were found, respectively, in 5.6 and 1.4% of the patients compared with 2.3 and 1% of the controls (P=NS). PLA2 polymorphism of GPIIb/IIIa was seen in 27.8 and 10.1% in patients and controls, respectively [odds ratio (OR), 3.4; 95% confidence interval (CI), 1.08-6.44, P<0.001]. Approximately 15.3% of VTE patients compared with 5.9% of controls had coinheritance of more than one genetic risk factor (P=0.007) and more recurrent events occurred in such patients. Patients with PLA2 polymorphism had more recurrent events than the other patients (P=0.02). Patients with more than one genetic risk factor and recurrent events were younger. The prevalence of these polymorphisms is different from some previously published data in other populations, but is consistent with some others. Higher prevalence of PLA2 polymorphism of GPIIa/IIIb in VTE patients is indicative of the impact of this polymorphism in the pathogenesis of VTE in this population. Because of the impact of coinheritance on the recurrence and the age of occurrence, such patients may need to be managed differently.

The GPIIIA PlA2 polymorphism is associated with an increased risk of cardiovascular adverse events

BackgroundThe clinical impact of PlA2 polymorphism has been investigated in several diseases, but the definition of its specific role on thrombotic cardiovascular complications has been challenging. We aimed to explore the effect of PlA2 polymorphism on outcome in patients with atherosclerosis.MethodsWe studied 400 consecutive patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention. A replication study was conducted in 74 hypertensive patients with cerebrovascular events while a group of 100 healthy subjects was included as control population. PlA genotype was determined by PCR-RFLP on genomic DNA from peripheral blood cells. Major adverse cardiac events (MACE), were considered as end points, and recorded at a mean follow up of 24 ± 4.3 months.ResultsThe frequencies of PlA2 polymorphism was similar between groups and genotype distribution was in Hardy-Weinberg equilibrium. In patients with CAD, the presence of PlA2 allele was associated with higher incidence of cardiac death (13.1% vs. 1.5%, p = 0.0001), myocardial infarction (10.7% vs. 2.6%, p = 0.004) and needs of new revascularization (34.8% vs. 17.7%, p = 0.010). Accordingly, the Kaplan-Meier analysis for event free survival in patients harboring the PlA2 allele showed worse long-term outcome for these patients (p = 0.015). Cox regression analysis identified the presence of PlA2 as an independent predictor of cardiac death (OR: 9.594, 95% CI: 2.6 to 35.3, p = 0.002) and overall MACE (OR: 1.829, 95% CI: 1.054 to 3.176, p = 0.032). In the replication study, the PlA2 polymorphism increased the risk of stroke (OR: 4.1, 95% CI: 1.63-12.4, p = 0.02) over TIA and was identified as an independent risk factor for stroke (B:-1.39; Wald: 7.15; p = 0.001).ConclusionsOur study demonstrates that in patients with severe atherosclerosis the presence of PlA2 allele is associated with thrombotic cardiovascular complications.

Glycoprotein IIIa gene polymorphism and coronary artery disease

Objective — Prevalence of glycoprotein IIIa gene polymorphisms (PlA2) has been reported to be elevated in persons who die of sudden death. PlA2 has been suggested as contributing to the development of atherosclerosis via coronary plaque rupture and thrombus formation. In this prospective study, we investigated the correlation between the PlA2 polymorphism, atherosclerotic plaque burden, and its prognostic significance.Methods and results — One hundred and seventy-eight patients (mean age 51 ± 9.6 years) suspected to have atherosclerotic coronary artery disease underwent a coronary angiography and were evaluated for gene polymorphisms. Patients were followed up for 4 years for major adverse cardiac events (MACE). Thirty-eight patients (21%) had the PlA2 polymorphism.There was no statistically significant correlation between presence of atherosclerotic plaque burden, severity of coronary artery stenosis, and glycoprotein genotype. During the follow-up there were no significant differences between the 2 groups with regard to MACE.Any cause of death and cardiovascular death were higher in patients with PlA2 polymorphism but these differences were not significant. On univariate analysis, smoking, presence of severe coronary artery disease, and presence of myocardial infarction were correlated with elevated risk of MACE; presence of atypical angina was correlated with fewer MACE. On multivariate analysis, smoking was an independent risk factor for a MACE. On univariate or multivariate analysis, there was no relation between the PlA2 polymorphism and a MACE.Conclusions — The glycoprotein IIb/IIIa genotype was not shown to indicate the presence of atherosclerotic plaque.There was no correlation between the genotype and plaque vulnerability.

TCT-209: The GPIIIA PlA2 Polymorphism is Associated with an Increased Risk of Cardiovascular Adverse Event

TCT-209: The GPIIIA PlA2 Polymorphism is Associated with an Increased Risk of Cardiovascular Adverse Event

Role of PLA2 polymorphism on clinical events after percutaneous coronary intervention

We examined the relationship between the PLA2 polymorphism of the platelet GPIIIa receptor and major adverse cardiac events (MACE) after percutaneous coronary intervention (PCI). PLA2 polymorphism has been associated with increased thrombosis and myocardial infarction. The association of PlA2 with MACE post-PCI has not been determined. 200 patients with normal baseline CKMB undergoing non-urgent PCI for symptomatic coronary artery disease were tested for the PLA2 polymorphism and followed for 1 year while on aspirin and clopidogrel. MACE were recorded and adjudicated by an independent, blinded committee. Baseline demographic and lesion characteristics, platelet aggregation, activated clotting time and use of GP Ilb/llla blockers were similar between the 2 groups. The normal (A1A1), heterozygous (A1A2), and homozygote (A2A2) variants were found in 144 (72%), 55 (27.5%), and 1 (0.5%) patients, respectively. The presence of the PLA2 genetic polymorphism had no influence on 1-year MACE: 7.1% for the A1A1 group versus 6.5% for the A1A2 group (P=NS). The rate of any CKMB elevation post-PCI was 39% vs. 38% respectively (P=NS). In this study, the GPIIIa PlA2 polymorphism was frequent (27.5%), but the homozygous variant was very infrequent (0.5%). The presence of PLA2 had no influence on peri-procedural or one-year clinical outcomes.

Platelet PlA2Polymorphism and the Risk for Thrombosis in Heparin-Induced Thrombocytopenia

Platelet glycoprotein (GP) IIb/IIIa has an important role in platelet aggregation. A polymorphism of platelet GPIIIa (PlA2, also called HPA1b) has been associated with a higher risk of thrombosis, but its implication in heparin-induced thrombocytopenia (HIT) is unclear. To investigate the hypothesis that the PlA2 polymorphism influences the prothrombotic effects of HIT, we conducted a prospective study of 66 consecutive patients with a laboratory diagnosis of HIT. The end point of the study was the diagnosis of a thrombus within 30 days of the positive HIT test result. The Diagnostica Stago (Asnières, France) enzyme-linked immunosorbent assay was used to detect HIT antibodies, and a polymerase chain reaction assay was used to detect the PlA2 polymorphism. Of the 66 patients, thrombotic complications developed in 27 (41%). Patients with the PlA2 allele demonstrated a significantly higher thrombosis risk than did patients without (69% vs 32%; P = .0088; odds ratio, 4.68; 95% confidence interval, 1.39-15.72). The risk was stronger for arterial thrombosis and for patients 60 years or older. There was a significant association between the PlA2 polymorphism of GPIIIa and the risk of thrombosis in patients with HIT antibodies.

Increased activity of phosphatase PP2A in the presence of the PlA2 polymorphism of αIIbβ3

Polymorphisms in αIIbβ3 are important genetic factors that alter platelet biology and have been associated with susceptibility to thromboembolic disorders. To define the molecular mechanisms that lead to variance in thrombotic diathesis dictated by the β3 polymorphism, we examined regulation of intracellular signaling by αIIbβ3, and studied the effects of a common β subunit PlA2 polymorphism. We found that PP2A regulates αIIbβ3 control of the ERK signaling in a polymorphism specific fashion. In CHO cells, exogenous expression of αIIbβ3 reduced ATP-stimulated ERK phosphorylation and more so for PlA2 than PlA1. Interestingly, reduced level of ERK phosphorylation correlated with an increase in PP2A activity, with higher activity associated with PlA2 than PlA1. We tested the effect of PP2A on αIIbβ3-dependent adhesion, and found that PP2A overexpression increased cell adhesion, while phosphatase inhibitors decreased cell adhesion. We propose that PlA2 alters cell signaling at least in part by increasing β3-associated PP2A activity.

The PlA1/A2 polymorphism of glycoprotein IIIa and cerebrovascular events in hypertension: increased risk of ischemic stroke in high-risk patients

The platelet GPIIIa plays a pivotal role in platelet aggregation. Previous studies showed an association between the GPIIIa Pl(A1/A2) polymorphism and coronary thrombosis, while there is only contrasting evidence about its role in stroke. We explored the possibility that this polymorphism represents a risk factor for stroke in hypertensive patients. We studied two populations. In loco, we genotyped 140 hypertensive control individuals and 28 hypertensive patients with ischemic stroke. Furthermore, we performed an analysis of previously published data of 451 Sardinian hypertensive patients, already characterized and genotyped. Association analysis revealed that the Pl(A2) distribution was similar between hypertensive patients with and without stroke, but when considering a more homogeneous population of high-risk hypertensive patients, defined according to ESH/ESC 2003 guidelines, we observed that the frequency of the Pl(A2) allele was higher among stroke versus nonstroke patients (stroke, 46.4%; nonstroke, 22.6%; P = 0.01). The multiple regression analysis taking into account this polymorphism among other factors known to contribute to ischemic stroke confirmed the Pl(A2) allele as an additive risk factor for stroke (B = 0.986, Wald = 4.943, P < 0.03), increasing the risk of stroke by 2.9 (95% confidence interval = 1.23-6.85, P < 0.02). Similar results were obtained in the Sardinian population: in hypertensive patients with three or more risk factors, Pl(A2) increases the risk (odds ratio = 2.8, 95% confidence interval = 1.3-6.0, P < 0.001) and is an additive risk factor for stroke (B = 1.073, Wald = 6.920, P < 0.01). Our data suggest that the Pl(A2) polymorphism is a genetic determinant of ischemic stroke in a selected high-risk hypertensive population.

Invited commentary

Aspirin is widely used to reduce graft thrombosis after coronary artery bypass grafting. However, aspirin only prevents approximately 25% of all ischemic vascular events and there are many causes, including all the causes of aspirin resistance for the other events. Aspirin resistance is the inability of aspirin to block platelet production of thromboxane A2 and subsequent platelet activation and aggregation. Increasing degrees of aspirin resistance may correlate independently with increasing risk of cardiovascular events. The study by Lim and colleagues [1Lim E. Carballo S. Cornelissen J. et al.Dose-related efficacy of aspirin after coronary surgery in patients with PlA2 polymorphism (NCT00262275).Ann Thorac Surg. 2007; 83: 134-139Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar] analyzed a genetic polymorphism within a subgroup of a prospective randomized trial. They attempted to evaluate the role of genetic polymorphism on the aspirin response in patients after coronary artery bypass grafting. The authors postulated that several genetic polymorphisms are common and some may affect responses to aspirin. In particular, PIA2 polymorphism seems to cause aspirin resistance. As with most genetic studies, the results were not clear-cut and statistical significance was not achieved, although trends were similar to published results. The design of this study is a major weakness for determining correlation between clinical findings and genetic polymorphisms. Basically most studies on genetic polymorphism need several populations of subjects. Several different subject populations or a highly selected group can establish a correlation between clinical findings and polymorphisms. Analytic studies that investigate the association of biochemical aspirin resistance and clinical events must quantitatively account for potential confounders (eg, age, sex, ethnicity, and clinical conditions), hematologic and biochemical factors (eg, hyperlipidemia, platelet count, and hemoglobin level), and nonadherence. The analysis in this study did not consider aspirin resistance that can be diagnosed in the laboratory by measurement of platelet thromboxane A2 production or thromboxane-dependent platelet function. Potential causes of aspirin resistance include inadequate dose, drug interactions, genetic polymorphisms involved in thromboxane biosynthesis, upregulation of nonplatelet sources of thromboxane biosynthesis, and increased platelet turnover. To prove the association between the polymorphism and clinical risk, statistical exclusion of confounders is required to reach a conclusion. Differential sensitivity to aspirin may have potential clinical implications, whereby specific antiplatelet therapy is best tailored to a patient’s PIA2 genotype. A well-designed study in a larger population is necessary to confirm the association between genetic polymorphisms and aspirin resistance. Dose-Related Efficacy of Aspirin After Coronary Surgery in Patients With PlA2 Polymorphism (NCT00262275)The Annals of Thoracic SurgeryVol. 83Issue 1PreviewTo evaluate the impact of the genetic polymorphisms affecting aspirin response using platelet aggregation and the response to different aspirin doses after cardiopulmonary bypass, we performed a subanalysis of the results from a randomized trial evaluating low- and medium-dose aspirin and clopidogrel. Full-Text PDF

Dose-Related Efficacy of Aspirin After Coronary Surgery in Patients With Pl A2 Polymorphism (NCT00262275)

To evaluate the impact of the genetic polymorphisms affecting aspirin response using platelet aggregation and the response to different aspirin doses after cardiopulmonary bypass, we performed a subanalysis of the results from a randomized trial evaluating low- and medium-dose aspirin and clopidogrel. Blood was collected from consenting patients and DNA extracted. Polymerase chain reaction and restriction fragment length polymorphism analysis was performed to detect Pl(A2), C807T, and A842/C50T polymorphisms. Aspirin efficacy was assessed using light transmission platelet aggregometry, and reported as percentage aggregation and EC50 concentrations using the technique of Born. Of 90 patients, 80 consented to further genetic testing, of whom 63 patients were randomly assigned to medium- (325 mg) or low-dose (100 mg) aspirin. The Pl(A2), C807T, and A842/C50T gene frequencies were 30%, 66%, and 21%, respectively, with no identifiable differences in the baseline platelet aggregation. Postoperatively, after 5 days of aspirin, platelet aggregation was consistently but not significantly impaired with Pl(A2) and A842/C50T carriers and consistently but not significantly improved with C50T carriers. An interaction term was identified on percentage aggregation and EC50 using epinephrine. The interaction coefficient describes a higher aggregation of 19% (95% confidence interval: 2 to 36; p = 0.03) and less inhibition with an EC50 of -2.07 (-4.19 to 0.04; p = 0.06) in patients who were both Pl(A2) positive and receiving low-dose aspirin. Genetic polymorphisms that affect the response to aspirin are common. The impaired response of persons with the Pl(A2) polymorphism to aspirin may be dose related, with significant improvement observed in patients using medium- rather than low-dose aspirin.

A Module Map Showing Interaction between Apolipoprotein E and Phospholipase A2 Polymorphism in Lipid Profiles

Objective: Establish a possible conceptual relationship among Apo E and PLA2 polymorphism and lipid profiles. Methods: Five hundred subjects aged 65 to 74 years were randomly selected from a community in southern Taiwan to assess the relationship between Apo E and PLA2 polymorphisms and lipid profiles. Two hundred fifty-six participants agreed to have venous blood drawn for DNA studies. Results: By multiple linear regression, the PLA2 A2 allele showed a statistically significant influence on LDL-C (p = 0.0097), and the ApoΕ2 allele showed a statistically significant influence on HDL-C (p = 0.0004), however, the interaction between the PLA2 A2 allele and the ApoΕ2 allele was found to be significant in the blood fraction of HDL-C (p = 0.0388) and LDL-C (p = 0.0002). Decreasing HDL-C and increasing LDL-C were found when the PLA2 A2 and ApoΕ2 allele co-existed. Conclusion: The presence of a physiologic balance contributes significantly to homeostatic and compensatory responses regulating blood HDL-C and LDL-C profiles. A module map of the generation-control cycle and conditional activity among Apo E, PLA2, and lipid levels is presented, and both behaviours and biological perspectives under the consilience model may suggest a new approach to many kinds of complex disorders.

Invited commentary

Invited commentary

Association of PLA2 polymorphism of the ITGB3 gene with early fetal loss

To study the association between early fetal loss and the presence of the PLA2 polymorphism of the ITGB3 gene we conducted a case-control study on 98 cases (i.e., women in fertile age, who experienced at least one episode of early fetal loss) and 38 healthy controls. PLA2 polymorphism was present in 44.2% of cases and 18.4% of controls, and cases with one (n = 24) event had an odds ratio (OR) = 2.7 (95% confidence interval [CI] 0.7-10.0), with two events (n = 52) an OR = 3.8 (95% CI 1.3-11.5), and with three (n = 16) or four abortions (n = 6) had a combined OR = 4.4 (95% CI 1.2-17.0), compared to controls, indicating that PLA2 polymorphism may be implicated in an inherited form of thrombophilia, and to early fetal loss.

Effect of glycoprotein IIIa Pl A2 polymorphism on outcome of patients with stable coronary artery disease and effect of smoking

A polymorphism of glycoprotein IIb/IIIa has been associated with myocardial infarction and restenosis after percutaneous coronary intervention. The influence on outcome and the interaction of the Pl A1 genotype with classic risk factors for coronary artery disease (CAD) were characterized in patients with chronic CAD followed prospectively for 3 years. Pl A1 genotypes were assessed in 592 patients enrolled in the Medical, Angioplasty, or Surgery Study II, a randomized trial comparing treatments for patients with CAD and preserved left ventricular function. The incidence of the composite end point of cardiac death, myocardial infarction, and refractory angina requiring revascularization were determined in each genotype group. Risk was assessed with the Cox proportional-hazards model. The clinical characteristics and treatment of each genotype were similar. Although the composite end point tended to be more common in patients with the Pl A2 allele, only smokers with the Pl A2 allele had a significantly increased incidence of the composite end point (p = 0.01). Moreover, a 2.2-fold increased risk was apparent in smokers with the Pl A2 allele (p = 0.03). Thus, taken together, these data provide support for the interaction effect between smoking and the Pl A1 gene variant. Smokers with the Pl A2 polymorphism of platelet glycoprotein IIIa are at greater risk for subsequent cardiac events in stable coronary disease.