Association of F11 polymorphism rs2289252 with deep vein thrombosis and related phenotypes in population of Latvia

Introduction

Deep vein thrombosis (DVT) has a strong inherited predisposition that is partly explained by the strong genetic risk factors such as mutations in factor V, prothrombin, antithrombin III, protein C and S genes. Only recently the first GWAS have been performed on DVT resulting in discovery of novel genetic variants, however, the information on the common polymorphisms predisposing to the risk of DVT is still scarce.

Materials and Methods

Here we selected six SNPs (rs5361 in SELE, rs2066865 in FGG, rs2227589 in SERPINC1, rs1613662 in GP6, rs13146272 in CYP4V2, rs2289252 in F11) reported to be associated with venous thrombosis conditions and studied the association of these common variants in selected case (n = 177) and control (n = 235) groups from population of Latvia. Genotyping was performed using TaqMan hybridization probe SNP genotyping assay.

Results

Patients with DVT had a significantly higher frequency of F11 rs2289252 polymorphism (p = 0.001; OR [95%CI] = 1.61 [1.20-2.14]). When stratified by recurrence of DVT the tendency was observed that the same SNP had higher OR value in group of DVT patients with repeated episodes of DVT compared to patients with single DVT episode (p = 0.009; OR [95%CI] = 2.27[1.22-4.21] and p = 0.009; OR [95%CI] = 1.52[1.11-2.08] respectively), but due to limited group of cases this finding should be replicated.

Conclusion

We conclude that F11 gene variant rs2289252 contribute to inherited forms of DVT incidence and correlation of other analysed SNPs should be explored in populations with greater sample size and associated with various thrombosis related traits.     

An exploratory model for G × E interaction on hippocampal volume in schizophrenia; obstetric complications and hypoxia-related genes

Background

Smaller hippocampal volume has repeatedly been reported in schizophrenia patients. Obstetric complications (OCs) and single nucleotide polymorphism (SNP) variation in schizophrenia susceptibility genes have independently been related to hippocampal volume. We investigated putative independent and interaction effects of severe hypoxia-related OCs and variation in four hypoxia-regulated schizophrenia susceptibility genes (BDNF, DTNBP1, GRM3 and NRG1) on hippocampal volume in schizophrenia patients and healthy controls.

Methods

Clinical assessment, structural MRI scans, and blood samples for genotyping of 32 SNPs were obtained from 54 schizophrenia patients and 53 control subjects. Information on obstetric complications was collected from original birth records.

Results

Severe OCs were related to hippocampal volume in both patients with schizophrenia and healthy control subjects. Of the 32 SNPs studied, effects of severe OCs on hippocampal volume were associated with allele variation in GRM3 rs13242038, but the interaction effect was not specific for schizophrenia. SNP variation in any of the four investigated genes alone did not significantly affect hippocampal volume.

Conclusions

The findings suggest a gene–environment (G × E) interaction between GRM3 gene variants and severe obstetric complications on hippocampus volume, independent of a diagnosis of schizophrenia. Due to the modest sample size, the results must be considered preliminary and require replication in independent samples.     

D-dimer relates positively with increased blood pressure in black South Africans: The SABPA study

Introduction

Hypertension is highly prevalent in black South Africans in which morbidity and mortality from stroke are on the increase. Elevated blood pressure and haemostatic markers can induce changes in blood rheology and endothelial function which could result in a procoagulant state that increases the risk for cerebrovascular disease. Information about the coagulation and fibrinolytic systems of people from African descent are limited. We therefore, investigated the haemostatic profile and its relationships with blood pressure in black South Africans.

Materials and methods

We measured ambulatory blood pressure and haemostatic markers of 201 black and 208 white school teachers. The haemostatic markers included measurements representing coagulation and fibrinolysis (von Willebrand factor, fibrinogen, plasminogen activator inhibitor-1, fibrin D-dimer and clot lysis time).

Results

Black participants displayed significantly higher blood pressure, von Willebrand factor, fibrinogen, plasminogen activator inhibitor-1 and D-dimer levels and longer clot lysis times (p ≤ 0.001). Single, partial and multiple regression analyses showed that systolic (p ≤ 0.011) and diastolic blood pressure (p = 0.010) correlated positively with D-dimer in black participants, while systolic (p ≤ 0.001) and daytime diastolic blood pressure (p = 0.011) correlated negatively with clot lysis time in white participants.

Conclusion

The black population had a more prothrombotic profile, with higher levels of coagulation markers and inhibited fibrinolysis, than the white study participants. The positive association between blood pressure and elevated D-dimer in the blacks may contribute to the high prevalence of hypertension and related increased cardiovascular and cerebrovascular risk in this group.     

Sustained high plasma plasminogen activator inhibitor-1 levels are associated with severity and mortality in septic patients

Background

Higher plasma plasminogen activator inhibitor-1 (PAI-1) levels have been reported in septic patients. However, some questions remain unanswered, such as whether there is an association between plasma PAI-1 levels and sepsis severity and mortality, and inflammation state during the first week.

Methods

Multicenter, observational and prospective study carried out in six Spanish Intensive Care Units of 260 patients with severe sepsis. Circulating levels of PAI-1 and tumour necrosis factor (TNF)-α were measured at day 1, 4 and 8. End-point was 30-day mortality.

Results

Nonsurviving septic patients (n = 89) presented higher PAI-1 levels than surviving (n = 171) at day 1 (58.4 (33.3-83.8) vs 36.5 (21.1-62.5) ng/mL; p < 0.001), 4 (34.0 (14.7-53.3) vs 16.2 (10.2-27.4) ng/mL; p < 0.001) and 8 (30.6 (16.2-47.8) vs 18.9 (10.4-29.5) ng/mL; p = 0.004). We found a positive correlation of PAI-1 levels with SOFA, lactic acid, aPTT, INR and TNF-α, and negative with platelet count at day 1, 4 and 8. Logistic regression analyses showed that PAI-1 levels at day 1 (p < 0.001), 4 (p < 0.001) and 8 (p = 0.001) were associated with 30-day mortality. On ROC curve analysis to predict 30- day survival, the area under the curve of PAI-1 levels at day 1, 4 and 8 were 0.65 (95% CI = 0.58-0.72; p < 0.001), 0.69 (95% CI = 0.60-0.78; p < 0.001) and 0.65 (95% CI = 0.54-0.75; p = 0.005) respectively.

Conclusions

The most interesting findings of our study, to our knowledge the largest series reporting PAI-1 levels during follow-up in septic patients, were that plasma PAI-1 levels during the first week were associated with inflammation, severity and mortality.     

No genetic association between NCAM1 gene polymorphisms and schizophrenia in the Chinese population

Background

The neural cell adhesion molecule 1(NCAM1, aliases NCAM and CD56) is a cell-surface molecule which makes homophilic adhesion between neural cells involved in cell migration, axon outgrowth and synaptic plasticity. Recent studies reported that NCAM1 might act as a candidate schizophrenia susceptibility gene.

Method

We genotyped five SNPs (rs1943620, rs1836796, rs1821693, rs686050, rs584427) within the NCAM1 gene and conducted a case-control study in 288 schizophrenic patients and 288 healthy subjects in the Chinese Han population. We compared allele and genotype frequencies and haplotype distributions between cases and controls.

Result

No significant differences in allele and genotype frequencies were found for each single SNP between schizophrenic patients and healthy subjects. Moreover, there were no significant differences in haplotype distributions between cases and controls (global χ² = 1.318, P = 0.725, df = 3).

Conclusion

Our study suggests that the five SNPs within NCAM1 gene we studied may not play a major role in the schizophrenia susceptibility in the Chinese Han population.     

CVD risk factors are related to plasma fibrin clot properties independent of total and or γ’ fibrinogen concentration

Introduction

Cardiovascular disease (CVD) risk factors are associated with total fibrinogen concentration and/or altered clot structure. It is however, unclear whether such associations with clot structure are ascribed to fibrinogen concentration or other independent mechanisms. We aimed to determine whether CVD risk factors associated with increased total and/or γ’ fibrinogen concentration, were also associated with altered fibrin clot properties and secondly whether such associations were due to the fibrinogen concentration or through independent associations.

Materials and methods

In a plasma setting CVD risk factors (including total and γ’ fibrinogen concentration) were cross-sectionally analysed in 2010 apparently healthy black South African participants. Kinetics of clot formation (lag time, slope and maximum absorbance) as well as clot lysis times were calculated from turbidity curves.

Results

Of the measured CVD risk factors age, metabolic syndrome, C-reactive protein (CRP), high density lipoprotein (HDL)-cholesterol and homocysteine were significantly associated with altered fibrin clot properties after adjustment for total and or γ’ fibrinogen concentration. Aging was associated with thicker fibres (p = 0.004) while both metabolic syndrome and low HDL-cholesterol levels were associated with lower rates of lateral aggregation (slope), (p = 0.0004 and p = 0.0009), and the formation of thinner fibres (p = 0.007 and p = 0.0004). Elevated CRP was associated with increased rates of lateral aggregation (p = 0.002) and consequently thicker fibres (p < 0.0001). Hyperhomocysteinemia was associated with increased rates of lateral aggregation (p = 0.0007) without affecting fibre thickness.

Conclusion

Final clot structure may contribute to increased CVD risk in vivo through associations with other CVD risk factors independent from total or γ’ fibrinogen concentration.     

A genetic schizophrenia-susceptibility region located between the ANKK1 and DRD2 genes

Background

The gene coding for the D2 dopamine receptor (DRD2) is considered to be one of the most pertinent candidate genes in schizophrenia. However, genetic studies have yielded conflicting results whereas the promising TaqIA variant/rs1800497 has been mapped in a novel gene, ANKK1.

Methods

We investigated eleven single nucleotide polymorphisms (SNPs) spanning the DRD2 and ANKK1 genes, using both a case–control association study comparing 144 independent patients to 142 matched healthy subjects, and a transmission disequilibrium test in 108 trios. This classical genetic study was coupled with a cladistic phylogeny-based association test of human variants, and with an interspecies evolution study of ANKK1.

Results

Case–control study, followed by a 108 trios family-based association analysis for replication, revealed an association between schizophrenia and the ANKK1 rs1800497 (p = 0.01, Odds Ratio = 1.5, 95% Confidence Interval = 1.1–2.2), and the intergenic rs2242592 (p = 2 · 10^− 4, OR = 1.8, 95%CI = 1.3–2.5). A significant SNP–SNP interaction was also found (p < 10^− 5, OR = 2.0, 95%CI = 1.6–2.5). The phylogeny-based association test also identified an association between both these polymorphisms and schizophrenia. Finally, interspecies comparison of the sequences from chimpanzee, orangutan, rhesus macaque and human species suggested specific involvement of ANKK1 in the human lineage.

Conclusions

Intergenic rs2242592 appears to be involved in the genetic vulnerability to schizophrenia, whereas the ANKK1 rs1800497 appears to have a modifying rather than causative effect. Finally, ANKK1 may be a specific human lineage-trait involved in a specific human disease, schizophrenia.     

Relationship Between ABCB1 Polymorphisms,Thromboelastography and Risk of Bleeding Events in Clopidogrel-Treated Patients With ST-Elevation Myocardial Infarction

Introduction

This study sought to investigate the relationship of polymorphisms in ABCB1 and the predictive value of thromboelastography (TEG) on bleeding risk in clopidogrel-treated patients with ST-elevation myocardial infarction (STEMI).

Methods

467 consecutive patients with STEMI undergoing percutaneous coronary intervention (PCI) were enrolled. Twenty tag single nucleotide polymorphisms (SNPs) selected from ABCB1 gene and CYP2C19*2, *3, *17 were detected by the ligase detection reaction. Platelet reactivity was assessed by TEG. The follow-up period was 12 months.

Results

By receiver operating characteristic curve analysis, the TEG platelet mapping assay value of ADP inhibition had the best predictive value of bleeding academic research consortium definition (BARC) ≥ 3b bleedings, yielding an area under the curve (AUC) of 0.707 (95% CI 0.662-0.749, p = 0.009; cut-off value > 93.4%). ADP inhibition can also predict BARC ≥ 3 bleedings with an AUC of 0.594 (95% CI 0.546-0.640, p = 0.05; cut-off value > 92.5%). After adjustment for established risk factors of bleeding including the gain of function CYP2C19*17 allele, age, female gender, renal function, the multivariable logistic regression model demonstrated that ADP inhibition > 92.5% (OR 2.247, 95%CI 1.082-4.665, P = 0.03), carriage of rs1045642 (OR 2.943, 95%CI 1.195-7.247, P = 0.019) and rs7779562 (OR 0.453, 95%CI 0.219-0.936, P = 0.032) were independent predictors of BARC ≥ 3 bleedings. These associations were validated in a second cohort of 504 STEMI patients.

Conclusions

In STEMI patients treated with clopidogrel after PCI, the ABCB1 tag SNP rs1045642 is associated with higher risk of bleedings while rs7779562 is associated with lower bleeding risk, and ADP inhibition in TEG has a predictive value of bleedings.     

Direct microscopic monitoring of initial and dynamic clot lysis using plasmin or rt-PA in an in vitro flow system

Introduction

Plasmin is a direct-acting thrombolytic agent with a favorable safety profile upon intra-arterial delivery in pre-clinical and phase I studies. However, the thrombolytic efficacy of plasmin, relative to that of rt-PA, remains to be established. We have compared the dynamics of clot lysis with plasmin or rt-PA in an in vitro perfusion system, in which thrombolytic agent is administered locally, allowed to induce lysis for short intervals, then washed with plasma in a re-circulation circuit.

Materials and Methods

Whole blood human clots were prepared in observation chambers, exposed to plasmin or rt-PA at equimolar concentrations (1.2/1.0, 1.8/1.5 and 2.4/2.0 mg/ml) for measured intervals of time, followed by perfusion with human plasma. Clot size was monitored by digital analysis of sequential photographs obtained through an optical microscope.

Results

Plasma perfusion after incubation with thrombolytic agent rapidly removed superficial clot fragments. This initial decrease in clot size was greater with plasmin than with rt-PA when tested at the highest concentrations of agent (0.63 ± 0.11 vs. 0.30 ± 0.11, p = 0.001 for clots with non-cross-linked fibrin and 0.53 ± 0.15 vs. 0.14 ± 0.15, p = 0.02, for clots with cross-linked-fibrin). Subsequent clot lysis during plasma flow was greater after prior incubation with rt-PA. Longer incubation times of plasmin resulted in larger portions of the clot being washed free. Repeated plasmin incubations and plasma perfusions of a clot successfully induced stepwise reductions in clot size.

Conclusions

Initial clot lysis is greater with direct exposure using plasmin than rt-PA. During washout and circulation with plasma, rt-PA induced continued clot lysis, while plasmin lysis was curtailed, presumably because of plasmin inhibition.     

Biomarkers for post thrombotic syndrome: A case-control study

Introduction

There is limited knowledge on the etiology of post thrombotic syndrome (PTS), although several mechanisms have been proposed.The objectives are to explore the role of different pathogenic mechanisms for PTS, through measurement of an elaborate panel of biomarkers in patients with and without PTS.

Materials and Methods

Patients with a history of deep vein thrombosis (DVT) with PTS (cases) and without PTS after minimal 2 years follow-up (controls), were selected from the outpatient clinic of two Dutch hospitals. As a reference to the normal population healthy individuals (HI) without a history of venous thromboembolism were invited to participate. The population consisted of: 26 cases, 27 controls, and 26 HI.A panel of predefined biomarkers was measured in venous blood.

Results

D-dimer showed a decreasing trend from cases to controls to HI; p = 0.010. Thrombin/antithrombin complex levels were significantly higher in cases than in controls; p = 0.032, and HI; p = 0.017. APC-ratio was significantly lower in cases compared to controls; p = 0.032, and HI; p = 0.011. A significant trend of increasing proTAFI from cases, to controls, and HI; p = 0.002 was found. There were no differences in inflammatory markers (CRP, Interleukin-6, Interleukin-8). Thrombomodulin, tissue-plasminogen activator, and von Willebrand factor were higher in patients compared to HI. There was a significant trend of decreasing sVCAM, from cases, to controls, and HI; p = 0.029.

Conclusions

Patients with PTS displayed increased coagulation activity, an altered pattern of fibrinolytic marker expression, and increased endothelial activation. We found no evidence of systemic inflammation in patients with PTS at 63 months since the last DVT.     

Genetic determinants of acenocoumarol and warfarin maintenance dose requirements in Slavic population: A potential role of CYP4F2 and GGCX polymorphisms

Introduction

VKORC1 and cytochrome CYP2C9 genetic variants contribute largely to inter-individual variations in vitamin K antagonists (VKAs) dose requirements. Cytochrome P450 4 F2 isoform (CYP4F2), gamma-glutamyl carboxylase (GGCX) and apolipoprotein E (APOE) polymorphisms have been suggested to be of minor significance.

Materials and Methods

We sought to assess the impact of those polymorphisms on dose requirements in Central-Eastern European cohort of 479 patients receiving acenocoumarol (n = 260) or warfarin (n = 219).

Results

There were no differences between the acenocoumarol and warfarin groups with regard to the gender, age, body mass index and international normalized ratio. The VKORC1 c.-1639A allele carriers required a lower dose of acenocoumarol and warfarin than the non-carriers (28.0 [21.0–35.0] vs. 42.0 [28.0–56.0] mg/week, p < 0.0001; 35.0 [28.0–52.0] vs. 52.0 [35.0–70.0] mg/week, p = 0.0001, respectively). Carriers of *2 and/or *3 variant alleles for CYP2C9 also required a lower dose of warfarin as compared with *1*1 carriers (35.0 [31.5–52.5] vs. 43.8 [35.0–60.2] mg/week, p = 0.02; 35.0 [23.5–35.0] vs. 43.8 [35.0-60.2] mg/week, p < 0.0001, respectively). Similarly, possession of G allele of GGCX c.2084 + 45 polymorphism was associated with lower warfarin dose (35.0 [26.3–39.2] vs. 45.5 [35.0–65.1] mg/week, p = 0.03). No effect of CYP2C9*2,-*3 and GGCX c.2084 + 45G > C polymorphisms on acenocoumarol dosage was observed. Interestingly, carriers of CYP4F2 c.1297A variant required a higher dose of acenocoumarol and warfarin than non-carriers (43.8 [35.0–60.2] vs. 35.0 [35.0–52.5] mg/week, p = 0.01; 35.0 [28.0–52.5] vs. 28.0 [28.0–42.0] mg/week, p = 0.05).

Conclusions

We have shown for the first time, that besides VKORC1 and CYP2C9 genetic variants, the CYP4F2 c.1297A and GGCX c.2084 + 45G have a moderate effect on VKAs dose requirements in Slavic population from Central-Eastern Europe.     

TPH2 is not a susceptibility gene for suicide in Japanese population

Background

Serotonergic systems mediate a control of aggression and/or impulsivity in human and are suggested to be involved in suicidal behavior. The newly identified neuronal tryptophan hydroxylase isoform 2 (TPH2), the rate-limiting enzyme in serotonin synthesis, represents a prime candidate in numerous genetic association analyses of suicidal behavior; however, the results are still inconclusive. The discrepancy may result from the heterogeneity of pathogenesis of suicidal behavior and/or methodological mismatches. We, therefore, attempted to replicate the association of TPH2 gene with suicide using a case-control study of 234 completed suicides and 260 control subjects in Japanese population.

Methods

We genotyped 15 tagging-single nucleotide polymorphisms (SNPs) including 4 SNPs, which were previously reported to be associated with suicidal behavior, using the TaqMan probe assays and the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method.

Results

We found no significant differences in genotypic distributions (uncorrected p = 0.06–0.98) or allelic frequencies (uncorrected p = 0.09–0.95) of the fifteen SNPs between the completed suicides and control groups. Haplotypes constructed with these SNPs were also not associated with suicide (uncorrected p = 0.03–0.96 and corrected p = 0.20–1.00). Even when we took sex and suicidal methods (violent or non-violent) into account for the analyses, no significant differences in genotypic distributions, allelic/haplotypic frequencies were found in the two groups.

Conclusion

Our results suggest that the common SNPs and haplotypes of the TPH2 gene are unlikely to contribute to the genetic susceptibility to suicidal behavior in Japanese population.     

Reduced plasma fibrin clot permeability and susceptibility to fibrinolysis are associated with increased intima-media thickness in patients with primary antiphospholipid syndrome

Introduction

Formation of denser fibrin networks displaying impaired lysability has been reported in subjects at an increased risk of atherosclerosis. Given recent data on prothrombotic fibrin clot phenotype reported in patients with antiphospholipid syndrome (APS), we tested the hypothesis that altered fibrin clot properties are associated with increased intima-media thickness (IMT) observed in PAPS.

Materials and methods

We studied 30 consecutive patients with PAPS and 30 controls matched for age, sex and the type of previous thromboembolism. We assessed plasma fibrin clot permeability (K_s) and clot lysis time (CLT) with their potential determinants. The IMT was measured in 3 segments of the carotid arteries.

Results

Patients with APS had 15.2% lower K_s (p = 0.002) and 9.7% prolonged CLT (p = 0.039) compared with controls. The IMT in the APS group was greater in the common carotid artery (5.7%; p = 0.002), at the bifurcation (17.46%; p < 0.001), and the internal artery (9.26%; p = 0.015). Patients with triple positivity in the antiphospholipid antibody profile (n = 9; 30%) had lower K_s and greater IMT (both, p < 0.05), compared with those with single positivity (n = 13; 43.3%). Multivariate analysis adjusted for potential confounders showed that in APS patients, oxidized low-density lipoproteins (p = 0.019) were the only independent predictor of K_s, while thrombin activatable fibrinolysis inhibitor activity (p < 0.001) predicted CLT. Plasminogen activator inhibitor-1 (PAI-1) was found to be the independent predictor of the IMT in the common carotid artery (p = 0.004), and in the internal carotid artery (p < 0.001).

Conclusions

Reduced K_s and susceptibility to lysis are associated with greater IMT in PAPS, which might contribute to the early atherosclerosis in this disease.     

The association of the JAK2 46/1 haplotype with non-splanchnic venous thrombosis

Background

The inherited JAK2 46/1 haplotype is strongly associated with the development of myeloproliferative neoplasms (MPNs), and its increased frequency has also been reported in splanchnic venous thrombosis (SVT). In the present study, the role of the JAK2 46/1 haplotype in non-splanchnic venous thrombosis (non-SVT) was investigated.

Methods and Results

We genotyped 438 patients with non-SVT, 226 patients with MPNs and 459 healthy controls for three single nucleotide polymorphisms (SNPs) which tag the JAK2 46/1 haplotype (rs12342421 G > C, rs12343867 T > C and rs10974944 C > G). We found statistically significant association of the rs12342421 GC + CC genotypes (OR = 1.40; p = 0.023) and the rs12343867 TC + CC genotypes (OR = 1.83; p = 7.02x10^- 5) with non-SVT. We also found that the CC haplotype of these two SNPs was associated with an increased risk of the disease (OR = 1.68; p = 0.009). Stratification analysis indicated that the observed association of the JAK2 46/1 haplotype with non-SVT was probably largely free of confounding effect of thrombophilic risk factors. In addition, we established a strong association of SNPs rs12342421 and rs10974944 and their CG haplotype with MPNs and with JAK2 V617F-positive MPNs.

Conclusions

This study provides statistical evidence that SNPs rs12342421 and rs12343867 are associated with an increased risk of non-SVT. Consistently, haplotypes of the SNPs were also associated with non-SVT risk, suggesting that inherited genetic variation in the JAK2 gene may play a role in the pathogenesis of non-SVT. Furthermore, the reported associations of the JAK2 46/1 haplotype with MPNs as well as with the occurrence of the JAK2 V617F mutation in MPNs were confirmed.     

A case-control study provides evidence of association for a common SNP rs974819 in PDGFD to coronary heart disease and suggests a sex-dependent effect

Introduction

Peden et al. have revealed a significant association between four new risk loci and coronary heart disease (CHD) in Europeans and South Asians. The goal of this study is to evaluate the contribution of these genetic loci to CHD risk in Han Chinese.

Methods

We recruited 161 CHD patients and 112 controls proved by angiography originated from Ningbo in the Eastern China, and performed a case-control association study of the four significant SNPs.

Results

Among the four tested SNPs, we found a significant association of rs974819 in PDGFD gene with CHD (allele p = 0.04; OR = 1.45, 95% CI = 1.02 - 2.08) and the allele A/G of rs974819 shows significant difference in females (allele p = 0.04; OR = 1.83, 95% CI = 1.01 - 3.31). A further meta-analysis showed that rs974819 of PDGFD gene was significantly associated with an increasing risk of CHD (OR = 1.08, 95% CI = 1.05 - 1.11) in both Europeans and South Asians including Han Chinese.

Conclusions

Our findings suggests that rs974819 of PDGFD is also a CHD risk factor in Han Chinese. In addition, it presents a sex-dependent genetic effect.     

Influence of coronary artery disease-associated genetic variants on risk of venous thromboembolism

Introduction

We investigated whether genetic variations robustly associated with coronary artery disease are also associated with risk of venous thromboembolism in a well-defined, female case–control study (n = 2753) from Sweden.

Materials and Methods

39 single nucleotide polymorphisms in 32 loci associated with coronary artery disease in genome-wide association studies were identified in a literature search and genotyped in the ThromboEmbolism Hormone Study (TEHS). Association with venous thromboembolism was assessed by logistic regression.

Results

Only rs579459 in the ABO locus demonstrated a significant association with VTE. A tentative association between ANRIL and VTE in the discovery analysis failed to replicate in a meta-analysis of 4 independent cohorts (total n = 7181).

Conclusions

It appears that only the ABO locus is a shared risk factor for coronary artery disease and VTE.     

Increased activation of blood coagulation in pregnant women with the Factor V Leiden mutation

Background

The risk of venous thromboembolism is enhanced in pregnant carriers of the Factor V Leiden mutation. The primary aim of the study was to compare prothrombin fragments 1 + 2, soluble fibrin and D-dimer levels in pregnant Factor V Leiden mutation carriers with those in non-carriers. Secondary aims were to evaluate whether these biomarkers could predict placenta-mediated complications or venous thromboembolism, and to study blood coagulation after caesarean section with thromboprophylaxis and after vaginal delivery without thromboprophylaxis.

Material/Methods

Prothrombin fragments 1 + 2, soluble fibrin and D-dimer levels were studied longitudinally in 476 carriers with singleton pregnancies from gestational weeks 23–25 until 8–10 weeks postpartum.

Results

Prothrombin fragments 1 + 2 and D-dimer levels gradually increased during pregnancy. D-dimer levels were higher in carriers, both during pregnancy and puerperium, compared to non-carriers. D-dimer levels above 0.5 mg/l were found in about 30% and 20% of the heterozygous carriers at 4–5 and 8–10 weeks postpartum, respectively. Soluble fibrin levels were mainly unchanged during pregnancy, with no difference between carriers and non-carriers. Biomarker levels were similar in carriers with uncomplicated and complicated pregnancies.

Conclusion

Higher D-dimer levels indicate increased blood coagulation and fibrinolysis activity in carriers. The high proportion of carriers with D-dimer levels exceeding 0.5 mg/l postpartum must be considered when assessing the probability of venous thromboembolism. Large overlaps in biomarker levels in normal and complicated pregnancies suggest that these biomarkers cannot be used as predictors. Thromboprophylaxis following caesarean section may prevent increased activation of blood coagulation.     

Tamoxifen induces resistance to activated protein C

Introduction

The estrogen antagonist tamoxifen (TAM) increases the thrombotic risk similar to estrogen containing oral contraceptives (OC). In OC users this risk is attributed to alterations of hemostasis resulting in acquired resistance to activated protein C (APC). TAM-induced APC resistance has not been reported yet.

Materials and Methods

Blood samples were collected prospectively from women with breast cancer before (n = 25) and monthly after start of adjuvant TAM treatment (n = 75). APC resistance was evaluated on basis of the effect of APC on the endogenous thrombin generation potential. To detect increased in vivo APC generation APC plasma levels were measured using a highly sensitive oligonucleotide-based enzyme capture assay. Routine hemostasis parameters were measured additionally.

Results

APC sensitivity decreased by 41% (p = 0.001) compared to baseline after one month of TAM application and remained significantly decreased during the study period. Free protein S increased (p = 0.008) while other analyzed procoagulant factors, inhibitors, and activation markers of coagulation decreased or did not change significantly. In five patients the APC concentration increased to non-physiological levels but an overall significant increase of APC was not observed.

Conclusions

This is the first study showing acquired APC resistance under TAM therapy. Acquired APC resistance might explain the increased thrombotic risk during TAM treatment. Observed changes of hemostasis parameters suggest different determinants of TAM-induced APC resistance than in OC-induced APC resistance. The presence of acquired APC resistance in TAM patients warrants further evaluation if these patients may benefit from antithrombotic prophylaxis in the presence of additional thrombotic risk factors.     

Unprovoked proximal venous thrombosis is associated with an increased risk of asymptomatic pulmonary embolism

Introduction

Pulmonary embolism (PE) is common in patients with deep venous thrombosis (DVT). The outcome of DVT with concomitant symptomatic PE is worse than the outcome of isolated DVT. The risk factors for DVT and simultaneous asymptomatic PE have not been systematically studied yet.

Aim

To evaluate the frequency and risk factors for asymptomatic PE in patients with DVT.

Patients/methods

In 155 consecutive patients with a first episode of DVT and no PE symptoms, a ventilation-perfusion lung scan was performed. Body mass index (BMI) and waist-to-hip ratio (WHR) were calculated and concentrations of D-dimer, high-sensitivity CRP (hsCRP), tissue plasminogen activator (t-PA) and troponin were measured. Laboratory tests for thrombophilia were performed.

Results

Asymptomatic PE was present in 36% of patients. No differences in gender, age, BMI and WHR were found between the patients with and without PE. PE was more common in patients with proximal DVT than in those with distal DVT (42% vs. 17%, p < 0.01), and in patients with unprovoked DVT compared to patients with provoked DVT (51% vs. 28%, p < 0.01). The risk of silent PE was the highest in patients with unprovoked proximal DVT (OR, 6.9; 95% CI, 2.3–21.0). Patients with asymptomatic PE had significantly higher values of D-dimer, hsCRP, t-PA and troponin than patients with isolated DVT.

Conclusions

Asymptomatic PE affected more than one third of patients with a first DVT. Unprovoked proximal DVT is the most important risk factor for the occurrence of silent PE.     

Influence of DRD2 and ANKK1 genotypes on apomorphine-induced growth hormone (GH) response in alcohol-dependent patients

Background

D₂ receptor function can be assessed by growth hormone (GH) response to apomorphine. Several association studies between dopamine receptor polymorphisms and results of the apomorphine challenge test with normal and alcohol-dependent subjects yielded inconsistent results. In this pilot study, we tested polymorphisms from the DRD2 region for GH response to apomorphine challenge in more detail.

Methods

Apomorphine challenge tests measuring GH responses on 5 time points were performed on day 1 of alcohol detoxification in 43 patients with alcohol dependence; patients were genotyped for 11 polymorphisms including DRD2, ANKK1, NCAM1 and TTC12.

Results

Associations (p < 0.05) were found for ANKK1 (rs11604671, rs1800497) and DRD2 (rs6276, rs1076560), which are located on adjacent chromosomal positions. Consistent with PET studies suggesting a reduced D₂ receptor availability in patients carrying the ANKK1 rs1800497 T polymorphism (formerly known as DRD2 TaqI A1) we found a reduced GH response to apomorphine in those subjects.

Conclusion

This has been the first study showing significant associations between apomorphine-induced GH response and SNPs in DRD2 and ANKK1 in alcohol-dependent patients. In this respect, our preliminary results are in line with other reports which suggested that DRD2 and ANKK1 polymorphisms influence D₂ receptor availability and signal transduction in the dopaminergic pathways. Small sample size in our study limits the generalizability of our results.