F11 rs2289252T and rs2036914C Polymorphisms Increase the Activity of Factor XI in Post-trauma Patients with Fractures Despite Thromboprophylaxis.
ABSTRACT: OBJECTIVE:To evaluate the association between F11 rs2289252, rs2036914 polymorphisms and the activity of clotting factor XI in post-trauma patients with fractures receiving routine anticoagulation therapy for deep venous thrombosis (DVT). METHODS:A case-control study involving 110 consecutive post-trauma patients with fractures and DVT in our hospital was conducted from April 2014 to October 2015; these patients comprised a DVT group. Another 40 sex- and age-matched patients with fractures but without DVT served as controls. Additionally, 40 sex- and age-matched healthy people were chosen as a normal group. Venous blood samples (2 mL) were drawn from all participants and genomic DNA extracted from the leukocytes of the patients with fracture-related DVT, whose genotype and allele frequency distribution of F11 gene rs2089252 and rs2036914 single nucleotide polymorphism were then assessed by a sequencing method. The activity of factor XI was measured by a solidification method in all participants, including those in control and normal groups. RESULTS:The activity of factor XI in patients with fracture-related DVT and F11 rs2089252 CT was 1.16 times that of those with CC genotypes (P < 0.0001), whereas in patients with fracture-related DVT and F11 rs2089252 TT genotypes it was 1.32 times that of those with CC genotypes (P < 0.0001), in patients with fracture-related DVT and F11 rs2089252 T allele it was 1.24 times that of those with C allele (P < 0.05), in patients with fracture-related DVT and F11 rs2036914 CC it was 1.35 times that of those with TT genotypes, in patients with fracture-related DVT and F11 rs2036914 CT genotypes it was 1.12 times that of those with TT genotypes (P < 0.05), and in patients with fracture-related DVT F11 and rs2036914 C allele it was 1.22 times that of those with T allele (P < 0.05). The activity of factor XI was significantly higher in the control than in the normal group (P < 0.05). CONCLUSIONS:High activity of factor XI indicates a risk of occurrence of DVT in post-trauma patients with fractures. F11 rs2089252 and rs2036914 (single nucleotide polymorphisms) are associated with activity of factors XI in such patients despite prophylaxis.
Project description:Single nucleotide polymorphisms (SNPs) in a 4q35.2 locus that harbors the coagulation factor XI (F11), prekallikrein (KLKB1), and a cytochrome P450 family member (CYP4V2) genes are associated with deep venous thrombosis (DVT). These SNPs exert their effect on DVT by modifying the circulating levels of FXI. However, SNPs associated with DVT were not necessarily all in F11, but also in KLKB1 and CYP4V2. Here, we searched for evidence for common regulatory elements within the 4q35.2 locus, outside the F11 gene, that might control FXI plasma levels and/or DVT risk. To this end, we investigated the regulation of the orthologous mouse gene cluster under several metabolic conditions that impact mouse hepatic F11 transcription. In livers of mice in which HNF4?, a key transcription factor controlling F11, was ablated, or reduced by siRNA, a strong decrease in hepatic F11 transcript levels was observed that correlated with Cyp4v3 (mouse orthologue of CYP4V2), but not by Klkb1 levels. Estrogens induced hepatic F11 and Cyp4v3, but not Klkb1 transcript levels, whereas thyroid hormone strongly induced hepatic F11 transcript levels, and reduced Cyp4v3, leaving Klkb1 levels unaffected. Mice fed a high-fat diet also had elevated F11 transcription, markedly paralleled by an induction of Klkb1 and Cyp4v3 expression. We conclude that within the mouse F11, Klkb1, Cyp4v3 gene cluster, F11 and Cyp4v3 frequently display striking parallel transcriptional responses suggesting the presence of shared regulatory elements.
Project description:Essentials Deep vein thrombosis (DVT) has a large unknown genetic component. We sequenced coding areas of 734 hemostasis-related genes in 899 DVT patients and 599 controls. Variants in F5, FGA-FGG, CYP4V2-KLKB1-F11, and ABO were associated with DVT risk. Associations in KLKB1 and F5 suggest a more complex genetic architecture than previously thought. SUMMARY: Background Although several genetic risk factors for deep vein thrombosis (DVT) are known, almost all related to hemostasis, a large genetic component remains unexplained. Objectives To identify novel genetic determinants by using targeted DNA sequencing. Patients/Methods We included 899 DVT patients and 599 controls from three case-control studies (DVT-Milan, Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis [MEGA], and the Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism [THE-VTE] study) for sequencing of the coding regions of 734 genes involved in hemostasis or related pathways. We performed single-variant association tests for common variants (minor allele frequency [MAF] ? 1%) and gene-based tests for rare variants (MAF ? 1%), accounting for multiple testing by use of the false discovery rate (FDR). Results Sixty-two of 3617 common variants were associated with DVT risk (FDR < 0.10). Most of these mapped to F5,ABO,FGA-FGG, and CYP4V2-KLKB1-F11. The lead variant at F5 was rs6672595 (odds ratio [OR] 1.58, 95% confidence interval [CI] 1.29-1.92), in moderate linkage with the known variant rs4524. Reciprocal conditional analyses suggested that intronic variation might drive this association. We also observed a secondary association at the F11 region: missense KLKB1 variant rs3733402 remained associated conditional on known variants rs2039614 and rs2289252 (OR 1.36, 95% CI 1.10-1.69). Two novel variant associations were observed, in CBS and MASP1, but these were not replicated in the meta-analysis data from the International Network against Thrombosis (INVENT) consortium. There was no support for a burden of rare variants contributing to DVT risk (FDR > 0.2). Conclusions We confirmed associations between DVT and common variants in F5,ABO,FGA-FGG, and CYP4V2-KLKB1-F11, and observed secondary signals in F5 and CYP4V2-KLKB1-F11 that warrant replication and fine-mapping in larger studies.
Project description:Elevated plasma concentrations of coagulation factor XI may increase risk of venous thromboembolism (VTE), but prospective data are limited. We studied prospectively the associations of plasma factor XI and a key F11 genetic variant with incident VTE in whites and African-Americans. We measured factor XI in 16,299 participants, initially free of VTE, in two prospective population cohorts. We also measured the F11 single nucleotide polymorphism rs4241824, which a genome-wide association study had linked to factor XI concentration. During follow-up, we identified 606 VTEs. The age, race, sex, and study-adjusted hazard ratio of VTE increased across factor XI quintiles (P?<?0.001 for trend), and the hazard ratio was 1.51 (95% CI 1.16, 1.97) for the highest versus lowest quintile overall, and was 1.42 (95% CI 1.03, 1.95) in whites and 1.72 (95% CI 1.08, 2.73) in African-Americans. In whites, the F11 variant was associated with both factor XI concentration and VTE incidence (1.15-fold greater incidence of VTE per risk allele). In African-Americans, these associations were absent. In conclusion, this cohort study documented that an elevated plasma factor XI concentration is a risk factor for VTE over extended follow-up, not only in whites but also in African-Americans. In whites, the association of the F11 genetic variant with VTE suggests a causal relation, but we did not observe this genetic relation in African-Americans.
Project description:OBJECTIVE:To explore the risk factors of perioperative deep vein thrombosis (DVT) in patients with traumatic fracture after orthopaedic surgery and their potential diagnostic values in clinical. DESIGN:Retrospective cohort study. SETTING:Clinical Laboratory of Honghui Hospital, Xi'an JiaoTong University College of Medicine, Xi'an, Shaanxi, China. MATERIALS AND METHODS:A retrospective cohort study was conducted with surgically treated fracture patients in Honghui Hospital from 1 May 2016 to 31 February 2017. χ 2 test, independent sample t test and regression analysis were applied to examine the correlation between perioperative DVT and the factors of preoperative time, fracture sites, D-dimer value and chronic diseases (hypertension, diabetes and coronary disease). RESULTS:462 patients were enrolled for analysis. The preoperative time of patients with DVT was significantly longer than that of non-DVT patients (7.14±5.51 vs 5.45±3.75) (P<0.01). χ 2 test showed the significant differences in the rate of DVT among patients with different fracture sites (P<0.01). By the receiver-operating characteristic curve analysis, the cut-off value of preoperative D-dimer and postoperative D-dimer in diagnosing perioperative DVT was 4.01 µg/mL and 5.03 µg/mL, respectively. Area under the curve was 0.593 (95% CI 0.533 to 0.652) and 0.728 (95% CI 0.672 to 0.780), respectively. The sensitivity and specificity of preoperative D-dimer for DVT diagnosis were 71.30% and 44.83%, and as for postoperative D-dimer were 63.90% and 70.51%. CONCLUSIONS:Fracture site was correlated to the incidence of DVT; prolonged preoperative time and increased D-dimer value were independent risk factors for DVT in patients with lower extremity traumatic fractures.
Project description:Objective: The study aimed to explore the associations of rs4988300 and rs634008 in the low-density lipoprotein receptor-related protein 5 (LRP5) gene with bone mineral density (BMD), bone turnover markers (BTM), and fractures in elderly patients with osteoporosis (OP). Methods: Our study included 328 unrelated OP patients with or without fractures. Genomic DNA was extracted for genotyping. BTM levels were assessed by electrochemiluminescence (ECL). Dual-energy X-ray absorptiometry (DXA) was employed to measure BMD in the lumbar spine (LS) and proximal femur. Basic features between the OP and fracture groups were analyzed using the t-test. The Chi-square test was performed to analyze the differences in allele and genotype frequencies. The associations of single-nucleotide polymorphisms (SNPs) with BMD and BTM in the subgroups were investigated by the analysis of covariance (ANCOVA) adjusted for confounding factors. Results: In both females and males, individuals with fractures exhibited higher BTM levels and lower BMD values than those with OP (P < 0.05). The allele and genotype frequencies of rs4988300 in the subgroups were significantly different (P < 0.05). In both females and males suffering from OP, participants with rs4988300 GG or rs634008 TT presented lower procollagen I N-terminal propeptide (PINP) levels (P < 0.05). Women with OP carrying rs4988300 GG exhibited lower BMD values at FN and TH (P < 0.05). In both females and males with fractures, individuals carrying rs4988300 GG genotype or rs634008 TT genotype exhibited lower PINP levels and BMD values at FN and TH than those with other genotypes (P < 0.05). Conclusions: Rs4988300 and rs634008 polymorphisms in the LRP5 gene are associated with bone phenotypes in the elderly with OP or fractures.
Project description:BACKGROUND The purpose of the study was to investigate the correlation between rs4754 and rs6840362 polymorphisms of secreted phosphoprotein 1 (SPP1) gene and fracture risk. MATERIAL AND METHODS rs4754 and rs6840362 were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 130 patients with fracture and 107 healthy controls matched with the former by age and sex. Hardy-Weinberg equilibrium (HWE) was assessed in the control group based on the genotype distributions of SSP1 poylmorphisms. The differences in genotype, allele, and haplotype frequencies between cases and controls were detected by the chi-square test, and the relative risk of fracture is expressed by odds ratio (OR) and 95% confidence interval (CI). The linkage disequilibrium (LD) and haplotype analyses were conducted with HaploView software. RESULTS The TT genotype in rs4754 had significant difference in patients with fracture and controls (10.77% and 4.59%, P=0.04) and the results showed that people carrying TT genotype of rs4754 were more susceptible to fractures than CC genotype carriers (OR=3.00, 95%CI=1.02-8.89). The T allele also had 1.54 times higher risk of fractures (OR=1.54, 95%CI=1.04-2.30), but this was not true for the rs6840362 polymorphism. LD between the 2 polymorphisms and haplotype C-T (rs6840362-rs4754) increased the susceptibility to fracture (OR=2.01, 95%CI=1.23-3.28). CONCLUSIONS SPP1 rs4754 polymorphism may be related to risk of fracture, but not rs6840362.
Project description:The COLIA1 Sp1 polymorphism has been associated with bone mineral density (BMD) and fracture. A promoter polymorphism, -1997 G/T, also has been associated with BMD. In this study, we examined whether these polymorphisms alone and in the form of haplotypes influence bone parameters and fracture risk in a large population-based cohort of elderly Caucasians. We determined the COLIA1 -1997 G/T (promoter) and Sp1 G/T (intron) polymorphisms in 6,280 individuals and inferred haplotypes. Femoral neck BMD and BMD change were compared across COLIA1 genotypes at baseline and follow-up (mean 6.5 years). We also investigated the relationship between the COLIA1 polymorphisms and incident nonvertebral fractures, which were recorded during a mean follow-up period of 7.4 years. Vertebral fractures were assessed by radiographs on 3,456 genotyped individuals. Femoral neck BMD measured at baseline was 3.8% lower in women carrying two copies of the T-Sp1 allele (P for trend = 0.03). No genotype dependent differences in BMD loss were observed. In women homozygous for the T allele of the Sp1 polymorphism, the risk of fragility fracture increased 2.3 times (95% confidence interval 1.4-3.9, P = 0.001). No such association was observed with the promoter polymorphism. In men, no association with either the Sp1 or the -1997 G/T promoter polymorphism was seen with BMD or fracture. High linkage disequilibrium (LD; D' = 0.99, r (2 )= 0.03) exists between the two studied polymorphisms. We observed three haplotypes in our population: haplotype 1 (G(promoter)-G(intron)) frequency (f) = 69%, haplotype 2 (G(promoter)-T(intron)) f = 17.6%, and haplotype 3 (T(promoter)-G(intron)) f = 13.4%. Haplotype 2 was associated with a 2.1-fold increased risk of fragility fracture in women (95% confidence interval 1.2-3.7, P = 0.001). We confirm that the COLIA1 Sp1 polymorphism influences BMD and the risk of fracture in postmenopausal Caucasian women. In contrast, we found no independent effect of the -1997 G/T promoter polymorphism on BMD or fracture.
Project description:This study aims to identify specific miRNAs profiles in osteoporotic patients with and without vertebral fractures. MiRNAs array analysis was performed on the plasma samples including a pool of 6 miRNA samples from osteoporotic patients with vertebral fractures, a pool of 6 miRNA samples from osteoporotic patients without fracture and another pool of 6 miRNA samples from nonosteoporotic patients to identify regulated miRNAs in the plasma. Overall design: In the study presented here, a pool of 6 miRNA samples from osteoporotic patients with vertebral fractures, a pool of 6 miRNA samples from osteoporotic patients without fracture and another pool of 6 miRNA samples from nonosteoporotic patients were analyzed to identify regulated miRNAs in the plasma.
Project description:Rare mutations in PROC, PROS1 or SERPINC1 as well as common variants in F5, F2, F11 and SERPINC1 have been identified as risk factors for deep vein thrombosis (DVT). To identify novel genetic risk factors for DVT, we have developed and applied next-generation DNA sequencing (NGS) of the coding area of hemostatic and proinflammatory genes. Using this strategy, we previously identified a single nucleotide variant (SNV) rs6050 in the FGA gene and novel, rare SNVs in the ADAMTS13 gene associated with DVT. To identify novel coding variants in the genetic predisposition to DVT, we applied NGS analysis of the coding area of 186 hemostatic and proinflammatory genes in 94 DVT cases and 98 controls and we identified 18 variants with putative role in DVT. A group of 585 Italian idiopathic DVT patients and 550 healthy controls was used to genotype all the 18 risk-associated variants identified by NGS. Replication study in the Italian population identified the rs2232710 variant in the protein Z-dependent protease inhibitor (ZPI) gene to be associated with an increased risk of DVT (OR 2.74; 95% CI 1.33-5.65; P = 0.0045; Bonferroni P = 0.081). However, the rs2232710 SNV showed no association with DVT in two Dutch replication cohorts the LETS study (454 patients and 451 controls) and the MEGA study (3799 patients and 4399 controls), indicating that the rs2232710 variant is not a risk factor for DVT.
Project description:As the mandible is susceptible to fracture, the aim of this study was to use multivariate logistic regression analysis to identify and distinguish various internal factors that may influence the location of mandibular fractures. The study included 1131 patients with maxillofacial fractures during the period from January 2000 to December 2009 to evaluate the association of mandibular fracture location (unilateral symphysis, body, angle, condylar, or bilateral condylar fractures) with various internal factors. Among the 1131 patients, 869 had mandibular fractures. Data on age, sex, soft tissue injuries, dental trauma, and maxillofacial fracture type were collected and analyzed using multivariate logistic regression. In total, 387, 210, 139, 319, and 172 patients were diagnosed with unilateral symphysis, body, angle, unilateral, or bilateral condylar fractures, respectively. The dental trauma in patients with bilateral condylar fractures differed from that in patients with unilateral condylar fractures. Patients with mandibular fracture (unilateral symphysis, body, unilateral or bilateral condylar) possessed an approximately equal risk of soft tissue injuries in the mandible. Patients with either unilateral or bilateral condylar fractures were associated with a low risk of mandibular angle fracture (OR < 1). Similarly, patients with mandibular angle fracture were associated with a low risk of unilateral or bilateral condylar fractures (OR < 1). Moreover, patients with symphysis fracture were associated with a low risk of bilateral condylar fractures (90 of 387 [23.3%], OR 0.899). By contrast, patients with bilateral condylar fractures were associated with a high risk of symphysis fracture (90 of 172 [52.3%], OR 17.38). Patients with condylar fractures, particularly those with bilateral condylar fractures, were infrequently associated with secondary mandibular fractures. Mandibular fractures tended to have less of an association with midfacial fractures. The occurrence of mandibular fractures is strongly correlated with age, sex, soft tissue injuries, dental trauma, and the pattern and position of the maxillofacial fractures in patients.