scholarly journals Prothrombin Arg541Trp Mutation Leads to Defective PC (Protein C) Pathway Activation and Constitutes a Novel Genetic Risk Factor for Venous Thrombosis

2020 ◽  
Vol 40 (2) ◽  
pp. 483-494 ◽  
Author(s):  
Xi Wu ◽  
Jing Dai ◽  
Xiaoqian Xu ◽  
Fang Li ◽  
Lei Li ◽  
...  
Keyword(s):  
Risk Factor ◽  
Family History ◽  
Venous Thrombosis ◽  
Genetic Risk ◽  
Protein C ◽  
Positive Family History ◽  
Genetic Risk Factor ◽  
Procoagulant Activity ◽  
Factor V Leiden Mutation ◽  
History Of

Objective: Defective PC (protein C) pathway predisposes patients to venous thromboembolism (VTE) and is mostly, but not exclusively, attributed to hereditary PC or PS (protein S) deficiencies and activated PC resistance caused by factor V Leiden mutation. Approach and Results: In a patient with acute mesenteric venous thrombosis and positive family history of VTE associated with the impaired PC pathway function determined by thrombin generation test, we identified a novel heterozygous prothrombin mutation p.Arg541Trp. Two more patients with positive family history of VTE carrying the same mutation were identified in a cohort of another 373 unrelated patients, making an overall prevalence of 0.8%. Family investigation revealed 11 individuals in the 3 pedigrees harboring the heterozygous prothrombin p.Arg541Trp mutation, and 8 of them (72%) had experienced episodes of VTE. Functional studies indicated the mutation moderately decreased procoagulant activity of prothrombin and had mild impact on the inactivation of thrombin by its inhibitor antithrombin. However, the amino acid residue substitution significantly compromised PC activation by thrombin, both in the absence and presence of soluble thrombomodulin, and thus rendered prothrombin function procoagulant biased. Conclusions: In summary, the prothrombin p.Arg541Trp mutation constitutes a new genetic risk factor of VTE by impairing function of PC pathway and tilting thrombin’s procoagulant activity over anticoagulant function.

scholarly journals Prothrombin R541W Mutation Impairs Protein C Activation and Constitutes a New Genetic Risk Factor for Venous Thrombosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 442-442
Author(s):  
XI WU ◽  
Dai Jing ◽  
Fang Li ◽  
Qin Xu ◽  
Changming Chen ◽  
...  
Keyword(s):  
Risk Factor ◽  
Family History ◽  
Venous Thrombosis ◽  
Genetic Risk ◽  
Protein C ◽  
Patent Application ◽  
Positive Family History ◽  
Procoagulant Activity ◽  
School Of Medicine ◽  
History Of

Defective protein C (PC) pathway predisposes patients to venous thromboembolism (VTE)and is mostly, but not exclusively, attributed tohereditary PC or protein S (PS) deficiencies and activated PC resistance caused by factor V Leiden mutation. In a patient with acute mesenteric venous thrombosis and positive family history of VTE associated with the impaired PC pathway function determined by thrombin generation test, we identified a novel heterozygous prothrombin mutation p.Arg541Trp. Two more patients with positive family history of VTE carrying the same mutation were identified in a cohort of another 373 unrelated patients, making an overall prevalence of 0.8%. Family investigation revealed 11 individuals in the three pedigrees harboring the heterozygous prothrombin p.Arg541Trp mutation, and 8 of them (72%) had experienced episodes of VTE. Functional studies indicated the mutation moderately decreased procoagulant activity of prothrombin and had mild impact on the inactivation of thrombin by its inhibitor antithrombin. However, the amino acid residue substitution significantly compromised PC activation by thrombin, both in the absence and presence of soluble thrombomodulin, and thus rendered prothrombin function procoagulant biased. In conclusion, the prothrombin p.Arg541Trp mutation constitutes a new genetic risk factor of VTE by impairing function of PC pathway and tilting thrombin's procoagulant activity over anticoagulant function. Figure Disclosures Ding: Shanghai General Hospital affiliated to Shanghai Jiao Tong University, Shanghai: Patents & Royalties: W.W, Q.D and X.W of the co-authors are named as inventors on a patent application related to this work.. Wang:Ruijin Hospital, Shanghai Jiao Tong University School of Medicine: Patents & Royalties: W.W, Q.D and X.W of the co-authors are named as inventors on a patent application related to this work.. WU:Ruijin Hospital, Shanghai Jiao Tong University School of Medicine: Patents & Royalties: W.W, Q.D and X.W of the co-authors are named as inventors on a patent application related to this work..

Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives

Blood ◽  
2009 ◽  
Vol 113 (21) ◽  
pp. 5314-5322 ◽  
Author(s):  
Willem M. Lijfering ◽  
Jan-Leendert P. Brouwer ◽  
Nic J. G. M. Veeger ◽  
Ivan Bank ◽  
Michiel Coppens ◽  
...  
Keyword(s):  
Family History ◽  
Venous Thrombosis ◽  
Protein C ◽  
Positive Family History ◽  
Protein S ◽  
Factor V ◽  
Recurrence Rates ◽  
Thrombotic Risk ◽  
History Of ◽  
Fv Leiden

Abstract Thrombophilia screening is controversial. In a retrospective family cohort, where probands had thrombosis and a thrombophilic defect, 2479 relatives were tested for thrombophilia. In antithrombin-, protein C–, and protein S–deficient relatives, annual incidences of venous thrombosis were 1.77% (95% CI, 1.14-2.60), 1.52% (95% CI, 1.06-2.11), and 1.90% (95% CI, 1.32-2.64), respectively, at a median age of 29 years and a positive family history of more than 20% symptomatic relatives. In relatives with factor V (FV) Leiden, prothrombin 20210G>A, or high FVIII levels, these were 0.49% (95% CI, 0.39-0.60), 0.34% (95% CI, 0.22-0.49), and 0.49% (95% CI, 0.41-0.51), respectively. High FIX, FXI, and TAFI, and hyperhomocysteinemia were not independent risk factors. Annual incidence of major bleeding in antithrombin-, protein C–, or protein S–deficient relatives on anticoagulants was 0.29% (95% CI, 0.03-1.04). Cumulative recurrence rates in relatives with antithrombin, protein C, or protein S deficiency were 19% at 2 years, 40% at 5 years, and 55% at 10 years. In relatives with FV Leiden, prothrombin 20210G>A, or high levels FVIII, these were 7%, 11%, and 25%, respectively. Considering its clinical implications, thrombophilia testing should address hereditary deficiencies of antithrombin, protein C, and protein S in patients with first venous thrombosis at young age and/or a strong family history of venous thrombosis.

scholarly journals Egg Allergy in infancy

1970 ◽  
Vol 9 (1) ◽  
pp. 28-30
Author(s):  
R Shrestha ◽  
D Shrestha ◽  
R Poudyal ◽  
N Mishra
Keyword(s):  
Risk Factor ◽  
Contact Dermatitis ◽  
Family History ◽  
Positive Family History ◽  
Egg White ◽  
Oral Exposure ◽  
Allergic Reactions ◽  
Egg Allergy ◽  
History Of

Egg allergies are one of the most common allergies of childhood and the reactions may vary from mild to severe. A family history of egg allergy or atopy is a risk factor for egg allergy. Most food-induced allergic reactions occur on first known oral exposure, especially in the case of eggs and peanuts. We report a case of nine months old infant who developed egg allery (contact dermatitis) after contact with egg white, with a positive family history of atopy and egg allergy. Keywords Egg allergy; contact dermatitis; infancy. DOI: http://dx.doi.org/10.3126/njdvl.v9i1.5766 NJDVL 2010; 9(1): 28-30

scholarly journals Positive family history of thyroid disease as a risk factor for differentiated thyroid carcinoma

2011 ◽  
Vol 121 (12) ◽  
pp. 441-447 ◽  
Author(s):  
Elwira Przybylik-Mazurek ◽  
Dorota Pach ◽  
Sylwia Kuźniarz-Rymarz ◽  
Marta Tracz-Bujnowicz ◽  
Krystyna Szafraniec ◽  
...  
Keyword(s):  
Risk Factor ◽  
Family History ◽  
Thyroid Carcinoma ◽  
Thyroid Disease ◽  
Positive Family History ◽  
Differentiated Thyroid Carcinoma ◽  
History Of

scholarly journals Parkinson’s disease determinants, prediction and gene–environment interactions in the UK Biobank

2020 ◽  
Vol 91 (10) ◽  
pp. 1046-1054 ◽  
Author(s):  
Benjamin Meir Jacobs ◽  
Daniel Belete ◽  
Jonathan Bestwick ◽  
Cornelis Blauwendraat ◽  
Sara Bandres-Ciga ◽  
...  
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Family History ◽  
Genetic Risk ◽  
Positive Family History ◽  
Risk Scores ◽  
Uk Biobank ◽  
Gene Environment ◽  
History Of

ObjectiveTo systematically investigate the association of environmental risk factors and prodromal features with incident Parkinson’s disease (PD) diagnosis and the interaction of genetic risk with these factors. To evaluate whether existing risk prediction algorithms are improved by the inclusion of genetic risk scores.MethodsWe identified individuals with an incident diagnosis of PD (n=1276) and controls (n=500 406) in UK Biobank. We determined the association of risk factors with incident PD using adjusted logistic regression models. We constructed polygenic risk scores (PRSs) using external weights and selected the best PRS from a subset of the cohort (30%). The PRS was used in a separate testing set (70%) to examine gene–environment interactions and compare predictive models for PD.ResultsStrong evidence of association (false discovery rate <0.05) was found between PD and a positive family history of PD, a positive family history of dementia, non-smoking, low alcohol consumption, depression, daytime somnolence, epilepsy and earlier menarche. Individuals with the highest 10% of PRSs had increased risk of PD (OR 3.37, 95% CI 2.41 to 4.70) compared with the lowest risk decile. A higher PRS was associated with earlier age at PD diagnosis and inclusion of the PRS in the PREDICT-PD algorithm led to a modest improvement in model performance. We found evidence of an interaction between the PRS and diabetes.InterpretationHere, we used UK Biobank data to reproduce several well-known associations with PD, to demonstrate the validity of a PRS and to demonstrate a novel gene–environment interaction, whereby the effect of diabetes on PD risk appears to depend on background genetic risk for PD.

scholarly journals A Novel Genetic Risk Factor for Venous Thrombosis

2011 ◽  
Vol 57 (4) ◽  
pp. 637-638
Author(s):  
Rogier M Bertina ◽  
Hans L Vos
Keyword(s):  
Risk Factor ◽  
Venous Thrombosis ◽  
Genetic Risk ◽  
Genetic Risk Factor

Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and venous thrombosis

2007 ◽  
Vol 97 (06) ◽  
pp. 907-913 ◽  
Author(s):  
Argirios Tsantes ◽  
Pantelis Bagos ◽  
Evdoxia Rapti ◽  
Georgios Mantzios ◽  
Violeta Kapsimali ◽  
...  
Keyword(s):  
Risk Factor ◽  
Venous Thrombosis ◽  
Plasminogen Activator ◽  
Genetic Risk ◽  
Plasminogen Activator Inhibitor ◽  
Genetic Risk Factor ◽  
Published Data ◽  
Antiphospholipid Antibody ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor

SummaryThe effect of the 675 insertion/deletion (4G/5G) polymorphism of plasminogen activator inhibitor-1 (PAI-1) gene on the risk of venous thromboembolism (VTE) remains controversial. In this study, we performed a meta-analysis of published data regarding this issue. A comprehensive electronic search was carried out up until September 2006. A total of 22 articles were included in the analysis that was performed using random effects models. Eighteen papers, concerning patients without another known risk factor, comprised 2,644 cases and 3,739 controls. The alleles contrast (4G vs. 5G allele) yielded a statistically significant odds ratio (OR) of 1.153 (95% confidence interval [CI]: 1.068–1.246). In a sub-analysis of five studies that included 256 cases with another genetic risk factor and 147 controls, the combined per-allele OR was still significant (OR:1.833,95% CI:1.325–2.536). On the contrary, the analysis of five studies regarding cases with a non-genetic risk factor for VTE (antiphospholipid antibody syndrome, Behcet disease) provided insignificant results in all aspects. There was no evidence for heterogeneity and publication bias in all analyses. Based on our findings, the 4G allele appears to increase the risk of venous thrombosis, particularly in subjects with other genetic thrombophilic defects. Recommendation for detection of this polymorphism in evaluating thrombophilia in such patients might be considered.

scholarly journals PROCc.574_576del polymorphism: a common genetic risk factor for venous thrombosis in the Chinese population

2012 ◽  
Vol 10 (10) ◽  
pp. 2019-2026 ◽  
Author(s):  
L. TANG ◽  
X. LU ◽  
J. M. YU ◽  
Q. Y. WANG ◽  
R. YANG ◽  
...  
Keyword(s):  
Risk Factor ◽  
Venous Thrombosis ◽  
Genetic Risk ◽  
Chinese Population ◽  
Genetic Risk Factor

scholarly journals Factores de riesgo genético y diagnóstico prenatal

2021 ◽  
Vol 81 (03) ◽  
pp. 209-225
Author(s):  
Alisandra Morales de Machín ◽  
Karelis Urdaneta ◽  
Lisbeth Borjas ◽  
Karile Méndez ◽  
Enrique Machín ◽  
...  
Keyword(s):  
Risk Factors ◽  
Risk Factor ◽  
Genetic Counseling ◽  
Genetic Risk ◽  
Diagnostic Procedures ◽  
Genetic Risk Factors ◽  
Genetic Risk Factor ◽  
Congenital Defects ◽  
Prenatal Diagnostic ◽  
History Of

Objective: To identify genetic risk factors and frequency and to describe congenital defects of the fetus. Methods: The research was conducted at the Genetic Research Institute of the Faculty of Medicine. University of Zulia. Maracaibo. We studied patients who attend to the prenatal genetic clinic. According to the Genetic risk factors Identified, it indicated different prenatal diagnostic procedures: fetal echography, fetal echocardiography, triple maternal serum marker, amniocentesis for fetal karyotype and molecular analysis. Results: We included 568 patients. 79.05% of the total showed only one genetic risk factor and the 20.95% two or more. The advanced maternal age was the most frequent genetic risk factor found (40.85%), followed by first-degree family history with a congenital defect (35.21%), abnormal fetal echography (13.73%), exposure to teratogenic agents (10.39%), history of recurrent abortion (7.04%), history of fetal death (4.22%), consanguinity (1.93%), and history of neonatal death (1.76%). They were diagnosed 101 fetuses with congenital defects, one balanced translocation, two fetal deaths and 26 spontaneous abortions. Conclusion: The genetic risk factors identification, served as a starting point to indicate prenatal diagnostic procedures allowed a health evaluation of the fetus and adequate genetic counseling. Key words: Prenatal diagnosis, Risk factors, Genetic counseling.

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