The genetics of venous thromboembolism

Gohil, Reya; Peck, George; Sharma, Pankaj

doi:10.1160/th09-01-0013

Cited by 171 publications

(41 citation statements)

References 174 publications

(97 reference statements)

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“…Identification of genetic determinants for D-dimer levels might aid risk prediction and stratification in clinical practice, and the minor alleles in F5 and FGA are associated with increased risk of venous thromboembolism [33-34]. However, based on our current understanding of D-dimer genetics, it is not practical to simply measure SNPs identified for D-dimer levels to predict new and recurrent venous thromboembolism, because all of the SNPs identified in this and the other studies explained at most 2% of total variance in D-dimer levels.…”

Section: Discussionmentioning

confidence: 99%

A genetic association study of D-dimer levels with 50K SNPs from a candidate gene chip in four ethnic groups

Weng

Tang

Rich

et al. 2014

Thrombosis Research

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Introduction D-dimer, a fibrin degradation product, is related to risk of cardiovascular disease and venous thromboembolism. Genetic determinants of D-dimer are not well characterized; notably, few data have been reported for African American (AA), Asian, and Hispanic populations. Materials and Methods We conducted a large-scale candidate gene association study to identify variants in genes associated with D-dimer levels in multi-ethnic populations. Four cohorts, comprising 6,848 European Americans (EAs), 2,192 AAs, 670 Asians, and 1,286 Hispanics in the NHLBI Candidate Gene Association Resource (CARe) consortium, were assembled. Approximately 50,000 genotyped SNPs in 2,000 cardiovascular disease gene loci were analyzed by linear regression, adjusting for age, sex, study site, and principal components in each cohort and ethnic group. Results across studies were combined within each ethnic group by meta-analysis. Results Twelve SNPs in coagulation factor V (F5) and 3 SNPs in the fibrinogen alpha chain (FGA) were significantly associated with D-dimer level in EAs with p < 2.0×10−6. The signal for the most associated SNP in F5 (rs6025, F5 Leiden) was replicated in Hispanics (p = 0.023), while that for the top functional SNP in FGA (rs6050) was replicated in AAs (p = 0.006). No additional SNPs were significantly associated with D-dimer. Conclusions Our study replicated previously reported associations of D-dimer with SNPs in F5 (F5-Leiden) and FGA in EAs; we demonstrated replication of the association of D-dimer with FGA rs6050 in AAs and the F5-Leiden variant in Hispanics.

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Section: Discussionmentioning

confidence: 99%

A genetic association study of D-dimer levels with 50K SNPs from a candidate gene chip in four ethnic groups

Weng

Tang

Rich

et al. 2014

Thrombosis Research

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“…A meta-analysis of 53 studies of a total of 8,364 cases found an association between the 677TT genotype and higher VTE risk, especially in non-American studies [10]. Likewise, another meta-analysis involving approximately 120,000 cases and 180,000 controls found a significant 57% increased risk of VTE in C677T homozygotes compared with heterozygotes and wild-types, in a Chinese population, whereas in Caucasians no significant association was found [11]. The MTHFR A1298C polymorphism is less well characterized but also reported to lead to increased VTE risk in the Iranian population [12].…”

Section: Introductionmentioning

confidence: 99%

MTHFR A1298C and C677T Polymorphisms Are Associated with Increased Risk of Venous Thromboembolism: A Retrospective Chart Review Study

et al. 2017

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Background: Methylene tetrahydrofolate reductase (MTHFR) is a key enzyme in homocysteine metabolism. This study aims to determine the impact of MTHFR polymorphisms on plasma homocysteine levels and risks of venous thromboembolism (VTE). Methods: This retrospective chart review study included a total of 188 subjects who were tested for MTHFR polymorphisms at Metrowest Coagulation Laboratory between April 2011 and April 2016. Two independent coders were trained to extract relevant clinical data for statistical analysis. Results: VTE occurred in 50% of patients with compound mutation, compared with only 28.6% of subjects from the wild-type group. Patients with heterozygous or homozygous A1298C or C677T variants had an intermediate risk of VTE. The median homocysteine level in the wild-type group was slightly lower than that of heterozygous or homozygous MTHFR variants. The difference, however, was not significant (p = 0.6193). Moreover, there was no difference in plasma homocysteine level between patients with VTE versus VTE-free (p = 0.4923). Conclusions: Heterozygous or homozygous MTHFR variants, especially a compound mutation, are associated with increased risk of VTE. Hyperhomocysteinemia does not correlate with MTHFR polymorphisms or VTE risk. Hence, MTHFR genotyping provides more consistent assessment of VTE risk. This information can be incorporated into risk stratification for early intervention and prophylaxis of VTE.

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“…More recently, a common F2 SNP (rs3136516 - A19911G) was also reported to be associated with increased plasma prothrombin activity and thrombosis risk in Caucasians, although at a lesser degree (27, 28, 41). Large studies and meta-analysis suggested that the rs3136516 G allele is associated with a slight increase in prothrombin activity and thrombotic risk (26, 42, 43). Prior studies (13, 26–28) indicated that chromosomes carrying the rs1799963 A allele almost always had the rs3136516 A allele, which was also confirmed in our study.…”

Section: Discussionmentioning

confidence: 99%

Functional Polymorphisms of the Coagulation Factor II Gene (F2) and Susceptibility to Systemic Lupus Erythematosus

et al. 2011

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Objective Two F2 functional polymorphisms, rs1799963 (G20210A) and rs3136516 (A19911G), are known to be associated with elevated prothrombin (encoded by F2) levels/activity and thrombosis risk. Since systemic lupus erythematosus (SLE) patients have high risk of thrombosis and accelerated atherosclerosis and also high prevalence of anti-prothrombin antibodies, we hypothesized that these two F2 polymorphisms could affect SLE risk. Methods We investigated these polymorphisms in 627 women with SLE (84% Caucasian Americans, 16% African Americans) and 657 female controls (78% Caucasian Americans, 22% African Americans). Results While the rs1799963 A allele was almost absent in African Americans, it was present at ~2% frequency in Caucasian Americans and showed no significant association with SLE. The rs3136516 G allele frequency was significantly higher in Caucasian SLE cases than controls (48.4% vs. 43.7%) with a covariate-adjusted odds ratio (OR) of 1.22 (95%CI: 1.03–1.46; P = 0.023). The association was replicated in African Americans (rs3136516 G allele frequency: 91.2% in cases vs. 82.2% in controls) with an adjusted OR of 1.96 (95%CI: 1.08–3.58; P = 0.022). Stratification of Caucasian SLE patients based on the presence or absence of cardiac and vascular events (CVE) revealed stronger association with the CVE-positive SLE subgroup than the CVE-negative SLE subgroup (OR: 1.42 vs. 1.20). Prothrombin activity measurements in a subset of SLE cases demonstrated higher activity in the carriers of the rs3136516 G allele. Conclusion Our results suggest a potential role for prothrombin and the crosstalk between hemostatic and immune/inflammatory systems in SLE and SLE-associated cardiovascular events, which warrant further investigation in independent samples.

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The genetics of venous thromboembolism

Cited by 171 publications

References 174 publications

A genetic association study of D-dimer levels with 50K SNPs from a candidate gene chip in four ethnic groups

A genetic association study of D-dimer levels with 50K SNPs from a candidate gene chip in four ethnic groups

MTHFR A1298C and C677T Polymorphisms Are Associated with Increased Risk of Venous Thromboembolism: A Retrospective Chart Review Study

Functional Polymorphisms of the Coagulation Factor II Gene (F2) and Susceptibility to Systemic Lupus Erythematosus

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