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Abstract

Introduction

Study aimed to determine the occurrence of 5 thrombosis-related single-nucleotide polymorphisms (SNPs) in patients with venous thromboembolism (VTE) (n = 2630) and a control group (n = 2637) in the Czech population.

Methods

The following gene SNPs were detected in both groups: F5 Leiden (rs6025), F2 (rs1799963), FGG, fibrinogen gamma' (rs2066865), F11 (rs2289252) and ABO (rs8176719). Statistical analysis was performed using SAS statistical software with population genetics tools.

Results

Heterozygotes for F5 Leiden were associated with a 5.58-fold and homozygotes F5 Leiden with a 33.46-fold increased risk of VTE. At SNP rs1799963 (F2, prothrombin), only heterozygotes had a significant 3.9-fold increased risk of VTE. The findings at SNP rs2066865 (fibrinogen gamma', FGG) showed a 1.37-fold increased risk of VTE for FGG heterozygotes and a 1.77-fold increased risk of VTE for FGG homozygotes. There is also a significant 1.42-fold increase risk of VTE in the heterozygotes and a 1.80-fold increase risk of VTE in the homozygotes of the SNP rs 2289252 (F11). Further higher increases in the risk of VTE in both variants were found in patients with VTE at rs8176719 (ABO, non-O). It corresponds to a 2.2-fold increase in the risk of VTE in heterozygotes and a 3.5-fold increase in the risk of VTE in homozygotes.

Conclusion

Besides F5 Leiden and prothrombin mutation, the study suggests that the gene polymorphisms of FGG (rs2066865), F11 (rs2289252) and ABO (rs8176719) play a role as an independent heritable risk factor for VTE in the Czech population.

Keywords

venous thromboembolism rs6025 rs1799963 rs2066865 rs2289252 rs8176719

Introduction and Study aim

In Europe, approximately 500,000 people die each year from complications of VTE, even though this disorder can be prevented with appropriate prophylaxis.¹ The incidence of VTE is still relatively high, with 148 cases of venous thrombosis and 95 cases of acute pulmonary embolism per 100,000 individuals occurring each year.² It is the third most common disease and the third leading cause of death from cardiovascular disease.³ The lifetime risk of VTE is also relatively high,⁴ likely due to the increasing prevalence of obesity, cancer, and ageing populations.⁵ However, the course of VTE is not stationary, and anticoagulation therapy may not influence its dynamics. After acute venous thrombosis, many patients develop post-thrombotic syndrome, which clinically manifests as varying degrees of chronic venous insufficiency.⁶ The most severe complication of acute venous thrombosis, however, is acute pulmonary embolism (PE). Its incidence is approximately 100 per 100,000 population per year.⁷ Another serious complication of embolization into the pulmonary circulation is chronic thromboembolic pulmonary hypertension (CTEPH), which occurs with a certain time lag in 2%–4% of patients with PE. Without treatment, the prognosis for CTEPH is poor, with historical data showing mortality rates of 70%–90% after 5 years.⁸ Another complication of PE is the so-called post-pulmonary syndrome, manifested as new or progressive dyspnea and exercise intolerance after the end of anticoagulation therapy.⁹ Up to 31% of cases of VTE recur after the first episode, too.¹⁰ A higher number of recurrences is observed in so-called unprovoked VTE,¹¹ which leads to a tendency to prolong anticoagulation therapy.¹² The reason for this is also the increased mortality (up to 34%) observed in patients with recurrent VTE.¹³ The goal of effective treatment to reduce the incidence and complications of VTE, including its recurrence, may therefore be individualized prevention in the future. The disease itself is multifactorial,¹⁴ with many acquired, but also hereditary risk factors and varying prevalence among different ethnic groups.¹⁵ Since 2008, newly published results of genome-wide association studies (GWAS) have included the examination of hundreds of thousands to millions of known SNPs in cohorts of tens of thousands to hundreds of thousands of individuals who have had VTE and controls that have not had VTE.^16–22 With the gradual increase in the number of identified SNPs and participants in new GWAS, dozens of the latest genetic associations with VTE have been discovered, mainly with a small impact on their risk. Therefore, the selection criterion for their use was set to require alleles associated with VTE to reach statistical significance in GWAS.²³ In addition to the F5 Leiden and prothrombin gene mutation, which Manuzzi et al²⁴ already consider "classic polymorphisms" associated with the risk of VTE, this requirement was met only by newly discovered SNPs in the fibrinogen gamma' gene /FGG/ (rs2066895), F11 gene (rs2289252), and ABO gene /non-O/ (rs8176719), which were repeatedly identified in the GWAS above and their recent meta-analyses in European population. Their overview is presented in Table 1.

Table 1.

An Overview of Five Single Nucleotide Polymorphisms (SNPs) Associated with Venous Thromboembolism as Reported in Studies Conducted Within the European Population.

Chromosome	Gene	SNP				Reference
			(16)	(17)	(18)	(19)	(20)	(21)	(22)
1	F5	rs6025	X	X	X	X	X	X	X
11	F2	rs1799963	X	X	X	/	X	X	X
4	FGG	rs2066865	X	X	X	X	X	/	X
4	F11	rs2289252	X	*	*	X	*	X	X
9	ABO	rs8176719	X	X	X	X	*	/	X

Studies			MEGA	MEGA	UK Biobank	INVENT	13 GWAS	6 GWAS	ARIC
			LETS	GWAS	GWAS	18 GWAS	metaanalyse	metaanalyse	GWAS
					metaanalyse	metaanalyse

X indicates that the SNP was tested; /, the SNP was not tested; *, the next SNP in the gene was tested; GWAS, genome-wide association study;

ARIC, Atheroslerosis Risk in Communities Study; INVENT, International Network Against Venous Thrombosis; LETS;

Leiden Thrombophilia Study; MEGA, Multiple Environmental and Genetic Assessment Study

However, this is no longer true for the Asian population^25,26 or American blacks.²²

Our study aimed to determine the prevalence of these 5 SNPs in patients with VTE compared to their findings in individuals who did not have VTE in the Czech population, which as an ethnic group is referred to as the European Western Slavic population.

Methods

The sample consisted of 2630 patients with VTE, including 2143 patients registered at the Thrombotic Center of the Institute of Clinical Biochemistry and Laboratory Diagnostics of the General University Hospital and the First Faculty of Medicine of Charles University in Prague. This registry included adult individuals (≥ 18 years) from the capital city of Prague and the Central Bohemian Region of the Czech Republic who were newly diagnosed with VTE between the years 2011–2017. Diagnostic criteria for VTE were a positive finding of venous thrombosis with duplex sonography and confirmation of acute embolism with multidetector computed tomography or perfusion scintigraphy of the lung ventilation. All these patients received anticoagulation treatment in the acute phase of VTE. This sample was supplemented by 487 individuals from the nationwide Czech post-Monica study register²⁷ who reported in the questionnaire that they had experienced VTE and were being treated with anticoagulants at that time. According to the completed questionnaire, the control group consisted of 2637 healthy individuals who had not experienced VTE. This group consisted of 1512 blood donors, healthy volunteers, and 1125 participants in the Czech post-MONICA study.²⁷ Baseline and clinical data for the control group and individuals who had experienced VTE are presented in Table 2. All patients with VTE and the control group provided written informed consent for DNA testing in accordance with the Helsinki Declaration. The genetic study focusing on VTE risk factors was approved by the Ethics Committee of the General University Hospital and the First Faculty of Medicine of Charles University in Prague (No. NT 11176-5). The Czech post-MONICA population study was approved by the Institute for Clinical and Experimental Medicine Ethics Committee and the Faculty of Thomayer University Hospital in Prague. All study participants were Caucasians living in the Czech Republic. Ethnically, the Czechs are considered a Western Slavic nation.

Table 2.

Baseline and Clinical Data of Patients with Venous Thromboembolism (VTE) and Control Subjects.

	Controls	VTE patients
total–number (%)	2637 (100)	2630 (100)
male – number (%)	1516 (57.5)	926 (35.2)
female–number (%)	1121 (42.5)	1704 (64.8)
age–mean (SD), years	43.6 (12.8)	40.8 (14.8)
only deep venous thrombosis (%)	−	1816 (69)
only pulmonary embolism (%)	−	342 (13)
deep venous thrombosis and pulmonary embolism (%)	−	472 (18)
VTE recurrence (%)	−	613 (23)

In the laboratory analyses, the SNPs of the following genes were investigated: F5 Leiden (rs6025), F2 prothrombin (rs1799963), FGG (rs8176719), F11 (rs2289252) and ABO /non-O/ (rs8176719) in uncoagulated peripheral blood samples. Genomic DNA was extracted from their leukocytes and isolated using the MagNA Pure LC Nucleic Acid Extraction System™ with the MagNA Pure DNA Isolation Kit I™ (all products from Roche Diagnostics, Mannheim, Germany). Mutations were determined using real-time polymerase reaction in a process called FRET (Fluorescence Resonance Energy Transfer). The analyses were performed using the LightCycler^® 480 System with LC^® 480 Genotyping Master Kits (all products supplied by Roche Diagnostics, Mannheim, Germany). Specific primers and fluorescence-labelled probes were designed and custom-made in collaboration with TIB MOLBIOL (Berlin, Germany). Categorical variables were expressed as numbers and percentages. Comparisons between groups were made using Fisher's exact test. Logistic analysis tests were performed to assess the clinical impact of alleles and genotypes. Results were presented as odds ratios (ORs) for risk versus non-risk homozygotes and corresponding 95% confidence intervals (CIs). Statistical analysis was performed using SAS statistical software (SAS version 9.4, SAS/Genetics™ 13.1, SAS Institute Inc., NC, USA) with population genetics tools. We consider findings with p < 0.05 as significant differences in the representation of risk alleles and genotypes.

Results

The genetic findings in patients with VTE (n 2630) and controls (n 2637) are shown in Table 3. All findings in controls met the Hardy-Weinberg equation (HWE). Compared to the control group, an increased representation of SNP rs6025 (F5 Leiden), rs1799963 (F2, prothrombin), rs2066865 (fibrinogen gamma', FGG), rs2289252 (F11) and rs8176719 (ABO, non-O) was found in patients with VTE (all with p <0.001). Heterozygotes for F5 Leiden were associated with a 5.58-fold increased in the risk of VTE (OR 5.58; 95% CI 4.74-6.56), while homozygotes had up to a 33.46-fold increased risk of VTE (OR 33.46; 95% CI 10.52-106.40). At SNP rs1799963 (F2, prothrombin), only heterozygotes had a significant 3.9-fold increased risk of VTE (OR 3.90; 95% CI: 2.90-5.25). Compared to the control and VTE patient groups, the OR for the homozygous variant of F2 was not significant. The findings at SNP rs2066865 (fibrinogen gamma', FGG) showed a 1.37-fold increased risk of VTE for FGG heterozygotes (OR 1.37; 95% CI: 1.22-1.54) and a 1.77-fold increased risk of VTE for FGG homozygotes (OR 1.77; 95% CI: 1.43-2.18). There is also a significant 1.42-fold increase risk of VTE in the heterozygotes (OR 1.42; 95% CI: 1.25-1.6) and a 1.80-fold increase risk of VTE in the homozygotes (OR 1.80; 95% CI: 1.55-2.13) of the SNP rs 2289252 (F11). Further higher increases in the risk of VTE in both variants were found in patients with VTE at rs8176719 (ABO, non-O). It corresponds to a 2.2-fold increase in the risk of VTE in heterozygotes (OR 2.19; 95% CI: 1.91-2.51) and a 3.5-fold increase in the risk of VTE in homozygotes (OR 3.52; 95% CI: 2.99-4.13).

Table 3.

Results of Alleles and Genotypes Frequencies, Logistic Regression (Odds Ratio with 95% Wald Confidence Limits) and Fisherś Exat Test p-Value Between Controls (n 2637) and VTE Patients (n 2630) fof the Five VTE Risk SNPs.

			Risk Allele Frequencies		Genotypes Frekvencies
Gene and dbID	SNP	Risk Allele	Controls	VTE Patients	Controls	VTE Patients	Odds Ratio (95% CI)	Fisher's Exat Test: P-Value
F5 (Leiden) rs6025	691 G>A	A	4.19%	18.82%	A/A 0.11%G/A 8.15%G/G 91.73%	A/A 2.7%G/A 32.24%G/G 65.06%	A/A versus GG:33.46(10.52-106.40)G/A versus G/G:5.58 (4.74-6.56)	<0.0001
F2 (protrombin)rs1799963	20210 G>A	A	1.16%	4.26%	A/A 0.04%G/A 2.24%G/G 97.72%	A/A 0.15%G/A 8.21%G/G 91.63%	A/A versus GG:4.28(0.48-8.29)G/A versus G/G:3.9(2.9-5.25)	<0.0001
FGGrs2066865	10043 C>T	T	24.49%	30.45%	C/C 57.25%C/T 36.53%T/T 6.22%	C/C 48.39%C/T 42.33%T/T 9.29%	T/T versus C/C:1.77(1.43-2.18)C/T versus C/C:1.37(1.22-1.54)	<0.0001
F11rs2289252	22771 C>T	T	39.59%	47.19%	C/C 37.18%C/T46.47%T/T 16.35%	C/C 28.00%C/T 49.61%T/T 22.38%	T/T versus C/C:1.80(1.55-2.13)C/T versus C/C:1.42(1.25-1.60)	<0.0001
ABOrs8176719	c.261 del G	G	41.17%	56.51%	-/- 35.06%-/G 47.55%G/G 17.39%	-/- 17.48%-/G 52.02%G/G 30.50%	G/G versus -/-:3.52(2.99-4.13)-/G versus -/-:2.19(1.91-2.51)	<0.0001

Discussion

Significant associations of the tested 5 SNPs, rs6025 (F5 Leiden), rs1799963 (F2, prothrombin), rs2066865 (FGG, fibrinogen gamma'), rs2289252 (F11) and rs8176719 (ABO, non-O) with VTE were demonstrated alongside findings of the GWAS above in patients with ischemic stroke and VTE,²⁸ in patients with cancer and VTE,²⁹ in patients with CTEPH³⁰ and in pregnant women with VTE.³¹ Examination of these 5 SNPs was also used to determine the likelihood of first VTE¹⁶ or the likelihood of VTE recurrence after the completion of anticoagulation therapy.^17,32 In both studies, the likelihood of first VTE and VTE recurrence increased with the increased finding of risk alleles. Mutation in the gene for coagulation Factor V (F5 Leiden, rs6025) is associated with resistance to activated protein C (APC). APC limits clot formation during normal hemostasis by proteolytic inactivation of Factors Va.³³ Therefore, the mutated coagulation Factor FV Leiden is less effectively degraded by APC than standard coagulation Factor V after activation, leading to increased thrombin formation and hypercoagulable state. In the control group, a similar frequency of the F5 Leiden heterozygotes (8.15%) was found as in the previously published prevalence of the F5 Leiden heterozygotes (8.91%) in the Czech population.³⁴ However, the F5 Leiden heterozygotes in patients with VTE were found to be 32.2%. This means that F5 Leiden plays a significant role in the etiopathogenesis of VTE, which is consistent with the preventive measures currently being carried out in the Czech Republic when genetic testing is indicated.³⁵ Mutation of the F2 gene G20210A (rs1799963) is associated with increased prothrombin levels and the risk of venous thrombosis.³⁶ Variant 20210 A has a more effective poly (A) site, leading to increased mRNA and protein expression of prothrombin regardless of promoter and gene.³⁷ In our cohort of patients with VTE, a higher frequency of heterozygous variant (8.21%) of F2 was recorded compared to 2.24% in the control group (p <0.001). The homozygous variant of F2 is rare, with a frequency of 0.04% in the control group and 0.15% in the group of individuals with a history of VTE. However, the OR finding for the homozygous variant of F2 was insignificant compared to the control and VTE patient groups. SNP rs2066865 (fibrinogen gamma', FGG, 10034 C/T) is associated with reduced levels of fibrinogen gamma' and a reduced ratio of fibrinogen gamma' to total fibrinogen. This reduced level of fibrinogen gamma' and increased level of total fibrinogen are associated with an increased risk of venous thrombosis.^38,39 According to the results of our study, the association between VTE and FGG mutation is also demonstrated in the Czech Republic. Another SNP, rs2289252, in the F11 gene, is independently associated with VTE.⁴⁰ In our study, after statistical analysis, we confirmed this finding. Higher levels of the coagulation Factor XI antigen and its activity have been reported in VTE patients with homozygous and heterozygous rs2289252 variants.⁴¹ Therefore, higher levels of coagulation Factor XI will also be found in our VTE patients if they are carriers of rs2289252.An important outcome of our study is that up to 16.35% of homozygous F11 variant rs2289252 was observed even in the control group. The importance of increased coagulation Factor XI levels as an etiological cause of VTE and arterial thrombosis is now widely discussed, particularly after the discovery of new anticoa-gulants, Factor XI inhibitors. These inhibitors have been reported to have a more favourable effect (less bleeding) than treatment with other oral anticoagulation therapy.⁴²

The ABO genotype ("non-O") allows for better differentiation of heterozygous and homozygous variants than serological determination of ABO blood groups. Rs8176719 represents a site in the ABO gene, designated as c.261delG, and is a key SNP in determining blood type O.⁴³ An allele that encodes blood type A or B will have the G allele at this site. If a deletion has occurred at this site, which completely removed this nucleotide, the corresponding allele is considered rs8176719 (-) and encodes the most common blood type O allele. The ABO blood group ("non-O") is now commonly considered a risk factor for VTE.⁴⁴ We also found a significant increase in "non-O" in our group of patients with VTE. Rs8176719 is one of the top polymorphisms associated with increased plasma levels of coagulation Factor VIII and its carrier von Willebrand Factor.⁴⁵ These elevated plasma levels of Factor VIII⁴⁶ and von Willebrand Factor⁴⁷ have previously been described as a risk factor for VTE.

A similar epidemiological study of the occurrence of mutations in FGG, F11 and ABO, "non- O" in patients with VTE compared to their occurrence in a control group has not yet been published in the Czech Republic. However, the impact of our study is limited by the fact that the occurrence of VTE was determined in the nationwide Czech post-Monica study based only on self-reported data from a completed questionnaire, without objective verification.

Therefore, it would be helpful to expand the study on the significance of 5 SNP in the F5, F2, FGG, F11, and ABO genes in a prospective study. It would also be helpful to evaluate the significance of their combined occurrence of risk alleles and the determination of the so-called weighted risk score. Using this score, the risk of VTE in Caucasians increased 1.41 times (95% CI 1.27-1.56) with each additional risk allele.⁴⁸

Conclusion

In addition to F5 Leiden and prothrombin mutation, the study indicates that the gene polymorphisms of FGG (rs2066865), F11 (rs2289252), and ABO (rs8176719) are independent heritable risk factors for VTE in the Czech population.

Addendum: All authors contributed to the critical revision of the manuscript and approved the final version. In addition, Tomas Kvasnicka contributed to concept and design study and drafted the manuscript; Kovarova-Kudrnova Zuzana and Brzezkova Radka participated in the study design and performed the classification of VTE cases; Renata Cifkova classified control cases; Daniela Duskova classified control cases; Petra Bobcikova and Alena Syruckova analysed the SNPs; Martin Sevcik and Zuzana Zenahlikova provided statistical advice and Jan Kvasnicka contributed to concept and design study.

Footnotes

Acknowledgements

The authors thank the staff and participants of the study for their important contributions. This study was supported by grant MH CZ DRO VFN 64 165 (given by the Czech Ministry of Health).

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Grant MH CZ DRO VFN 64 165 (given by the Czech Ministry of Health,

ORCID iD

Tomas Kvasnicka

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The Prevalence of the Thrombotic SNPs rs6025,rs1799963,rs2066865,rs2289252 and rs8176719 in Patients with Venous Thromboembolism in the Czech Population

Abstract

Introduction

Methods

Results

Conclusion

Keywords

Introduction and Study aim

Methods

Results

Discussion

Conclusion

Footnotes

Acknowledgements

Declaration of Conflicting Interests

Funding

ORCID iD

References