47 – Are there genetic predisposing factors for VTE?

47 – Are there genetic predisposing factors for VTE?

Jennifer A. Bell, Michael Huo, Jay R. Lieberman.

Response/Recommendation: There are 5 classic thrombophilias that have a genetic predisposition for venous thromboembolism (VTE).  A large proportion of the inherited risk factors for VTE remain undiscovered and many new loci associated with VTE risk continue to be identified.

Strength of Recommendation: Strong.

Rationale: VTE, comprising deep venous thrombosis (DVT) and pulmonary embolism (PE), is a multifactorial disease with many known acquired and inherited risk factors.  Family history of VTE has been estimated to have an odds ratio (OR) of 2.2 to 2.71,2.  Over the last 60 years, many gene variations that affect VTE risk have been identified through family-based studies.  Initial reports of familial aggregation of VTE was first described in the 1990s.  Five thrombophilias have been described including: hereditary antithrombin deficiency; protein C deficiency; protein S deficiency; Factor V Leiden and prothrombin mutation.  These classic thrombophilias have been associated with increased VTE risk and familial aggregation of VTE3,4.  Other loci such as non-O blood (ABO), fibrinogen gamma (FGC) and hyperhomocystenemia (MTHFR) have since been associated with increased VTE risk.  Many more loci associated with increased VTE risk continue to be discovered through genome-wide association5–9.

Protein C, protein S and antithrombin are natural coagulation inhibitors and deficiencies result in a hypercoagulable state.  Mutations are typically due to loss of function mutations in the PROC, PROS1 and SERPINC1 genes encoding proteins C, protein S and antithrombin, respectively.  Protein C and protein S are vitamin K-dependent glycoproteins that inhibit Factor VIIIa and Factor Va, cofactors in the activation for Factor X and prothrombin, respectively10.  Protein C and protein S deficiency are both autosomal dominant traits and present in less than 1% of the general population and 2-3% in patients with VTE4.  Patients with DNA analysis confirmed protein C deficiency have been reported to have relative risk of 6.5 for VTE, compared to control subjects11.  In a family study, first-degree relatives with protein S deficiency had a 5 times greater risk of thrombosis compared to subjects with normal PROS1 gene12.  In a case-control study comparing patients with first time VTE to controls, patients with S levels in the 2.5th percentile and <0.10th percentile had an OR of 2.31(95% confidence interval [CI], 1.06-5.05) and 5.44 (95% CI, 0.61-48.78), respectively13.

Antithrombin is a serine protease inhibitor and functions to inhibit thrombin and activated Factor X (FXa), resulting in decreased generation and half-life of thrombin.  The SERPIN1 gene is located at chromosome 1q 23-25, and the most common mutations are missense and nonsense mutations.  Of the 5 classic thrombophilias, antithrombin deficiency is the least common, present in less than 0.2% of the general population and 1% in patients with VTE4.  A meta-analysis evaluating VTE in antithrombin deficient individuals compared to controls found an OR of 14.0 (95% CI, 5.5 to 29.0) for the first VTE and the annual VTE risk in antithrombin deficient subject to be 2.3% (95% CI, 0.2-6.5%)14.  While antithrombin deficiency is the least common of the classic thrombophilias, deficiencies result in high relative risk of a first VTE and recurrence.

Factor V and prothrombin are coagulation factors and gain of function mutations result in hypercoagulable state. Factor V Leiden is due to resistance to activated protein C (APC-resistance) on Factor V.  When inactivated protein C attaches to thrombin, APC is formed and inactivates Factor Va and VIIIa by cleaving specific sites.  The most common mutation, rs6025, is due to a single-point mutation that replaces arginine with glutamine at the APC cleavage site5,15.  Factor V Leiden mutation is the most common thrombophilia, and has been estimated to be associated with up to 20% of patients with first VTE events11.  Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study evaluated patients with a first VTE event, heterozygous mutations were found in 14.8% of patients and 5.2% of controls, and homozygous mutations in 0.7% and 0.2%, respectively.  Subjects with Factor V Leiden mutation had an OR of 3.3 compared to control subjects (95% CI, 2.6-4.1)16.

Prothrombin is a precursor to thrombin, that is proteolytically cleaved by Xa to form thrombin.  The most common mutation of gene F2 is G20210A, a point mutation that substitutes adenosine for guanosine and results in a gain-of-function mutation17.  Patients who are heterozygote for prothrombin G20210A have higher levels of plasma prothrombin, however, the exact mechanism of increased VTE risk is not well understood.  In a case-control study, the prothrombin A20210 allele was found in 8.01% of VTE patients compared to 2.29% control subjects (p<0.001), and was associated with an increased risk of VTE (OR 3.88; 95% CI, 2.23 to 6.74)18.  Other case-control series have reported similar OR from 2.8 to 3.817,19.

A large proportion of VTE’s heritability remains undiscovered.  There is a continued effort to identify loci associated with VTE through genome-wide association studies (GWAS), which compare the DNA of large cohorts of patients with VTE to control subjects.  In three recent GWAS, 14, 22, and 20 susceptibility genes for VTE have been discovered, respectively7–9.  Previously identified and novel single nucleotide polymorphisms (SNPs) identified in these three studies can be found in Table 1.  Many previously known VTE loci are associated with the coagulation cascade.  Herrera-Riveor et al., identified 20 susceptibility genes for VTE that do not participate directly in the coagulation cascade and proposed increased VTE risk was due to possible effect on platelet formation or function, cardiovascular development and repair, and/or inflammation7.  Ideally, in the future, genetic profiles could be established for surgical patients to assess the risk for developing a VTE.  Further studies will need to evaluate mechanism of actions of newly found VTE loci and their potential mechanism of VTE.

The 5 classic inherited thrombophilias include protein C deficiency, protein S deficiency, antithrombin deficiency, Factor V Leiden and prothrombin G20210A.  Protein C, protein S, and antithrombin deficiencies are most commonly due to a loss of function mutation, resulting in a hypercoagulable state.  Factor V Leiden and prothrombin G20210A are due to gain of function mutations and are more commonly found in unselected patients with VTE.  However, the classic thrombophilias make up a small proportion of inherited risk for VTE, and research on new loci and their risk for VTE need to be determined.

Table 1.          Genome-wide significant VTE loci from three GWAS8,9,20.

Gene/Locusrs IDChromosomePosition A1A2Consequence
F5rs60251169519049TCArg534Gln
C4BPArs28427001207282149ACintron
F5rs45241169511755CTLys858Arg
KIF26Brs17569121245588095AGintronic
RGSL1rs558974621182512200GTintronic
CSRNP1rs130845802127962493TC5’UTR
PROS1rs6795524268619981GAintron
POLE4rs74965230275182831CTintergenic
RP11-122C5.1rs16867574339188182CTdownstream
STXBP5rs7739314393650604CAdownstream
FGGrs20668654155525276AGdownstream
F11rs42534174187199005CTintron
FGGrs20668644155525695AGintron
F11rs22892524187207381TCintron
F11rs20369144187192481TCintron
F11rs42534214187204937AGintron
HLA-Crs2074492538708554TCupstream
OSMR-AS1rs4869589538707871TGintron
SCARA5rs100873016147709180AGintron
GRK5rs10886430631239869GAintron
STXBP5rs93735236147701133TGintron
ZFPM2rs47348798106583124AGintron
MYRFrs174536827820792ACintron
ZFPM2rs45418688106590705ACintron
ASH2Lrs149680046837968307TCmissense
ABOrs94113779136145404ACintron
ABOrs81767499136131188TCsynonymous
ABOrs6872899136137106AGintron
ABOrs25190939136141870TCintron
ABOrs5794599136154168CTintron
TSPAN15rs787077131071245276TCintron
SBNO1rs1282468510121010256GTintron
TSPAN15rs787077131071245276CTintron
NRG3rs16499361083969121TCintronic
F2rs17999631146761055AG3’UTR
VWFrs2162961161551927GAintron
F2 (LRP4)§rs1919450751146933311AGDownstream (intron)
F2rs31365161146760756GAintron
F10rs321175212123817569GAintron
CATSPERBrs57328376126154670GAintron
MPHOSPH9rs285143612123667354GTintron
VWFrs1558519126153738GAintron
VWFrs216311126128443TCThr1381Ala
PLCG2rs1244505013113787459TCintron
SMG6rs10484831492235039TCintron
AGBL1rs727556801587509243CAncRNA intronic
PEPDrs7318391681870969AGintron
GP6rs1654425171966457CTsynonymous
SLC44A2rs22889041910742170GAGln154Arg
CYP27C1rs75853141933899065TCintron
PLEKrs18673121955538980CAintron
SLC44A2rs45489951910740871GCintron
GP6(NLRP2) §rs16711351955511873GCDownstream (intron)
PSG8rs595593051943283623AGintronic
SNRNP7019:495961451949596145CTintronic
(CD93)rs60830372023182559ATintergenic
EDEM2rs107475142033775369AGintron
PROCRrs60887352033745676TCintron
PROCRrs8671862033764554GASer219Gly
NCAM2rs622074342122780048TCintronic
A4GALTrs96079282243111772ACintron
BRCC3rs7051718X154332656TCintron
F9rs6048X138633280AGThr194Ala
(BCOR) §rs3002417X39708724TCintergenic
F8rs143478537X154424170GCupstream

VTE=Venous thromboembolism; GWAS=Genome-wide association studies; A1=Reference Allele; A2: Alternate Allele.

† Reference SNP Cluster ID.

‡Variant position on the chromosome.

§Genes of variants that are outside of protein-coding transcript bounds are shown with the nearest gene in parentheses.

References:

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8.    Klarin D, Busenkell E, Judy R, et al. Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease. Nat Genet. 2019;51(11):1574-1579. doi:10.1038/s41588-019-0519-3

9.    Lindström S, Wang L, Smith EN, et al. Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism. Blood. 2019;134(19):1645-1657. doi:10.1182/blood.2019000435

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11. Koster T, Rosendaal FR, Briët E, et al. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study). Blood. 1995;85(10):2756-2761.

12. Makris M, Leach M, Beauchamp NJ, et al. Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S. Blood. 2000;95(6):1935-1941.

13. Pintao MC, Ribeiro DD, Bezemer ID, et al. Protein S levels and the risk of venous thrombosis: results from the MEGA case-control study. Blood. 2013;122(18):3210-3219. doi:10.1182/blood-2013-04-499335

14. Croles FN, Borjas-Howard J, Nasserinejad K, Leebeek FWG, Meijer K. Risk of Venous Thrombosis in Antithrombin Deficiency: A Systematic Review and Bayesian Meta-analysis. Semin Thromb Hemost. 2018;44(4):315-326. doi:10.1055/s-0038-1625983

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17. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996;88(10):3698-3703.

18. Margaglione M, Brancaccio V, Giuliani N, et al. Increased risk for venous thrombosis in carriers of the prothrombin G–>A20210 gene variant. Ann Intern Med. 1998;129(2):89-93. doi:10.7326/0003-4819-129-2-199807150-00003

19. Hillarp A, Zöller B, Svensson PJ, Dahlbäck B. The 20210 A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost. 1997;78(3):990-992.

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