rs2066865 — FGG 10034C>T

3' region variant in the fibrinogen gamma chain gene that shifts the gamma/gamma-prime isoform ratio, altering clot structure and increasing venous thromboembolism risk by 22-37% per allele in multiple large GWAS

See your personal result for FGG

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

The Fibrinogen Gamma Isoform Switch — How rs2066865 Tilts the Clotting Balance

Fibrinogen is the blood's primary scaffolding protein — the raw material that thrombin converts into fibrin, the structural backbone of every blood clot. But fibrinogen is not a single molecule. The liver produces two principal isoforms that differ at their gamma chain tip: fibrinogen gamma-A11 fibrinogen gamma-A
The predominant isoform (~85-90% of total fibrinogen) with standard interactions with thrombin, platelets, and Factor XIII and fibrinogen gamma-prime22 fibrinogen gamma-prime
A minority isoform (~10-15% of total) with an extended gamma chain that uniquely binds thrombin, Factor XIII, and has distinct platelet interactions. The rs2066865 variant determines how much gamma-prime your liver makes relative to gamma-A — and that ratio turns out to matter for your thrombosis risk.

The Mechanism

The FGG gene on chromosome 4 encodes the fibrinogen gamma chain. Two alternative polyadenylation sites in its 3' downstream region33 3' downstream region
The non-coding region after the gene's stop codon that controls mRNA processing and determines which protein isoform is produced create two mRNA transcripts: a shorter one producing the standard gamma-A chain and a longer one producing the extended gamma-prime chain. The rs2066865 variant (10034C>T on the coding strand; G>A on the plus strand) sits in this alternative splicing control region and shifts the balance toward the shorter transcript — meaning carriers of the A allele produce proportionally less fibrinogen gamma-prime and more gamma-A.

Fibrinogen gamma-prime has several unique properties that modulate clot risk. It binds thrombin with high affinity through exosite II, effectively sequestering thrombin and limiting its availability for further coagulation. It also alters clot architecture44 clot architecture
Fibrinogen gamma-prime produces clots with a looser, more porous structure that is more easily dissolved by fibrinolysis — the body's clot-clearing system. When gamma-prime levels fall (as in A-allele carriers), clots form more readily and are more resistant to fibrinolysis — a procoagulant shift by two independent mechanisms simultaneously.

The Evidence

The original landmark study by Uitte de Willige et al.55 Uitte de Willige et al.
Published in Blood 2005, the first paper to identify rs2066865 as an independent DVT risk factor identified this variant as an independent deep venous thrombosis risk factor through the gamma-prime fibrinogen mechanism. The largest genetic confirmation came from a UK Biobank and Veterans Affairs genome-wide study by Klarin et al.66 UK Biobank and Veterans Affairs genome-wide study by Klarin et al.
816,694 participants; p-value 10⁻⁸⁸ for VTE association; OR 1.22 per A allele — one of the strongest genetic signals in the VTE literature with over 800,000 participants, establishing an odds ratio of approximately 1.22 per A allele at genome-wide significance (p = 10⁻⁸⁸).

In a prospective population-based study from Norway77 prospective population-based study from Norway
640 VTE cases among 3,734 age-weighted participants in the Tromsø cohort, homozygous AA carriers showed a hazard ratio of 1.7 (95% CI 1.2–2.3) for VTE. When active cancer was present, the risk compounded further to HR 2.0 — synergy between genetic and acquired thrombotic risk.

A large Czech study of 2,630 VTE patients versus 2,637 controls88 2,630 VTE patients versus 2,637 controls
Kvasnicka et al. 2025, Clinical and Applied Thrombosis/Hemostasis confirmed a dose-response relationship: heterozygous GA carriers had 1.37-fold increased VTE risk and homozygous AA carriers had 1.77-fold increased risk. A separate microvascular surgery cohort found microvascular thrombosis rates of 7.6% (GG), 22.7% (GA), and 33% (AA)99 microvascular thrombosis rates of 7.6% (GG), 22.7% (GA), and 33% (AA)
Drizlionoka et al. 2019; 104 patients undergoing microvascular flap surgery, with plasma fibrinogen concentrations also rising with each A allele.

The association extends beyond venous thrombosis. In Han Chinese participants1010 Han Chinese participants
Discovery and replication cohorts totaling 1,268 PE cases and 17,663 controls, rs2066865 reached genome-wide significance for pulmonary embolism (p = 3.81 × 10⁻¹⁴, OR 1.37). In systemic lupus erythematosus patients, the variant showed OR 1.91 for venous thrombosis in white participants and OR 2.19 for arterial thrombosis in Hispanic Americans — suggesting that the procoagulant phenotype interacts with the inflammatory milieu of autoimmune disease.

Practical Implications

The per-allele OR of ~1.22 translates to a moderate absolute risk increase. Unlike the rare, high-penetrance thrombophilias (Factor V Leiden homozygosity, antithrombin deficiency), rs2066865 is common enough — about 7% of people carry two A alleles — that it contributes meaningfully to population-attributable VTE burden. The effect is additive: each additional A allele incrementally shifts the gamma/gamma-prime ratio and modestly elevates risk.

For carriers, awareness is most actionable before high-risk periods: surgery, prolonged immobilization, long-haul travel, hormonal changes (pregnancy, oral contraceptive initiation), and during cancer treatment. The variant also modifies fibrinogen levels measurably — AA homozygotes in the Drizlionoka cohort had nearly double the plasma fibrinogen of GG homozygotes — which is itself an established cardiovascular risk factor.

Interactions

The most clinically important interactions are with other inherited thrombophilias. Carriers of both rs2066865 A allele(s) and Factor V Leiden (rs6025)1111 Factor V Leiden (rs6025)
F5 R506Q, the most common inherited thrombophilia at 5% carrier frequency in Europeans; creates resistance to activated protein C, a natural anticoagulant or prothrombin G20210A (rs1799963)1212 prothrombin G20210A (rs1799963)
F2 3'UTR variant that elevates prothrombin production by 30%; the second most common inherited thrombophilia face a compounded risk from independent pro-coagulant mechanisms acting simultaneously. Similarly, Factor XI rs22892521313 Factor XI rs2289252
F11 intronic variant associated with elevated Factor XI levels and modestly elevated VTE risk is included in clinical thrombophilia panels alongside rs2066865. Acquired thrombophilic states — cancer, antiphospholipid syndrome, pregnancy — add independently to the genetic baseline.

Genotype Interpretations

What each possible genotype means for this variant.

GG Standard Gamma-Prime Normal

Normal fibrinogen gamma/gamma-prime ratio — no elevated VTE risk from this variant

You carry two copies of the common G allele (plus-strand), corresponding to the C allele in the FGG coding region. Your liver produces the typical proportion of fibrinogen gamma-prime relative to gamma-A — roughly 10-15% gamma-prime — giving your clots normal architecture and thrombin-sequestering capacity. This is the most common genotype globally, found in approximately 54% of people across major populations.

AG Reduced Gamma-Prime Intermediate

One copy of the 10034T allele — modestly reduced gamma-prime fibrinogen and 1.37-fold increased VTE risk

The rs2066865 A allele shifts alternative polyadenylation in the FGG 3' region toward the shorter transcript, reducing production of the fibrinogen gamma-prime chain. Gamma-prime has two distinct anticoagulant properties: it binds thrombin at exosite II (effectively inactivating free thrombin in the clot microenvironment) and it promotes looser, more porous clot architecture that fibrinolytic enzymes can dissolve more efficiently. Reduced gamma-prime production impairs both mechanisms.

The additive inheritance pattern means each A allele contributes incrementally — one A allele produces an intermediate phenotype between GG (normal) and AA (maximally reduced gamma-prime). In the microvascular surgery cohort, GA heterozygotes had plasma fibrinogen of 4.28 g/L versus 3.9 g/L for GG carriers, and a microvascular thrombosis rate of 22.7% versus 7.6%.

Key risk amplifiers to be aware of: - Surgery and immobility: The baseline VTE risk elevation is modest but compounds meaningfully with surgical provocation. - Cancer: Active cancer synergizes with this variant — the Norwegian Tromsø cohort found combined HR of 2.0 for VTE in carriers with active cancer. - Combined thrombophilias: Co-inheritance with Factor V Leiden (rs6025) or prothrombin G20210A (rs1799963) creates compounded risk from independent mechanisms.

AA Low Gamma-Prime High Risk

Two copies of the 10034T allele — substantially reduced gamma-prime fibrinogen and 1.7-fold increased VTE risk

With two copies of the A allele, both copies of your FGG gene preferentially produce the shorter gamma-A mRNA transcript, minimizing gamma-prime output. This represents the maximum shift in the gamma/gamma-prime ratio achievable by this SNP alone, producing the highest fibrinogen concentrations, the least thrombin-sequestering capacity, and the densest clot architecture of any genotype.

The procoagulant phenotype operates through two converging mechanisms: 1. Reduced thrombin sequestration: Less gamma-prime means less thrombin captured in the clot microenvironment, leaving more free thrombin available to amplify coagulation. 2. Dense clot architecture: Gamma-prime normally creates porous fibrin networks that fibrinolytic enzymes can degrade. Without it, clots become compacted and fibrinolysis-resistant.

The 1.7-fold HR for VTE translates to meaningful absolute risk elevation, particularly when combined with acquired risk factors. In the Tromsø cohort, AA carriers with active cancer had a 6.4% cumulative VTE incidence at 6 months versus 3.1% in non-carriers — doubling of absolute risk in the cancer setting.

Clinical considerations for AA homozygotes: - Elective surgery: The ~33% microvascular thrombosis rate observed in surgical cohorts suggests meaningful perioperative risk. Proactive thromboprophylaxis discussion is warranted. - Cancer: Synergistic risk with active cancer; consider formal thrombophilia disclosure in oncology records. - Extended immobility: Any prolonged immobility (hospitalization, post-surgical recovery, long-haul travel) should prompt compression and possibly pharmacological prophylaxis. - Combined thrombophilias: Co-inheritance with other thrombophilic variants (such as Factor V Leiden or prothrombin G20210A) compounds risk from independent mechanisms — a thrombophilia panel can identify whether additional inherited clotting risk is present.