rs57035593 — TC2N

TC2N — A Newly Discovered Hemostasis Gene Linked to Clot Risk

Most people have heard of Factor V Leiden or prothrombin G20210A as genetic drivers of venous blood clots. TC2N (Tandem C2 Domains, Nuclear) barely appeared on coagulation researchers' radar until 2022 — yet genome-wide studies now place this gene at a locus with one of the most statistically significant associations with venous thromboembolism (VTE) identified to date. VTE¹¹ VTE
venous thromboembolism, encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE) is responsible for approximately 100,000–300,000 deaths per year in the United States alone. Understanding its genetic architecture helps identify people at elevated baseline risk who may benefit from more vigilant prevention strategies.

The Mechanism

TC2N encodes a 490-amino-acid protein containing two tandem C2 domains²² C2 domains
calcium- and lipid-binding structural motifs found in many signaling proteins, including synaptotagmins and protein kinase C (C2A spanning residues 223–342; C2B spanning residues 344–471). The protein carries a nuclear localization signal and is predicted to be active in the nucleus, with phosphorylation sites documented in platelet proteomics datasets — raising the possibility that TC2N participates in nuclear signaling cascades relevant to hemostatic cell function.

The rs57035593 variant sits deep within intron 5 of TC2N (c.469+502, 502 nucleotides from the exon boundary) on the minus strand of chromosome 14q32.12. As an intronic variant, it does not change the TC2N protein sequence. Instead, it almost certainly acts as a tag SNP³³ tag SNP
a variant in strong linkage disequilibrium with a nearby causal regulatory or coding variant that is harder to genotype directly or as a regulatory element affecting TC2N expression in relevant tissues. GTEx data show that this variant is an eQTL for the nearby CATSPERB gene in whole blood, suggesting complex local regulatory architecture in this chromosomal region.

The biological plausibility of TC2N in hemostasis was formally tested and confirmed: CRISPR/Cas9 knockdown of tc2n in zebrafish⁴⁴ CRISPR/Cas9 knockdown of tc2n in zebrafish
laser-mediated endothelial injury model; fish with tc2n knockdown showed significantly abnormal thrombus formation, demonstrating the gene is required for normal in vivo hemostasis produced a measurable hemostatic phenotype in the laser endothelial injury model, placing TC2N alongside well-validated coagulation genes. This makes TC2N one of only a handful of GWAS-nominated VTE loci to have direct experimental functional validation in an in vivo model.

The Evidence

The primary GWAS evidence comes from a landmark cross-ancestry meta-analysis by Thibord et al.⁵⁵ cross-ancestry meta-analysis by Thibord et al.
Circulation 2022, 81,669 VTE cases and controls across European, African, and Hispanic ancestries, 135 independent loci, GCST90797304 which identified rs57035593 at genome-wide significance (p = 3×10⁻³⁸, β = 0.071 per T allele). This effect size, while modest on an individual scale, is consistent with the polygenic architecture of VTE — cumulative risk from many loci adds up substantially.

Independent confirmation comes from Ghouse et al.⁶⁶ Ghouse et al.
Nature Genetics 2023, 81,190 VTE cases and 1,419,671 controls, 93 risk loci of which 62 were previously unreported and the subsequent Wolford et al. multipopulation GWAS⁷⁷ Wolford et al. multipopulation GWAS
Blood Advances 2025, 27,987 cases and 1,035,290 controls from 9 international cohorts, 38 genome-wide significant loci, which provided the zebrafish validation. Together these three large studies, spanning over 100,000 VTE cases globally, converge on TC2N as a genuine VTE susceptibility locus with both statistical and experimental support.

Practical Actions

TC2N rs57035593 is a common variant — roughly half of people globally carry at least one T allele. Like other polygenic VTE risk factors, it operates in the background of overall thrombotic risk, amplified by situational risk factors such as prolonged immobility, surgery, oral contraceptive use, pregnancy, cancer, or dehydration. People who carry two T alleles (about 8–11% of Europeans and East Asians) carry the highest baseline genetic risk from this particular locus.

Because anticoagulant therapy for primary VTE prevention has its own bleeding risks, genetic risk alone is not sufficient to justify prophylactic anticoagulation. The clinical value of knowing this genotype lies in heightened awareness during high-risk periods: long-haul travel, hospitalization, post-surgical recovery, and pregnancy. These are the windows where preventive measures — compression stockings, early mobilization, adequate hydration, and when clinically indicated, pharmacological prophylaxis — have strong evidence behind them.

Interactions

TC2N rs57035593 is one of over 90 validated VTE susceptibility loci. Its effect is additive with other known thrombophilic variants: Factor II prothrombin G20210A (rs1799963), Factor V Leiden (rs6025), and fibrinogen gamma-chain variants (rs2066865). Individuals who carry rs57035593-TT alongside any of these high-penetrance variants face compounded risk that approaches the level seen with monogenic thrombophilias. The Ghouse et al. polygenic risk score showed that individuals in the top 0.1% of cumulative genetic VTE risk have risk equivalent to homozygous F2/F5 variant carriers — a finding that underscores why the full polygenic context matters.

Oral contraceptives and hormone replacement therapy are the most clinically relevant environmental interactions: estrogen-containing preparations increase VTE risk 3–6-fold in the general population, and this effect is additive with genetic predisposition from multiple VTE loci including TC2N.