rs10739076 — PLGRKT PLGRKT Plasminogen Receptor/Fibrinolysis

Intergenic PCOS susceptibility locus downstream of PLGRKT (plasminogen receptor); the C allele is the risk allele associated with increased PCOS susceptibility, reduced fibrinolytic capacity, and prothrombotic physiology in affected women

See your personal result for PLGRKT

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.

PLGRKT rs10739076 — The Fibrinolysis Gene Variant Linked to PCOS Thrombotic Risk

Polycystic ovary syndrome affects 5–15% of women of reproductive age and carries a substantially elevated risk of cardiovascular and thrombotic complications. A 2018 genome-wide meta-analysis by Day et al. in PLoS Genetics11 Day et al. in PLoS Genetics
10,074 PCOS cases and 103,164 controls of European ancestry, fixed-effect inverse-variance-weighted meta-analysis identified rs10739076 near the PLGRKT gene as one of three newly discovered PCOS susceptibility loci — reaching genome-wide significance (P<5×10⁻⁸). PLGRKT encodes the plasminogen receptor with a C-terminal lysine, a transmembrane protein that is central to the fibrinolytic system and, as emerging data show, to metabolic regulation in adipose tissue.

The Mechanism

PLGRKT (Plg-RKT)22 PLGRKT (Plg-RKT)
plasminogen receptor with C-terminal lysine; gene ID 55848, chromosome 9, complement strand is a structurally unique transmembrane receptor that tethers plasminogen to the surface of cells by exposing a C-terminal lysine residue. Plasminogen bound to Plg-RKT is co-localized with the urokinase receptor (uPAR), allowing efficient conversion to plasmin33 plasmin
a broad-spectrum serine protease that degrades fibrin clots and extracellular matrix. This cell-surface plasmin generation is the final step of fibrinolysis — the process that dissolves blood clots after they form.

The rs10739076 variant lies approximately 2 kb downstream of PLGRKT's last exon in an intergenic region that likely contains regulatory elements influencing PLGRKT expression. The locus also neighbors the relaxin/insulin-like family genes INSL4, INSL6, RLN1, and RLN2, which are endocrine hormones with roles in reproductive function. The C risk allele at rs10739076 is the population-major allele globally (~65%), meaning most people — and most women with PCOS — carry at least one C allele.

Beyond fibrinolysis, Samad et al. 202244 Samad et al. 2022
using adipose tissue from bariatric surgery patients and high-fat-diet mice lacking PLGRKT showed that PLGRKT deficiency leads to increased adipose inflammation, insulin resistance, hepatic steatosis, and impaired PPARγ signaling — linking this plasminogen receptor to the metabolic dysregulation characteristic of PCOS.

The Evidence

Women with PCOS already have a well-documented prothrombotic state independent of genotype. Mannerås-Holm et al. 2011 (74 PCOS women, 31 controls)55 Mannerås-Holm et al. 2011 (74 PCOS women, 31 controls)
Journal of Clinical Endocrinology & Metabolism found significantly elevated PAI-1 activity (the primary inhibitor of fibrinolysis) and fibrinogen in PCOS, with PAI-1 predicted by high insulin and low SHBG (R²=0.526, P<0.001). Burchall et al. 2016 (107 PCOS/67 controls)66 Burchall et al. 2016 (107 PCOS/67 controls)
Seminars in Thrombosis and Hemostasis confirmed "impaired fibrinolysis in PCOS" with PAI-1 elevated at 4.80 vs 3.66 U/mL (p<0.01) independent of age and BMI, plus elevated plasminogen levels — a pattern consistent with an overloaded fibrinolytic system that can't keep up with clot formation.

The rs10739076 C allele adds a genetic layer to this baseline prothrombotic risk. The 2024 Indian cohort study by Dadachanji et al. (497 PCOS cases, 233 controls)77 Dadachanji et al. (497 PCOS cases, 233 controls)
European Journal of Obstetrics & Gynaecology found that rs10739076 was associated with reduced fasting glucose and protective effects on insulin resistance, gonadotropin, and lipid levels in PCOS women — suggesting the variant modifies metabolic severity within PCOS rather than simply conferring susceptibility. The 2025 multi-ancestry GWAS by Zhao et al. in Nature Genetics88 2025 multi-ancestry GWAS by Zhao et al. in Nature Genetics
12,419 Chinese + 13,773 European PCOS cases; 94 independent loci identified confirmed substantial cross-ancestry genetic architecture for PCOS, validating the PLGRKT-adjacent locus as a robust PCOS susceptibility signal.

Epidemiologically, the thrombotic consequences are clear: PCOS women have approximately a 2-fold elevated risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) versus controls, with the risk rising further with combined oral contraceptive use (RR 2.14, 95% CI 1.41–3.24).

Practical Actions

For women carrying the C risk allele — particularly CC homozygotes — the combination of PCOS biology and genetic predisposition at the fibrinolytic locus warrants specific attention to thrombotic risk factors. Marine omega-3 fatty acids (EPA/DHA) have consistent evidence for improving metabolic dysfunction in PCOS: reducing triglycerides, decreasing insulin resistance (negative association with HOMA-IR, β=−0.089), and reducing inflammatory markers. A 2024 review of clinical trials found n-3 PUFAs demonstrate "hypotriglyceridemic, cardioprotective and anti-inflammatory effects" in PCOS, making them a well-supported adjunct to standard care.

PAI-1 levels — the direct marker of fibrinolytic impairment — should be monitored in CC homozygotes with confirmed or suspected PCOS, as elevated PAI-1 combined with genetic susceptibility at the PLGRKT locus creates compounding prothrombotic risk. Oral contraceptive selection is particularly relevant: combined oral contraceptives (COCs) independently increase VTE risk ~2-fold in PCOS, so progestin-only options or non-hormonal methods may be preferable in women with additional thrombotic risk factors.

Interactions

rs2479106 and rs7852296 (DENND1A): These PCOS susceptibility loci at chromosome 9q33.3 affect androgen biosynthesis in theca cells. Women carrying risk alleles at both DENND1A and PLGRKT loci may have compounding PCOS severity — elevated androgens driving the hormonal phenotype alongside impaired fibrinolysis driving thrombotic risk. No compound effect study has directly examined this combination.

rs13405728 (LHCGR): The LH/hCG receptor PCOS locus. Elevated LH in PCOS independently elevates thrombotic risk through platelet activation; combination of LHCGR and PLGRKT locus risk genotypes represents a plausible but unstudied compound thrombotic risk pathway.

Nutrient Interactions

omega-3 fatty acids increased_need

Genotype Interpretations

What each possible genotype means for this variant.

AA Protective Genotype Normal

Low-risk genotype at the PLGRKT PCOS locus

You have two copies of the reference A allele at rs10739076, the protective genotype at this PLGRKT fibrinolysis locus. This is the minority genotype globally — approximately 12% of people carry it — making it relatively uncommon, especially in East Asian populations (~1%) and Europeans (~10%). The A allele is not associated with elevated PCOS susceptibility through this locus. If you do not otherwise have PCOS, this genotype contributes no additional fibrinolytic risk from the rs10739076 locus.

AC One Risk Copy Intermediate

One copy of the PCOS-linked C allele — modest increase in PCOS susceptibility and fibrinolytic risk

The rs10739076 locus sits ~2 kb downstream of the PLGRKT gene, which encodes a transmembrane plasminogen receptor that anchors plasminogen to cell surfaces and facilitates its activation to plasmin — the central fibrinolytic enzyme. In adipose tissue, PLGRKT also regulates metabolic homeostasis: PLGRKT-deficient mice on a high-fat diet develop insulin resistance, hepatic steatosis, and elevated adipose inflammation, linking this plasminogen receptor to the metabolic dysfunction seen in PCOS.

The AC heterozygous genotype reflects one copy of the C allele that became genome-wide significantly associated with PCOS in the Day 2018 meta-analysis. In the 2024 Indian cohort study by Dadachanji et al., rs10739076 was associated with reduced fasting glucose and favorable effects on insulin resistance and lipid levels within PCOS populations, suggesting the variant modifies metabolic severity rather than simply conferring susceptibility in a linear dose-response manner.

Women with PCOS already face approximately 2-fold elevated venous thromboembolism risk versus controls, driven in part by elevated PAI-1 and impaired fibrinolysis. For AC carriers who have PCOS or PCOS-adjacent features (irregular cycles, hirsutism, insulin resistance), this genotype provides relevant context for thrombotic risk counseling and proactive management.

CC Two Risk Copies High Risk

Two copies of the PCOS-linked C allele — highest genetic risk at this fibrinolysis locus; prothrombotic and metabolic monitoring indicated

PLGRKT encodes the transmembrane plasminogen receptor Plg-RKT, which exposes a C-terminal lysine on the cell surface to tether plasminogen and co-localize it with the urokinase receptor (uPAR), enabling efficient plasmin generation. Plasmin is the central protease of fibrinolysis — it degrades fibrin clots and extracellular matrix, keeping vessel walls clear after injury or coagulation. Reduced PLGRKT function impairs this cell-surface plasmin generation, tipping the coagulation- fibrinolysis balance toward clot retention.

The rs10739076 C allele, the lead SNP at this novel PCOS locus in the Day 2018 meta-analysis (P<5×10⁻⁸, genome-wide significance), acts as a genetic tag for downstream effects on PLGRKT expression or the neighboring relaxin/insulin-like gene cluster (INSL4, INSL6, RLN1, RLN2). Separately, PLGRKT has been shown to regulate adipose metabolic homeostasis — PLGRKT-deficient mice develop insulin resistance, hepatic steatosis, elevated adipose inflammation, and impaired PPARγ signaling when challenged with a high-fat diet, mirroring metabolic features prominent in PCOS.

The 2024 Dadachanji study found rs10739076 associated with reduced fasting glucose and favorable metabolic traits within PCOS cohorts, suggesting the C allele's risk effect may be modifiable by the metabolic environment. Elevated PAI-1 — the main fibrinolytic brake already elevated in PCOS — combined with this genotype creates layered prothrombotic risk. Epidemiological data confirm PCOS carries OR 2.16 for DVT and OR 2.44 for pulmonary embolism versus controls.