rs10739076 — PLGRKT PLGRKT Plasminogen Receptor/Fibrinolysis

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.