Selected ARHGEF3 Gene Polymorphisms Associated With Platelet Hyperaggregability in Patients With Venous Thromboembolism

So called “sticky platelet syndrome” (SPS) is an inherited thrombophilic thrombocytopathy characterized by platelet hyperaggregability to low concentrations of adenosine diphosphate and/or epinephrine using light transmission aggregometry and is a recognized cause of otherwise unexplained venous thromboembolism (VTE). Variants within the ARHGEF3 gene have previously been implicated in platelet-related traits, suggesting its potential role in thrombosis associated with SPS. We investigated the association between eight selected single nucleotide polymorphisms (SNPs) within the ARHGEF3 gene and the risk of VTE in 49 patients with SPS and VTE compared with 70 healthy controls. Genetic associations were evaluated using allelic, genotype-based (dominant and recessive models), and haplotype analyses, with stratification according to SPS subtype. In the overall SPS cohort, the minor allele of rs9851853 was significantly more frequent in patients with SPS and VTE compared to controls. SNP rs4681767 showed a borderline allelic association in the overall cohort but reached statistical significance in patients with SPS type II. Genotype-based analyses revealed significant associations for rs9851853 under the dominant model and for rs4681767 and rs1354034 under the recessive model, predominantly in the SPS type II subgroup. Haplotype analysis identified distinct risk- and protective haplotypes within the ARHGEF3 locus. The TAT haplotype was associated with an increased risk of VTE, whereas the CAC haplotype conferred a protective effect, more significantly in SPS type II patients. Our findings indicate that genetic variability within the ARHGEF3 gene, particularly rs9851853, rs4681767, and rs1354034, may modulate thrombotic susceptibility in patients with SPS, especially in the epinephrine-sensitive SPS type II.