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The genetic association between TSPAN15 and venous thromboembolism (VTE) is supported by robust evidence from large-scale genome‑wide association studies. A meta‑analysis comprising 7,507 VTE cases and 52,632 controls in the discovery cohort, with subsequent replication in an independent set of 3,009 cases and 2,586 controls, identified TSPAN15 as one of the novel susceptibility loci for VTE (PMID:25772935). The lead intronic variant, rs78707713, was consistently associated with VTE risk and contributed to an odds ratio of 1.31 with very strong statistical significance, underscoring the consistency of the association across multiple cohorts.
In terms of genetic evidence, although the reported variant is intronic and lacks a complete coding HGVS description, the recurrence of rs78707713 in independent studies strengthens the causative link to VTE. This gene‐based association was further supported by complementary data from a second study that also evaluated TSPAN15 in the context of VTE, even though that study additionally explored an association with ovarian cancer (PMID:31689458). Segregation data from family-based studies were not available; hence, the weight of evidence derives from large multi‑patient cohorts.
The functional evidence for TSPAN15, while primarily derived from studies evaluating its role in ADAM10 regulation in neuronal systems (PMID:29520422), provides key insights into the biological functions that TSPAN15 may exert in cellular signaling. In cell‑based assays, modulation of ADAM10 maturation and surface expression by TSPAN15 has been clearly demonstrated. Although these experiments were conducted in an Alzheimer disease model system, they offer a mechanistic framework that could be extrapolated to VTE pathophysiology through shared signaling pathways.
No substantive conflicting evidence was reported in the context of VTE. While one study noted that TSPAN15 variants might also be linked to ovarian cancer, the data do not dispute the association with venous thromboembolism, supporting a pleiotropic role for the gene in distinct pathologies.
Integrating the genetic and experimental findings, the evidence supports a strong association between TSPAN15 and VTE. The meta‑analytic data provide statistically rigorous support derived from thousands of VTE cases, and the functional insights, despite being in a related but separate disease context, offer biological plausibility. Overall, TSPAN15 is a promising genetic marker for VTE risk stratification and represents a valuable tool for diagnostic decision‑making and potential commercial assay development.
Key Take‑home: TSPAN15 serves as a clinically actionable genetic marker for VTE, with robust meta‑analytic support and mechanistic insights that enhance its utility in personalized patient management.
Gene–Disease AssociationStrongAssociation supported by a meta‑analysis including 7,507 VTE cases and replication in 3,009 additional cases (PMID:25772935); robust statistical significance across large cohorts. Genetic EvidenceStrongThe recurrent identification of the intronic variant rs78707713 across independent GWAS studies underscores the genetic contribution of TSPAN15 to VTE risk. Functional EvidenceLimitedFunctional assays demonstrated that TSPAN15 modulates ADAM10 maturation and surface expression (PMID:29520422); however, direct functional data in VTE models remain limited. |