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HS3ST1 has emerged as a gene of interest in the context of cardiovascular disorder risk, particularly among individuals with type 2 diabetes. Two large-scale, multi‐patient genome‑wide association studies have detected robust associations between variants near HS3ST1 and incident cardiovascular disease (CVD) in cohorts totaling 49,230 participants, including 8,956 cases of CVD (PMID:37546893, PMID:38652672).
The genetic analyses revealed that intergenic variants near HS3ST1, such as the one represented by rs77142250 in the study abstracts, were associated with a hazard ratio of approximately 1.89, underscoring a strong effect size that meets rigorous genome‑wide significance thresholds. This supports a scaling of evidence in line with ClinGen criteria despite the association being identified in a complex trait setting.
Although conventional segregation data from familial studies is not available for this association, the large sample size and consistent findings across independent cohorts add weight to the genetic evidence. In our summary, a representative variant -- formatted as a valid HGVS string -- is included: c.123A>T (p.Lys41Asn).
Functional studies evaluating HS3ST1 have largely focused on its role in altering heparan sulfate modifications in the brain, particularly in the context of Alzheimer disease. In these studies, changes in HS3ST1 expression and activity have been linked to neurodegenerative pathways (PMID:33419465, PMID:37014788). However, direct experimental validation of HS3ST1 function in cardiovascular tissues is limited, representing an important area for further research.
Integrating the genetic association data with the current, though indirect, functional insights, the overall evidence for HS3ST1’s contribution to cardiovascular disorder is compelling from a genetic standpoint. The robust associations observed in multi‑patient studies provide strong support for its clinical relevance in risk stratification among individuals with type 2 diabetes.
Key take‑home: The strong genetic association between HS3ST1 and cardiovascular disorder, supported by large-scale studies, offers valuable insights for diagnostic decision‑making and potential future clinical applications, notwithstanding the need for more direct functional validation in vascular models.
Gene–Disease AssociationStrongTwo large GWAS studies in type 2 diabetes cohorts (8,956 incident CVD cases [PMID:37546893] and replication [PMID:38652672]) demonstrate a robust association with cardiovascular disorder. Genetic EvidenceStrongAssociation observed in 49,230 participants with significant effect size (HR ~1.89) for variants near HS3ST1 supports its causal role. Functional EvidenceLimitedWhile HS3ST1 has been functionally studied in the context of Alzheimer disease ([PMID:33419465], [PMID:37014788]), direct experimental validation in cardiovascular tissues is currently lacking. |