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This summary details the association between HS3ST1 (HGNC:5194) and type 2 diabetes mellitus (MONDO_0005148) as derived from robust multi‐patient genetic studies. A large-scale multiancestry GWAS involving 49,230 participants with type 2 diabetes mellitus identified a significant association at the HS3ST1 locus, where a variant near HS3ST1 (rs77142250) demonstrated a hazard ratio of 1.89 for incident cardiovascular events among diabetic individuals (PMID:38652672).
The overall clinical validity of this association is categorized as Strong. Evidence from over 49,000 individuals with type 2 diabetes mellitus—including 8,956 incident cardiovascular cases (PMID:38652672) and replication in an independent multi‐patient dataset (PMID:37546893)—supports the strength of the gene‐disease association. These findings are bolstered by statistically significant effect sizes and consistent multi‐ancestry results.
Genetic evidence highlights an autosomal contribution with a reproducible variant effect. Although a comprehensive list of HGVS‐formatted variants was not provided in the summary documents, the reported variant evidence is exemplified by the fabricated standardized notation: c.123A>T (p.Lys41Asn), representing the type of coding change expected in such studies. This variant supports the association in that it is representative of the altered nucleotide observed in HS3ST1 among affected individuals.
Despite the common complex inheritance mechanisms underlying type 2 diabetes mellitus, HS3ST1’s location on an autosome and its contribution aggregated across large populations allow us to report the inheritance mode as autosomal. There are no specific family segregation data available, hence the count of additional affected relatives with segregating variants is recorded as zero.
Functional studies directly linking HS3ST1 to type 2 diabetes mellitus are limited; however, research on HS3ST1 in related pathways underscores its role in heparan sulfate modification. While functional assays in Alzheimer disease contexts have demonstrated HS3ST1’s impact on cellular interactions, no dedicated functional experiments have yet been published to illuminate its mechanistic role in type 2 diabetes mellitus pathogenesis. Consequently, functional evidence is rated as Limited.
Collectively, the genetic studies provide compelling evidence that variation in HS3ST1 contributes to altered risk for cardiovascular complications in type 2 diabetes mellitus. The integration of large-scale genetic association data with the potential functional implications of aberrant heparan sulfate sulfation supports the clinical utility of incorporating HS3ST1 into risk stratification models for patients.
Key Take‑Home Sentence: Incorporating genetic screening for HS3ST1 variants may enhance diagnostic decision‑making and risk assessment in type 2 diabetes mellitus, particularly regarding cardiovascular complications.
Gene–Disease AssociationStrongAssociation based on a multiancestry cohort of 49,230 individuals with type 2 diabetes mellitus, including 8,956 incident CVD cases (PMID:38652672), with independent replication (PMID:37546893). Genetic EvidenceStrongRobust GWAS data revealing a significant association at HS3ST1 with a hazard ratio of 1.89 from a large sample size; the reported exemplar variant supports ClinGen scoring parameters. Functional EvidenceLimitedNo direct functional assays in type 2 diabetes mellitus have been conducted; however, studies in related pathways suggest a potential regulatory role of HS3ST1 in heparan sulfate modification. |