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The association between FN3K (HGNC:24822) and diabetes mellitus (MONDO_0005015) is supported by population‐based genetic studies that have identified common variants in FN3K as contributors to variability in hemoglobin A1c (HbA1c) levels. In a study of 3,041 multi‐ethnic individuals (PMID:22540250), FN3K was evaluated among several genes, where race‑ethnic differences in risk allele frequencies were observed; however, no familial segregation or de novo variant analyses were reported. A subsequent study in 10,338 individuals (PMID:31564435) further implicated FN3K (in conjunction with FN3KRP) in influencing HbA1c levels, thereby potentially impacting diabetes diagnosis by revealing non‐glycemic genetic contributions.
Despite the robust sample sizes and rigor in design across these multi‐ancestry cohorts, the genetic evidence remains limited by the absence of segregation data and direct functional studies directly linking FN3K to the pathogenesis of diabetes mellitus. The reported associations predominantly arise from statistical correlations, and while the observed race‑ethnic heterogeneity enhances the understanding of modifier effects, the evidence does not extend to establish a clear causal mechanism. No specific protein‐altering FN3K variant was cited in the abstracts or variant lists, limiting the ability to pinpoint a discrete mutational event.
Furthermore, functional studies assessing the mechanistic impact of FN3K on glycemic control are lacking. The experimental data provided for other loci did not include assays that investigated FN3K expression, enzymatic activity, or downstream metabolic effects in animal or cellular models. This absence of corroborative functional findings emphasizes a need for further investigation to clarify the mechanism by which alterations in FN3K may modify diabetes risk.
In summary, while the genetic association between FN3K and diabetes mellitus is supported by large-scale, multi-ancestry studies demonstrating significant variability in risk allele frequencies and statistical association with HbA1c levels, the overall clinical validity is limited by the lack of segregation and experimental evidence. Additional investigations incorporating functional assays and family-based studies are necessary to enhance the clinical utility of FN3K in diagnostic decision-making and precision medicine approaches.
Key Take‑home sentence: Although FN3K is statistically associated with altered HbA1c levels in diverse populations, its role in diabetes mellitus remains limited without further functional and segregation evidence.
Gene–Disease AssociationLimitedAssociation based on two large multi-ancestry studies evaluating common variant contributions to HbA1c variability; however, the evidence lacks segregation and functional data (PMID:22540250, PMID:31564435). Genetic EvidenceLimitedGenetic evidence is derived solely from population-based association studies with significant sample sizes but without familial segregation or discrete variant characterization. Functional EvidenceLimitedNo functional assays or experimental studies were identified that directly assess the impact of FN3K variation on diabetes mellitus pathogenesis. |