Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Recent meta‑analysis studies have identified a significant association between KCNK16 and type 2 diabetes mellitus. In a large-scale genome‑wide association study involving 6,952 cases and 11,865 controls in stage 1, followed by replication in additional cohorts (PMID:22158537), KCNK16 emerged as one of eight new loci reaching genome‑wide significance. The robustness of these findings is underscored by the inclusion of diverse East Asian populations.
A subsequent replication study in a Japanese cohort, which genotyped 7,379 participants (5,315 cases and 2,064 controls), further corroborated the association. Despite a limited sample size for assessing individual SNP effects, the overall genetic risk score constructed from nine candidate loci, including KCNK16, was significantly associated with type 2 diabetes (PMID:24086726). This independent validation enhances the confidence in the reported association.
The genetic evidence, derived from complementary meta‑analysis and replication studies, indicates that common variants at the KCNK16 locus confer an increased risk for type 2 diabetes. Although no specific rare HGVS‐formatted variant has been reported in these studies, the consistent statistical signals and direction of effect across multiple cohorts provide strong evidence of the locus’s involvement in disease susceptibility.
Supporting the genetic findings, functional studies have shown that TALK‑1—the protein product of KCNK16—plays a critical role in modulating pancreatic β‑cell electrical activity and insulin secretion. In particular, research has demonstrated that modulation of TALK‑1 activity alters glucose‑stimulated insulin release, aligning well with the pathophysiology of type 2 diabetes (PMID:28403169). These experimental results offer mechanistic insights that complement the genetic associations.
In summary, the integration of large‐scale genetic studies and supportive functional data provides a coherent and compelling narrative for the role of KCNK16 in type 2 diabetes mellitus. Although additional experimental evidence exists beyond the ClinGen scoring maximum, the collective findings substantiate a strong gene‑disease relationship, highlighting the potential for clinical utility in diagnostic decision‑making and future translational research.
Key Take‑home: The robust association between KCNK16 and type 2 diabetes, supported by replicated genomic data and functionally relevant insights, underlines its promise as a target for improved disease prediction and therapeutic intervention.
Gene–Disease AssociationStrongLarge meta‑analyses across multiple cohorts exceeding 25,000 cases and 29,000 controls, along with replication in an independent Japanese population, provide robust statistical evidence supporting the association of KCNK16 with type 2 diabetes (PMID:22158537) (PMID:24086726). Genetic EvidenceStrongGenome‑wide association studies have consistently demonstrated significant associations at the KCNK16 locus. The reproducible risk allele effects and aggregate genetic risk scoring across studies underpin strong genetic evidence for its role in type 2 diabetes. Functional EvidenceModerateFunctional assays indicate that TALK‑1 modulates pancreatic β‑cell electrical activity and insulin secretion. These experimental observations align with type 2 diabetes pathophysiology, supporting the functional relevance of KCNK16 (PMID:28403169). |