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The association between ZFAND3 and type 2 diabetes mellitus is supported by multiple large-scale genetic studies in East Asian and Japanese populations. A comprehensive meta‑analysis first identified ZFAND3 as one of eight novel loci associated with type 2 diabetes, with stage 1 analyses enrolling 6,952 cases and 11,865 controls (PMID:22158537). Subsequent replication efforts, including a Japanese study with 5,315 cases and an independent cohort of 12,284 cases (PMID:24086726), consistently support the association, although the total evidence set comprises varied population cohorts.
Based on ClinGen criteria, the overall gene‑disease association is classified as Strong. The rationale is grounded on the large combined sample sizes—with over 25,000 cases across studies (PMID:22158537, PMID:24086726)—and the replication of the association in independent cohorts. Despite one study in a Saudi Arabian population reporting an effect in the opposite direction for the ZFAND3 variant (PMID:29451423), the weight of evidence remains robust.
The genetic evidence for ZFAND3’s role in type 2 diabetes is derived from genome‑wide association study (GWAS) data. Although no specific HGVS‐formatted coding variant is available from the provided reports, the collective signal observed in these studies indicates that risk alleles in ZFAND3 contribute at a statistically significant level to T2D susceptibility. The underlying inheritance pattern is complex, reflecting the multifactorial nature of type 2 diabetes, where multiple loci contribute to disease risk.
Functional or experimental evidence directly linking ZFAND3 to the pathophysiology of type 2 diabetes remains limited. To date, no published studies have presented detailed functional assays, animal models, or cellular rescue experiments that elucidate the mechanistic role of ZFAND3 in pancreatic beta‑cell function or insulin regulation. Consequently, while the genetic evidence is compelling, the biological mechanism underlying the association has yet to be fully characterized.
There is some conflicting evidence from the literature. In one study performed in a Saudi Arabian cohort, the risk allele in ZFAND3 demonstrated an effect in the opposite direction compared to previous findings (PMID:29451423). However, this observation does not outweigh the consistent and significant associations reported in the larger studies, suggesting that differences in ethnic background or genetic heterogeneity may modulate the observed effects.
In conclusion, the integration of multi‐population genetic data provides a Strong classification for the association between ZFAND3 and type 2 diabetes mellitus. Although functional evidence is limited, the replicated genetic associations across diverse cohorts underscore the clinical utility of considering ZFAND3 in diagnostic risk stratification and future research. Key take‑home: ZFAND3 is a validated genetic contributor to type 2 diabetes mellitus, warranting further functional investigation to uncover its role in disease pathogenesis.
Gene–Disease AssociationStrongLarge‐scale meta‑analysis and replication studies across >25,000 cases (PMID:22158537, PMID:24086726) support a robust association, despite one study showing an opposite effect (PMID:29451423). Genetic EvidenceStrongMultiple GWAS and replication studies indicate that risk alleles in ZFAND3 are significantly associated with type 2 diabetes, although a specific coding variant in HGVS format was not reported. Functional EvidenceLimitedThere are no direct experimental studies evaluating the functional impact of ZFAND3 in type 2 diabetes, leaving the pathogenic mechanism to be elucidated. |