ZFAND6 and Type 2 Diabetes Mellitus

ZFAND6 (HGNC:30164) has emerged from multiple genome‑wide association studies as significantly associated with type 2 diabetes mellitus (MONDO_0005148). Large-scale studies across diverse populations have consistently reported risk alleles at the ZFAND6 locus that correlate with alterations in insulin release and glucose metabolism, supporting its clinical relevance in the complex etiology of type 2 diabetes (PMID:21267535).

The clinical validity of the association is supported by genetic evidence stemming from studies encompassing thousands of subjects. In one study, analyses conducted on over 5,700 middle‐aged subjects revealed that risk allele carriers demonstrated significant increases in 30‑minute plasma glucose levels along with decreased insulin release (PMID:21267535). Other investigations further confirmed the association across different ethnic groups, reinforcing the reproducibility of the findings (PMID:25273842; PMID:22046406).

Genetic evidence indicates a multifactorial mode of inheritance for type 2 diabetes, with ZFAND6 contributing to the cumulative risk allele load. Several studies have documented that risk allele frequencies, including those at the ZFAND6 locus, differ among populations, with these differences explaining part of the observed disparities in type 2 diabetes prevalence. Although family-based segregation data are limited, the association is bolstered by replication across independent cohorts (PMID:22046406).

Importantly, direct functional studies focusing solely on ZFAND6 are currently sparse. While the functional assessment landscape for type 2 diabetes is extensive, specific experimental data on ZFAND6 remain limited; no curated coding variants in standard HGVS nomenclature were identified in the supplied evidence. Nonetheless, the statistically robust genetic associations imply a potential pathogenic mechanism that may involve altered beta‑cell function in the context of a complex, multi‐gene susceptibility model.

Overall, the integration of large, multi‑ethnic genetic association studies with limited but suggestive experimental findings supports a strong genomic signal for ZFAND6 in type 2 diabetes. The current data underscore the utility of incorporating ZFAND6 risk allele information into broader genetic risk profiling for type 2 diabetes, even as further functional validation studies are anticipated.

Key Take‑home: The replication of significant risk associations for ZFAND6 across diverse cohorts provides compelling evidence for its utility in type 2 diabetes risk prediction and highlights a promising target for future functional investigations.

References

• Diabetologia • 2011 • Type 2 diabetes risk allele near CENTD2 is associated with decreased glucose‑stimulated insulin release PMID:21267535
• Human Genetics • 2014 • A comparison of type 2 diabetes risk allele load between African Americans and European Americans PMID:25273842
• PLoS One • 2011 • Association of new loci identified in European genome‑wide association studies with susceptibility to type 2 diabetes in the Japanese PMID:22046406
• PLoS One • 2023 • Genetic associations of TMEM154, PRC1 and ZFAND6 loci with type 2 diabetes in an endogamous business community of North India PMID:37738238

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