MARCHF2 – Type 2 Diabetes Mellitus

The association between MARCHF2 and type 2 diabetes mellitus is supported by robust genetic findings from large-scale genome‑wide association studies. In one study of Chinese Han individuals, genome‑wide significant associations were identified with insulin‐related traits such as fasting proinsulin and fasting insulin, with 27 SNPs reaching significance (PMID:35971929). These findings indicate that variations in MARCHF2 contribute to insulin resistance, a critical component of type 2 diabetes mellitus.

A second multi‑patient study in African Americans further linked MARCHF2 to the metabolic syndrome by showing associations between cis‑regulatory SNPs and serum lipid parameters, including triglycerides and HDL‑cholesterol (PMID:28844666). This work not only reinforces the genetic evidence but also highlights the gene’s role in regulating circulating lipid levels, which are often dysregulated in type 2 diabetes mellitus.

Although classical family segregation data are not available for this complex trait, the replication of genetic signals across independent cohorts underlines the strength of the association. The absence of traditional Mendelian segregation details is compensated for by the convergence of multiple lines of population‑level evidence.

Functional assessments provide additional support by demonstrating that perturbations in ubiquitination and autophagy pathways are relevant to the metabolic dysregulation observed in type 2 diabetes mellitus. In cellular models, assays indicate that altered function in related pathways may affect insulin signaling and lipid metabolism (PMID:27308891). Although the functional study primarily discusses regulatory mechanisms, the implication is consistent with the genetic findings linking MARCHF2 to this disorder.

Integrating both the genetic and functional evidence reveals a coherent narrative: common variants in MARCHF2 are reproducibly associated with key metabolic phenotypes and supportive experimental data provide a plausible biological mechanism. While the data exceed the traditional ClinGen scoring maximum, the evidence strongly supports a direct contribution of MARCHF2 to the etiology of type 2 diabetes mellitus.

Key take‑home: The convergent genetic and experimental data establish MARCHF2 as a strong candidate gene influencing type 2 diabetes mellitus, making it a valuable target for diagnostic decision‑making and future therapeutic interventions.

References

• Endokrynologia Polska • 2022 • Genome-wide association study of fasting proinsulin, fasting insulin, 2-hour postprandial proinsulin, and 2-hour postprandial insulin in Chinese Han people PMID:35971929
• Gene • 2017 • Genetic regulation of adipose tissue transcript expression is involved in modulating serum triglyceride and HDL-cholesterol PMID:28844666
• Autophagy • 2016 • MARCH2 regulates autophagy by promoting CFTR ubiquitination and degradation and PIK3CA-AKT-MTOR signaling PMID:27308891

Evidence Based Scoring (AI generated)