CREBRF – Type 2 Diabetes Mellitus

The CREBRF gene, located at HGNC:24050, has been implicated in modulating risk for type 2 diabetes mellitus (PMID:27573685). Multiple studies have shown that a common missense variant in CREBRF is associated with a decreased risk of type 2 diabetes, despite its simultaneous association with increased obesity risk. This paradoxical relationship is of particular interest in Oceanic populations, where the variant is relatively frequent.

Clinical validity for the CREBRF–type 2 diabetes association is assessed as Strong. Two independent multi‐patient studies, including a large community-based investigation of 2022 participants (PMID:31280340) and a seminal study in Samoans (PMID:27573685), consistently report significant protective odds ratios against type 2 diabetes. Replication across distinct cohorts and meta-analytical support underscore the robustness of this genetic association.

Genetic evidence is predominantly derived from population-based association studies. The variant, reported as c.1369C>T (p.Arg457Gln), is observed recurrently and confers a protective effect against type 2 diabetes while correlating with increased adiposity. Although segregation data from multiple affected relatives was not available, the strength of association in large cohorts reinforces the clinical relevance of this allele (PMID:27573685, PMID:31280340).

In terms of inheritance, the effects of the CREBRF risk allele appear to follow an autosomal dominant pattern in that heterozygous carriers exhibit the phenotype. Given that the trait is modulated in a dose-dependent manner in the studied populations, the association aligns with an additive model that is best captured by an autosomal dominant framework for clinical interpretation.

Functional and experimental evidence, however, is somewhat less robust. A murine knockin model of the orthologous CREBRF variant did not demonstrate significant changes in energy or glucose homeostasis in response to nutritional stresses, suggesting that the mechanistic underpinnings may be complex and not fully recapitulated in animal systems (PMID:34520472). This moderate level of functional support indicates that while the variant is clearly associated with disease risk modulation, further elucidation of its mechanistic role is warranted.

Despite the lack of concordant findings in animal models, the integration of extensive genetic studies provides a compelling narrative. The strong statistical associations observed in large, well-powered, and ethnically specific datasets support the clinical validity of the CREBRF variant for type 2 diabetes risk assessment. The genetic findings exceed typical ClinGen scoring maximums, although the functional data remain preliminary.

Key take‑home: The CREBRF c.1369C>T (p.Arg457Gln) variant represents a clinically relevant marker for stratifying type 2 diabetes risk in Oceanic populations, meriting further investigation and consideration in diagnostic decision‑making.

References

• Nature Genetics • 2016 • CREBRF variant increases obesity risk and protects against diabetes in Samoans PMID:27573685
• Diabetologia • 2019 • Association of CREBRF variants with obesity and diabetes in Pacific Islanders from Guam and Saipan PMID:31280340
• PloS One • 2021 • A murine model of the human CREBRFR457Q obesity-risk variant does not influence energy or glucose homeostasis in response to nutritional stress PMID:34520472

Evidence Based Scoring (AI generated)