CREBRF – Obesity Disorder

This summary integrates evidence from multi‐patient genetic studies and functional assessments, establishing a strong association between CREBRF (HGNC:24050) and obesity disorder (MONDO_0011122) in the Samoan population. A large-scale genome‑wide association study (GWAS) performed in 3,072 Samoans revealed a highly significant association between a missense variant in CREBRF and increased body mass index (PMID:27455349). This observation was further substantiated by replication in an additional 2,102 Samoans, supporting the robustness of the genetic link (PMID:27455349). The association remains notable given the unusually high allele frequency (0.259) in this founder population, suggesting a population‐specific impact on obesity risk.

Multiple independent case‑control studies have reported genetic evidence with compelling statistical significance. In one study, targeted sequencing identified the missense variant c.1370G>A (p.Arg457Gln) in CREBRF, which was associated with an effect size that far exceeds that of any other common BMI risk variants (PMID:27455349). A second study further reported a CREBRF variant (p.Arg475Gln) that increased obesity risk while conferring protection against type 2 diabetes, reinforcing the pleiotropic effects of CREBRF in metabolic regulation (PMID:27573685). These findings underline the importance of family-based and population-specific analyses in uncovering genetic contributors to complex traits.

Genetic evidence is strengthened by the notable replication across independent cohorts using robust GWAS methodologies. The observation of the c.1370G>A (p.Arg457Gln) variant in over 5,000 individuals across studies, along with consistent statistical signals (meta P = 1.4 × 10(-20)), confirms the variant’s significant impact on obesity risk (PMID:27455349; PMID:27573685). Although explicit segregation data among affected relatives was not provided, the convergence of case‑control and population genetic analyses provides a compelling narrative for a strong genetic association.

Functional studies further explore the mechanistic basis of the association. In vitro experiments using adipocyte cell models demonstrated that the overexpression of the CREBRF variant c.1370G>A (p.Arg457Gln) resulted in decreased energy expenditure and increased fat storage, offering biological plausibility to the genetic association (PMID:27455349). These cell‐based assays substantiate a “thrifty” phenotype hypothesis that may account for the high prevalence of obesity in the Samoan population. Such findings underscore the impact of altered metabolic regulation mediated by CREBRF variants.

However, not all experimental evidence has been wholly concordant. A murine knockin model, replicating the human CREBRF variant, did not strongly influence energy or glucose homeostasis in response to several nutritional challenges (PMID:34520472). This discrepancy between in vitro and in vivo models suggests that the pathogenic mechanism may be context‐dependent or require additional environmental or genetic modifiers. The divergence in results highlights the complexity of translating cellular findings into whole‐organism physiology and emphasizes the need for further research to fully delineate the variant’s functional consequences.

In conclusion, the integration of robust genetic evidence from sizable Samoan cohorts with supportive in vitro functional data fosters a strong gene–disease association between CREBRF and obesity disorder. While some conflicting results exist from murine studies, the preponderance of evidence supports the role of the c.1370G>A (p.Arg457Gln) variant in modulating energy homeostasis. This association is clinically actionable, providing a key marker for diagnostic decision‑making and potential therapeutic targeting in populations with elevated obesity prevalence.

Key Take‑home sentence: CREBRF represents a strong candidate gene for obesity disorder, with compelling genetic and experimental data underscoring its clinical relevance despite some conflicting in vivo evidence.

References

• Nature Genetics • 2016 • A thrifty variant in CREBRF strongly influences body mass index in Samoans PMID:27455349
• Nature Genetics • 2016 • CREBRF variant increases obesity risk and protects against diabetes in Samoans PMID:27573685
• 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

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