AGRP – Obesity Disorder

Agouti-related protein (AGRP) has emerged as a key candidate gene modulating energy homeostasis and body weight. AGRP functions as an antagonist at melanocortin receptors, and dysregulation in its activity has been linked to increased susceptibility to obesity disorder (PMID:9892020). Early investigations have explored the genetic variability in AGRP with a focus on common and rare single nucleotide polymorphisms in multi‐patient cohorts.

Clinical validity for AGRP in obesity disorder is supported by evidence from large genetic association studies. A European American cohort involving 1982 unrelated individuals identified significant associations with body mass index (PMID:23900445), and a subsequent study in a cohort of 95 severe obesity patients further corroborated the association (PMID:19602223). These results justify a ClinGen gene‑disease association rating of Strong as multiple independent studies demonstrate reproducible association signals.

Genetic evidence includes diverse variant classes identified in AGRP. Reported variants span intronic and missense changes, including the representative variant c.199G>A (p.Ala67Thr) which exemplifies the missense changes detected in affected individuals. While genetic segregation in familial studies was not explicitly demonstrated (0 affected relatives reported), case‑control studies provide robust evidence for an association. These findings underpin the assignment of a Strong genetic evidence tier.

Experimental evidence further supports AGRP’s role in obesity. Functional assays have demonstrated that AGRP binds competitively to melanocortin receptors, thereby inhibiting alpha‑MSH–mediated cAMP generation, a mechanism that is directly concordant with its hypothesized role in appetite regulation (PMID:9892020). Such in vitro studies, which include binding studies and activity assays, rationalize the observation that altered AGRP activity contributes to the obesity phenotype, justifying a Moderate rating for functional evidence.

There is some conflicting evidence, as one study in a North Indian cohort did not find a significant association between certain AGRP polymorphisms and obesity. However, the majority of data, including large multi‑patient studies and functional assessments, consistently implicate AGRP in obesity disorder. This suggests that ethnic variation or methodological differences in study design may account for discrepant findings.

Taken together, the integration of robust genetic association data and supportive functional studies affirms AGRP’s significant contribution to obesity disorder. Key take‑home message: AGRP variants, including c.199G>A (p.Ala67Thr), offer actionable insights for diagnostic decision‑making and the development of targeted therapies in obesity disorder.

References

• International Journal of Obesity • 2014 • Genetic association analysis of 30 genes related to obesity in a European American population PMID:23900445
• BMC Medical Genetics • 2009 • Association between a rare SNP in the second intron of human Agouti related protein gene and increased BMI PMID:19602223
• Molecular Endocrinology (Baltimore, Md.) • 1999 • Characterization of Agouti-related protein binding to melanocortin receptors PMID:9892020

Evidence Based Scoring (AI generated)