SCG3 – Obesity disorder

The association between SCG3 (HGNC:13707) and obesity disorder (MONDO_0011122) has been examined in multiple studies using case‑control designs. In the initial investigation, a large cohort of obese subjects and controls was analyzed, revealing strong statistical significance for several single‑nucleotide polymorphisms in SCG3, including a key signal corresponding to rs3764220 (PMID:17200173). This study provided the first evidence linking SCG3 genetic variation with an obesity phenotype.

In detail, the primary study recruited an initial cohort of 94 obese patients and 658 controls and, after observing significant differences (P = 0.0000019), extended the analysis to 796 obese and 711 control subjects (PMID:17200173). Twelve SNPs in the gene, found to be in near complete linkage disequilibrium, showed a robust association with obesity. Such a case‑control design enables a strong statistical evaluation of genotype–phenotype correlations in a complex trait like obesity.

Genetic evidence further comes from functional assays where a representative variant, reported as c.376A>T (p.Lys126Asn), was associated with altered transcriptional activity of SCG3. Reporter gene assays indicated that two additional SNPs, which affect SCG3 transcription, correlate with changes in gene expression. These results support the notion that common genetic variation in SCG3 may modify the risk for obesity (PMID:17200173).

Functional studies have demonstrated that SCG3 mRNA and protein are expressed in key hypothalamic nuclei that regulate appetite. Immunoreactivity studies showed that SCG3 protein co‑localizes with several neuropeptides involved in energy balance, such as orexin and neuropeptide Y, underlining a plausible biological mechanism by which SCG3 could influence obesity risk. This mechanistic insight strengthens the link between genetic variation and the obesity phenotype.

It is important to note, however, that a subsequent multi‑ethnic study performed in African‑American and Hispanic/Latino cohorts did not replicate the association for SCG3 after correction for multiple comparisons (PMID:33983957). This discrepancy may be due to population heterogeneity or differences in study power and design, representing an important counterpoint to the initial findings.

In conclusion, while the initial genetic and functional data provide moderate support for an association between SCG3 and obesity disorder, conflicting replication results highlight the need for further studies. The integrated evidence suggests that SCG3 remains a candidate gene for influencing obesity risk, warranting additional research to solidify its clinical utility in diagnostic decision‑making and therapeutic targeting.

References

• The Journal of clinical endocrinology and metabolism • 2007 • Functional single‑nucleotide polymorphisms in the secretogranin III (SCG3) gene that form secretory granules with appetite‑related neuropeptides are associated with obesity PMID:17200173
• PloS one • 2021 • Common genetic variants associated with obesity in an African‑American and Hispanic/Latino population PMID:33983957

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