Novel Genetic Locus of Visceral Fat and Systemic Inflammation.

CONTEXT: Visceral fat (VF), more than fat elsewhere in the body [mostly subcutaneous fat (SF)], promotes systemic inflammation and related disease. The mechanisms of preferentially visceral accumulation of body fat are largely unknown.

OBJECTIVE

To identify genetic loci and mechanistic pathways of preferential accumulation of VF and associated low-grade systemic inflammation.

DESIGN

Genome-wide association study (GWAS).

SETTING AND

PARTICIPANTS

Population-based cohort of 1586 adolescents (aged 12 to 19 years) and adults (aged 36 to 65 years).

MAIN OUTCOME MEASURES: Abdominal VF and SF were measured with MRI, total body fat (TBF) was assessed with bioimpedance, and low-grade systemic inflammation was examined by serum C-reactive protein (CRP) measurement.

RESULTS

This GWAS of preferential accumulation of VF identified a significant locus on chromosome 6 at rs803522 (P = 1.1 × 10-9 or 4.3 × 10-10 for VF adjusted for SF or TBF, respectively). The major allele was associated with more VF; the association was similar in adolescents and adults. The allele was also associated with higher CRP level, but this association was stronger in adults than adolescents (P for interaction = 4.5 × 10-3). In adults, VF was a significant mediator (P = 1.9× 10-4) in the association between the locus and CRP, explaining 30% of the mediation. The locus was near ATG5, encoding an autophagy molecule reported to modulate adipocyte size and macrophage polarization.

CONCLUSION

A genetic locus near ATG5 regulates preferential accumulation of VF (vs SF) in youth and adulthood and contributes to the development of systemic inflammation in adulthood.