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. 2019 Sep 1;104(9):3735-3742.
doi: 10.1210/jc.2018-02656.

Novel Genetic Locus of Visceral Fat and Systemic Inflammation

Jean Shin  1   2   3 , Catriona Syme  1   2   3 , Dominic Wang  1   2   3 , Louis Richer  4 , G Bruce Pike  5 , Daniel Gaudet  6 , Tomas Paus  7   8 , Zdenka Pausova  1   2   3
Affiliations

Novel Genetic Locus of Visceral Fat and Systemic Inflammation

Jean Shin et al. J Clin Endocrinol Metab. .

Abstract

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.

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Figures

Figure 1.
Figure 1.
Manhattan and regional association plots from our GWAS of (A) VFSF and (B) VFTBF. Upper panels: The red dotted line indicates the genome-wide significance level of 5.0 × 10−8. The most significant locus is highlighted with red circle. The top SNP rs803522 is indicated by the purple diamond. The major allele frequency of this SNP is 0.87 in our cohort. Lower panels: Each point indicates an SNP tested in the GWAS within the shown genomic region. The top SNP rs803522 is indicated by the purple diamond. The right-side axis represents the estimated recombination rates from the HapMap Project samples (ftp://ftp.ncbi.nlm.nih.gov/hapmap/recombination/2008-03_rel22_B36/). The red-to-blue colors indicate the degree of linkage disequilibrium (LD) between each SNP and rs803522. The LD was based on the pairwise squared allelic correlation, r2, estimated using SYS parent data. The plots were created using LocusZoom (http://locuszoom.org/).
See this image and copyright information in PMC

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