Jean Shin1,2,3, Catriona Syme1,2,3, Dominic Wang1,2,3, Louis Richer4, G Bruce Pike5, Daniel Gaudet6, Tomas Paus7,8, Zdenka Pausova1,2,3. 1. The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. 2. Department of Physiology, University of Toronto, Toronto, Ontario, Canada. 3. Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada. 4. Department of Health Sciences, Université du Québec à Chicoutimi, Chicoutimi, Quebec, Canada. 5. Department of Radiology and Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada. 6. Lipidology Unit, Community Genomic Medicine Centre and ECOGENE-21, Department of Medicine, Université de Montréal, Saguenay, Quebec, Canada. 7. Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada. 8. Departments of Psychology and Psychiatry, University of Toronto, Toronto, Ontario, Canada.
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.
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.
Authors: J Kosacka; M Kern; N Klöting; S Paeschke; A Rudich; Y Haim; M Gericke; H Serke; M Stumvoll; I Bechmann; M Nowicki; M Blüher Journal: Mol Cell Endocrinol Date: 2015-03-26 Impact factor: 4.102
Authors: Rajat Singh; Youqing Xiang; Yongjun Wang; Kiran Baikati; Ana Maria Cuervo; Yen K Luu; Yan Tang; Jeffrey E Pessin; Gary J Schwartz; Mark J Czaja Journal: J Clin Invest Date: 2009-10-12 Impact factor: 14.808
Authors: You-Ying Chau; Roberto Bandiera; Alan Serrels; Ofelia M Martínez-Estrada; Wei Qing; Martin Lee; Joan Slight; Anna Thornburn; Rachel Berry; Sophie McHaffie; Roland H Stimson; Brian R Walker; Ramon Muñoz Chapuli; Andreas Schedl; Nick Hastie Journal: Nat Cell Biol Date: 2014-03-09 Impact factor: 28.824
Authors: Jean Shin; Catriona Syme; Dominic Wang; Louis Richer; G Bruce Pike; Daniel Gaudet; Tomas Paus; Zdenka Pausova Journal: J Clin Endocrinol Metab Date: 2019-09-01 Impact factor: 5.958