Journal
CIRCULATION-CARDIOVASCULAR GENETICS
Volume 9, Issue 2, Pages 162-171Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.115.001218
Keywords
bioinformatics; genetic epidemiology; genetics; obesity; triglycerides
Funding
- Swedish Heart Lung Foundation
- Swedish Research Council
- Novo Nordisk Foundation
- European Research Council
- EXODIAB
- IMI DIRECT Consortium
- Basque Government
- Heart and Lung foundation
- Swedish Diabetes Foundation
- Pahlsson Foundation
- Region Skane
- Knut and Alice Wallenberg Foundation
- Linneus Foundation
- Wellcome Trust [098051]
- United Kingdom NIHR Cambridge Biomedical Research Centre
- MRC Centre for Obesity and Related Metabolic Diseases
- Novo Nordisk Fonden [NNF12OC1016167, NNF14OC0011049, NNF14OC0011039, NNF16OC0021370, NNF13OC0005781, NNF11OC1014855, NNF15OC0016320] Funding Source: researchfish
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Background Obesity is a major risk factor for dyslipidemia, but this relationship is highly variable. Recently published data from 2 Danish cohorts suggest that genetic factors may underlie some of this variability. Methods and Results We tested whether established triglyceride-associated loci modify the relationship of body mass index (BMI) and triglyceride concentrations in 2 Swedish cohorts (the Gene-Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk [GLACIER Study; N=4312] and the Malmo Diet and Cancer Study [N=5352]). The genetic loci were amalgamated into a weighted genetic risk score (WGRS(TG)) by summing the triglyceride-elevating alleles (weighted by their established marginal effects) for all loci. Both BMI and the WGRS(TG) were strongly associated with triglyceride concentrations in GLACIER, with each additional BMI unit (kg/m(2)) associated with 2.8% (P=8.4x10(-84)) higher triglyceride concentration and each additional WGRS(TG) unit with 2% (P=7.6x10(-48)) higher triglyceride concentration. Each unit of the WGRS(TG) was associated with 1.5% higher triglyceride concentrations in normal weight and 2.4% higher concentrations in overweight/obese participants (P-interaction=0.056). Meta-analyses of results from the Swedish cohorts yielded a statistically significant WGRS(TG)xBMI interaction effect (P-interaction=6.0x10(-4)), which was strengthened by including data from the Danish cohorts (P-interaction=6.5x10(-7)). In the meta-analysis of the Swedish cohorts, nominal evidence of a 3-way interaction (WGRS(TG)xBMIxsex) was observed (P-interaction=0.03), where the WGRS(TG)xBMI interaction was only statistically significant in females. Using protein-protein interaction network analyses, we identified molecular interactions and pathways elucidating the metabolic relationships between BMI and triglyceride-associated loci. Conclusions Our findings provide evidence that body fatness accentuates the effects of genetic susceptibility variants in hypertriglyceridemia, effects that are most evident in females.
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