Do Genetic Factors Modify the Relationship Between Obesity and Hypertriglyceridemia? Findings From the GLACIER and the MDC Studies

Circ Cardiovasc Genet. 2016 Apr;9(2):162-71. doi: 10.1161/CIRCGENETICS.115.001218. Epub 2016 Feb 10.

Abstract

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 Malmö Diet and Cancer Study [N=5352]). The genetic loci were amalgamated into a weighted genetic risk score (WGRSTG) by summing the triglyceride-elevating alleles (weighted by their established marginal effects) for all loci. Both BMI and the WGRSTG were strongly associated with triglyceride concentrations in GLACIER, with each additional BMI unit (kg/m(2)) associated with 2.8% (P=8.4×10(-84)) higher triglyceride concentration and each additional WGRSTG unit with 2% (P=7.6×10(-48)) higher triglyceride concentration. Each unit of the WGRSTG was associated with 1.5% higher triglyceride concentrations in normal weight and 2.4% higher concentrations in overweight/obese participants (Pinteraction=0.056). Meta-analyses of results from the Swedish cohorts yielded a statistically significant WGRSTG×BMI interaction effect (Pinteraction=6.0×10(-4)), which was strengthened by including data from the Danish cohorts (Pinteraction=6.5×10(-7)). In the meta-analysis of the Swedish cohorts, nominal evidence of a 3-way interaction (WGRSTG×BMI×sex) was observed (Pinteraction=0.03), where the WGRSTG×BMI 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.

Keywords: bioinformatics; genetic epidemiology; genetics; obesity; triglycerides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Body Mass Index
  • Female
  • Gene Regulatory Networks
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Humans
  • Hypertriglyceridemia / blood
  • Hypertriglyceridemia / complications*
  • Hypertriglyceridemia / genetics*
  • Life Style
  • Male
  • Middle Aged
  • Obesity / blood
  • Obesity / complications*
  • Obesity / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Risk Factors
  • Sex Characteristics
  • Triglycerides / blood

Substances

  • Triglycerides