The current longitudinal investigation, including 8,283 white men and women from the ARIC study, showed that both body weight and ANGPTL4
[E40 K] genotype independently influence plasma TG concentrations, but together genotype and body weight do not interactively determine TG concentration. Persons carrying the ANGPTL4
[E40 K] A allele had lower concentrations of TGs than non-carriers at all exams, but TG concentrations increased as body weight increased uniformly in both genotype groups. These data indicate that while ANGPTL4
[E40 K] variation may confer CVD protection via maintenance of lower TG concentrations (14
), other environmental and lifestyle factors still operate as they would regardless of genotypic tendency. Having the “protective” genotype does not preclude the potent effects of lifestyle factors, such as increasing body weight, on a CVD risk factor like TG.
Our results are in contrast to those of previous studies investigating gene-environment (body weight) interactions with respect to lipid concentrations. Two cross-sectional studies reported interactions between measures of adiposity and the hepatic lipase 514C >T polymorphism, with both showing the T allele associated with greater high-density lipoprotein only in individuals who had a healthy body weight (BMI <25 kg/m2
) or less visceral adiposity (visceral adipose tissue <130 cm2
). Since the association between ANGPTL4
[E40 K] and TGs was reported only recently, there are no published studies of the interactive effects of environmental factors and ANGPTL4
[E40 K] genotype. ANGPTL4[E40 K] variation is hypothesized to decrease TG concentrations due to a loss of function of the ANGPTL4 protein, a reversal of lipoprotein lipase inhibition, and an increase in TG clearance (1
). Fat mass, or changes in fat mass, reflected by various measures of adiposity also influence TG concentration via lipoprotein lipase and also through modulation of hepatic lipase activity. For example, weight loss has been shown to increase LPL mRNA (18
) and BMI has been positively associated with hepatic lipase activity (10
), resulting in lower HDL and greater TG.
Because the mechanisms by which ANGPTL4[E40 K] variation and body weight influence TG concentrations are similar, we hypothesized that carriers of the ANGPTL4[E40 K] variant allele might be resistant to the influences of changes in adiposity (reflected here by body weight or waist circumference change). However, data showed that the positive slope of TG change associated with increasing body weight or waist circumference was similar in both genotype groups (i.e., the TG differential between genotype groups did not materially change as body weight and waist circumference changed over follow-up).
Strengths of this analysis include a large sample size and longitudinal measures of TG, body weight, and waist circumference. There are also potential limitations to this analysis. Although careful internal and external quality control procedures were followed in the current study (12
), TG concentrations are measured with a certain degree of error due to intraindividual variability, which could complicate the interpretation of changes in TG concentration over time. However, this should be nondifferential. Our measure of total adiposity (body weight) also includes lean body mass and thus may not detect possible body fat differences between the genotype groups; however, use of waist circumference, which is more highly correlated with total and central body adiposity than is weight, also showed no differential effect on TG change by genotype. The methods of modeling “change” in epidemiological analyses are debated, but we believe the approach used here was most appropriate, given the strong association between genotype and TG at baseline and the potential for measurement error in the outcome of interest (TG) (20
). Finally, these data were exclusively from white men and women from the United States and, therefore, cannot be generalized with confidence to other race groups or other geographical areas.
In conclusion, changes in plasma TG over time are similar between ANGPTL4[E40 K] A allele carriers and non-carriers, with A allele carriers maintaining relatively lower TG concentrations despite increases in TG concentration over 9 years of follow-up in both groups. Furthermore, ANGPTL4[E40 K] body weight and waist circumference changes impart a similar influence on TG regardless of genotype. As with all studies of gene x environment interaction, these findings require investigation in other large cohorts before definitive conclusions can be drawn, but they do suggest that to maintain low TG concentration and, thus, lower CVD risk, maintenance of healthy body weight and waist circumference are important, regardless of ANGPTL4[E40 K] genotype.
The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. The authors thank the staff and participants of the ARIC study for their important contributions.