|CUPPLES, L ADRIENNE|
|Lai, Chao Qiang|
Submitted to: Journal of Lipid Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/11/2006
Publication Date: 5/1/2006
Citation: Elosua, R., Ordovas, J.M., Cupples, L., Lai, C., Demissie, S., Fox, C., Polak, J.F., Wolf, P.A., D'Agostino, R.A., O'Donnell, C. 2006. Variants at the apoa5 locus, association with carotid atherosclerosis, and modification by obesity: the framingham study. Journal of Lipid Research. 47(5):990-6.
Interpretive Summary: Obesity has been identified “one of today’s most blatantly visible – yet most neglected – public health problems.” This rising epidemic of overweight and obesity has been called by some as “globesity” to clearly reflect that is a global problem and that, unless action is taken, billions will suffer from debilitating conditions associated with this disorder. Overeating and sedentary lifestyle are major environmental factors determining the current globesity; however, genetic factors are also important to predispose some people to obesity. However, the relationship between obesity and its health consequences (diabetes, cardiovascular disease) may be also determine by genetic factors. In this research we have examined the relation between common mutations at the APOLIPOPROTEIN A5 (APOA5) gene (that we have previously shown to be associated with blood triglyceride levels, a risk factor for heart disease) and intima media thickening (a non invasive measure of atherosclerosis) in 2,273 participants in the Framingham Heart Study. Our analysis demonstrated that polymorphisms at this gene were significantly associated with carotid intima media thickening IMT and therefore with increased heart disease risk particularly in obese participants. In summary, we have demonstrated that obesity acts as a trigger for heart disease risk in carriers of mutations at the APOA5 gene.
Technical Abstract: Objective: Genetic variation at the apolipoprotein A5 (APOA5) locus is associated with elevated triglyceride concentrations, a risk factor for atherosclerosis. Carotid intimal medial thickness (IMT) is a surrogate measure of atherosclerosis burden. We sought to determine the association of common APOA5 genetic variants with carotid IMT and stenosis. Methods and results: 2,273 Framingham offspring study participants underwent carotid ultrasound and had data on at least one of the five APOA5 variants (-1131T>C, -3A>G, 56C>G, IVS3+476G>A and 1259T>C). Although none of the individual variants were significantly associated with carotid measures, the haplotype defined by the presence of the rare allele of the 56C>G variant was associated with a higher common carotid artery (CCA) IMT compared to the wild-type haplotype (0.75 mm vs 0.73 mm, p<0.05). The rare allele of each of the -1131T>C, -3A>G, IVS3+476G>A and 1259T>C variants and the haplotype defined by the presence of the rare alleles in these four variants were each significantly associated with CCA IMT in obese participants. These associations remained significant even after adjustment for triglycerides. Conclusions: APOA5 variants were associated with CCA IMT, particularly in obese participants. The mechanism of these associations and the effect modification by obesity is independent of fasting triglyceride levels.