Genetic epistasis in the VLDL catabolic pathway is associated with deleterious variations on triglyceridemia in obese subjects

Abstract

Background: Abdominal obesity and hypertriglyceridemia (the hypertriglyceridemic-waist phenotype) increase cardiovascular risk. The very low-density lipoprotein (VLDL) is a triglyceride (TG)-rich particle. Frequent variations in the genes coding for enzymes and proteins involved in the VLDL catabolism have already been documented. The epistatic effect of such variants on the risk profile associated with abdominal obesity remains to be elucidated. Objective: This study aims to assess the effect of combinations of frequent single-nucleotide polymorphisms (SNPs) in the VLDL catabolic pathway on the relation between abdominal obesity and fasting TG. Method: Only gene variants in the lipoprotein lipase, apolipoprotein (apo) CIII, hepatic lipase and apo E genes known to be frequent in the general population (allele frequency45%) were included in this study. The presence of selected SNPs was detected by polymerase chain reaction-restriction fragment length polymorphisn in a sample of 640 non-diabetic French Canadians at high cardiovascular risk (405 obese, 235 non-obese). Results: Carrying more than two frequent gene variants involved in the VLDL catabolic pathway significantly increased the risk of hyperTG (odds ratio of TG41.7 mmol/l ¼ 4.15; P ¼ 0.001). This effect was proportional to the number of SNPs and genes involved and was significantly amplified by the presence of abdominal obesity defined on the basis of waist circumference. Conclusion: When combined with abdominal obesity, epistasis in the VLDL pathway has a deleterious effect on fasting TG and coronary artery disease risk profile according to the TG threshold (1.7 mmol/l) used in medical guidelines for the assessment of the metabolic syndrome and associated risk.

Additive effects of LPL, APOA5 and APOEvariant combinations on triglyceride levels and hypertriglyceridemia: results of the ICARIA genetic sub-study

“…Sousa et al [37] have also described an interaction for the risk of developing severe HTG associated with the combination APOA5 -1131C* APOE -ε2. In our study, however, we did not find a main TG-raising effect associated with the APOE -ε2 allele; conversely, this lack of association with TG levels has been described in other populations for the APOE -ε4 allele [38,39]. On other hand, the higher TG levels seen by us in APOA5*APOE and other variant combinations were not significantly associated with an interaction effect.…”

“…Prior analyses by another group [38] have shown an increase in the OR with effect from two TG-raising variants, depending on the waist circumference; indeed, the effect was amplified when the number of TG-raising polymorphisms rose together with the presence of abdominal obesity. This contrasts with data from the present study, since the association with HTG with effect from one TG-raising variant was independent of waist circumference.…”

Metabolic Syndrome: From the Genetics to the Pathophysiology

“…Owing to the difficulties of study design, few authors have reported the role of epistasis in the risk of MS-associated phenotypes such as hypertension [20], myocardial infarction and coronary artery disease [21], cholesterol levels [22], and triglyceridemia [23]. In this vein, we have shown that CLOCK and serotonin transporter (SLC6A4) variants interacting with environmental factors such as rotating shift work strongly affect the overall development of the MS or its isolated components, such as blood pressure or plasma triglycerides [24].…”

Gene-Gene Interaction between <i>APOA5</i> and <i>USF1</i>: Two Candidate Genes for the Metabolic Syndrome

“…For example, Pessi et al [24] found an interaction effect between FCGR2A and CRP on the intima media thickness in young Finnish men with a lack of independent effects of FCGR2A polymorphisms on IMT, and an investigation in French Canadians [25] showed significant interaction effect of gene variants in the VLDL catabolism.…”