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


METHODS
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 frequency>5%) were included in this study. The presence of selected SNPs was detected by polymerase chain reaction-restriction fragment length polymorphism 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 TG>1.7 mmol/l=4.15; P=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.


CONCLUSIONS
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.
Brisson
D
D
Department of medicine, Université de Montréal, University of Montreal Community Genomic Medicine Center and Lipid Clinic, Chicoutimi Hospital, Chicoutimi, Canada.
St-Pierre
J
J
Santuré
M
M
Hudson
T J
TJ
Després
J P
JP
Vohl
M C
MC
Gaudet
D
D
D053305:Apolipoprotein C-III / Q000235:genetics / Q000378:metabolism; D053329:Apolipoprotein E2 / Q000235:genetics / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism; D002170:Canada; D004843:Epistasis, Genetic; D005260:Female; D005602:France / Q000208:ethnology; D006801:Humans; D015228:Hypertriglyceridemia / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D008049:Lipase / Q000235:genetics / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D014280:Triglycerides / Q000097:blood; D049629:Waist-Hip Ratio
D053305:Apolipoprotein C-III; D053329:Apolipoprotein E2; D053327:Apolipoprotein E4; C504173:LIPC protein, human; D008079:Lipoproteins, VLDL; D047493:PPAR alpha; D047495:PPAR gamma; D014280:Triglycerides; D008049:Lipase; D008071:Lipoprotein Lipase