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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 frequency>5%) 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 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.

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.

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Acknowledgements

During this research, D Brisson was the recipient of a doctoral industry-partnered studentship from the Canadian Institutes for Health and Research (CIHR), in collaboration with Fournier Pharma, and from the ‘Réseau en santé cardiovasculaire (RSCV)- Fonds de la recherche en santé du Québec (FRSQ)’. J St-Pierre is the recipient of the ‘Walter & Jessie Boyd & Charles Scriver’ MD/PhD Studentship Award from the CIHR, the Canadian Genetic Disease Network, the Canadian Gene Cure Foundation and Theratechnologies (A Jean Degranpré Scholarship Award). JP Després is Scientific Director of the International Chair on Cardiometabolic Risk, which is supported by an unrestricted grant from Sanofi Aventis awarded to Université Laval. D Gaudet is the Canada Research Chair in preventive genetics and community genomics (www.chairs.gc.ca). This project was supported by the ECOGENE-21 project from the CAHR/CIHR program (grant #CAR43283) and AstraZeneca Canada Inc.

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Brisson, D., St-Pierre, J., Santuré, M. et al. Genetic epistasis in the VLDL catabolic pathway is associated with deleterious variations on triglyceridemia in obese subjects. Int J Obes 31, 1325–1333 (2007). https://doi.org/10.1038/sj.ijo.0803586

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