Low Nonfasting Triglycerides and Reduced All-Cause Mortality: A Mendelian Randomization Study

Study Questions:

Elevated fasting triglycerides are a marker of increased triglyceride-rich very low-density lipoprotein (VLDL) remnant particles and a risk marker for ischemic vascular disease. Are lifelong reduced concentrations of triglycerides on a genetic basis associated with reduced all-cause mortality?

Methods:

Using individuals from the Copenhagen City Heart Study in a Mendelian randomization design, the authors first tested whether low concentrations of nonfasting triglycerides were associated with reduced all-cause mortality in observational analyses (n = 13,957); second, whether genetic variants in the triglyceride-degrading enzyme lipoprotein lipase, resulting in reduced nonfasting triglycerides and remnant cholesterol, were causally associated with reduced all-cause mortality (n = 10,208).

Results:

During a median 24 and 17 years of 100% complete follow-up, 9,991 and 4,005 individuals died in observational and genetic analyses, respectively. In observational analyses, compared to individuals with nonfasting plasma triglycerides of 266-442 mg/dl, multivariably-adjusted hazard ratios for all-cause mortality were 0.89 (95% confidence interval, 0.78-1.02) for 177-265 mg/dl, 0.74 (0.65-0.84) for 89-176 mg/dl, and 0.59 (0.51-0.68) for individuals with nonfasting triglycerides <89 mg/dl. The odds ratio for a genetically derived 89 mg/dl (1 mmol/L) lower concentration in nonfasting triglycerides was 0.50 (0.30-0.82), with a corresponding observational hazard ratio of 0.87 (0.85-0.89). Also, the odds ratio for a genetically derived 50% lower concentration in nonfasting triglycerides was 0.43 (0.23-0.80), with a corresponding observational hazard ratio of 0.73 (0.70-0.77). The results were similar for cardiovascular disease mortality and after adjusting for high-density lipoprotein cholesterol.

Conclusions:

The authors concluded that genetically reduced concentrations of nonfasting plasma triglycerides are associated with reduced all-cause mortality, likely through reduced amounts of cholesterol in remnant lipoproteins.

Perspective:

Mendelian randomization design is an interesting method for determining the relationship between a plasma analyte and genetic variants that influence the level throughout life, which may be shown to increase or decrease all-cause or a disease-specific mortality. The implications are important for designing drug trials and potentially for determining at what age treatment might begin to be beneficial.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins, Diet

Keywords: Lipoproteins, LDL, Lipoprotein Lipase, Vascular Diseases, Cardiovascular Diseases, Lipoproteins, VLDL, Cholesterol, HDL, Lipoproteins, HDL, Triglycerides, Fasting, Lipoproteins, IDL


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