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

Abstract

Increased nonfasting plasma triglycerides marking increased amounts of cholesterol in remnant lipoproteins are important risk factors for cardiovascular disease, but whether lifelong reduced concentrations of triglycerides on a genetic basis ultimately lead to reduced all-cause mortality is unknown. We tested this hypothesis. Using individuals from the Copenhagen City Heart Study in a mendelian randomization design, we 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 associated with reduced all-cause mortality (n = 10 208). During a median 24 and 17 years of 100% complete follow-up, 9991 and 4005 individuals died in observational and genetic analyses, respectively. In observational analyses compared to individuals with nonfasting plasma triglycerides of 266-442 mg/dL (3.00-4.99 mmol/L), multivariably adjusted hazard ratios for all-cause mortality were 0.89 (95% CI 0.78-1.02) for 177-265 mg/dL (2.00-2.99 mmol/L), 0.74 (0.65-0.84) for 89-176 mg/dL (1.00-1.99 mmol/L), and 0.59 (0.51-0.68) for individuals with nonfasting triglycerides <89 mg/dL (<1.00 mmol/L). 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). Genetically reduced concentrations of nonfasting plasma triglycerides are associated with reduced all-cause mortality, likely through reduced amounts of cholesterol in remnant lipoproteins.