Low nonfasting triglycerides and reduced all-cause mortality: a mendelian randomization study.
BACKGROUND
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.


METHODS
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).


RESULTS
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).


CONCLUSIONS
Genetically reduced concentrations of nonfasting plasma triglycerides are associated with reduced all-cause mortality, likely through reduced amounts of cholesterol in remnant lipoproteins.
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark;
Mette
M
Thomsen
Anette
A
Varbo
Anne
A
Tybjærg-Hansen
Børge G
BG
Nordestgaard
D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics / Q000401:mortality*; D002784:Cholesterol / Q000097:blood*; D003627:Data Interpretation, Statistical; D003718:Denmark; D006801:Humans; D053208:Kaplan-Meier Estimate; D008071:Lipoprotein Lipase / Q000235:genetics* / Q000378:metabolism; D057182:Mendelian Randomization Analysis; D009026:Mortality / Q000639:trends; D011110:Polymorphism, Genetic; D019518:Postprandial Period; D011446:Prospective Studies; D012680:Sensitivity and Specificity; D014280:Triglycerides / Q000097:blood* / Q000235:genetics
D015415:Biomarkers; D014280:Triglycerides; D002784:Cholesterol; D008071:Lipoprotein Lipase