Abstract 19434: Smaller Ldl Peak Diameter is Causally Associated With Higher Risk of Coronary Heart Disease
Introduction: Although there are multiple lines of evidence that levels of low-density lipoprotein cholesterol (LDL-C) are causally associated with coronary heart disease (CHD), it remains unknown whether LDL particle size distribution, as assessed by peak LDL particle diameter, is associated with CHD risk independent of LDL-C levels.
Methods: We measured plasma lipoprotein particles and LDL peak diameter using a high-resolution ion mobility technique in 11,382 participants enrolled in the Malmö Diet and Cancer Study (MDC) (n = 4088) and the Pakistan Risk of Myocardial Infarction Study (PROMIS) (n = 7294). We first examined the association of LDL peak diameter with incident CHD events in the MDC cohort. Second, using genome-wide genotypes available in the two datasets, we sought associations with LDL peak diameter, and constructed a genetic risk score from genotypes associated with LDL peak diameter but not with levels of LDL-C or HDL-C or triglycerides or other lipoprotein subfractions. Using genotype data from an additional 60,801 CHD cases and 123,504 controls, we compared the Odds Ratio (OR) for incident CHD conferred by the observed variation in LDL peak diameter with the OR for CHD caused by the genetic risk score specifically associated with LDL peak diameter.
Results: Per standard deviation decrease in LDL peak diameter was associated with increased risk of incident CHD in the MDC cohort independent of age, sex, type-2 diabetes, history of hypertension, and tobacco use (OR: 1.15; P = 10-5). Of the variants associated with LDL peak diameter at the genome-wide significance threshold (P < 5 x10-8), six were found to be associated with this trait but not with other lipid levels in an analyses involving 188,577 participants from the Global Lipids Genetics Consortium. Each 1-SD decrease in LDL peak diameter as assessed by a risk score comprised of these six variants was associated with increased risk of CHD (OR: 1.20: P-value 3.5x10-3), which is similar to the OR for incident CHD risk conferred by a 1-SD decrease in the observed LDL peak diameter.
Conclusions: Using evidence from human genetic studies, we show that smaller LDL peak diameter is causally associated with higher risk of CHD independent of LDL-C or other plasma lipids.
Author Disclosures: D. Saleheen: Research Grant; Significant; Pfizer. Honoraria; Modest; Ely Lilly, Genentech, MedGenome. A. Rasheed: None. W. Zhao: None. S. Jabeen: None. P. Frossard: None. J. Danesh: None. D.J. Rader: None. O. Melander: None. R.M. Krauss: None.
- © 2016 by American Heart Association, Inc.