Abstract 18477: Understanding the Causal Relevance of Apo(a) Isoform Size, Lipoprotein (a) and Oxidized Phospholipids in Coronary Heart Disease
Introduction: The lipoprotein(a) (Lp[a]) pathway is implicated in the etiology of coronary heart disease (CHD). We used a genetic approach to disentangle the relevance to CHD of distinct components of this pathway: apolipoprotein(a) (apo[a]) isoform size, circulating Lp[a]) and oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB).
Methods: In up to 9015 CHD patients and 8629 matched controls enrolled in the PROMIS study, apo(a) isoform size was assayed using both genotypic (qPCR) and phenotypic (immunoblotting) methods; Lp(a) concentration was measured using an immunoturbidimetric assay; and OxPL-apoB levels were measured using a chemiluminescent ELISA. We calculated odds ratios (OR) for CHD with apo(a) isoform size and Lp(a) concentration. We identified genetic variants exclusively associated with each Lp(a)-related trait. We compared ORs for CHD per 1-SD differences in measured Lp(a)-related traits with ORs for CHD due to specific genetic variants that produced equivalent differences through an analysis of data on a further 60,801 CHD cases and 123,504 controls.
Results: The OR for CHD was 0.93 (0.90-0.97) per 1-SD increment in apo(a) isoform size, after adjustment for Lp(a) concentration. It was directionally concordant with the OR of 0.96 (0.94-0.98) per 1-SD increment in apo(a) isoform size due to rs2457564, a variant at the LPA locus associated with smaller apo(a) isoform size but not Lp(a) concentration. The OR for CHD was 1.10 (1.05-1.14) per 1-SD increment in Lp(a) concentration, after adjustment for apo(a) isoform size. It was directionally concordant with the OR of 1.27 (1.07-1.50) per 1-SD increment in Lp(a) concentration due to rs3777392, a variant at the LPA locus associated with Lp(a) concentration but not apo(a) isoform size. We also identified several SNPs at GWAS levels of significance at the LPA locus in association with OxPL-apoB levels (P= 4x10-13 for the lead variant). The association of the lead variant with OxPL-apoB became non-significant in analyses adjusted for apo(a) isoform size and/or Lp(a) levels.
Conclusions: Both smaller apo(a) isoform size and elevated Lp(a) concentration are independent and causal risk factors for CHD. Lp(a) pathway may cause atherogenicity through OxPL-apoB.
Author Disclosures: D. Saleheen: Research Grant; Significant; Pfizer. Honoraria; Modest; Eli Lilly, Genentech, MedGenome. P. Haycock: None. W. Zhao: None. A. Rasheed: None. A. Taleb: None. P. Frossard: None. S. Tsimikas: None. J.L. Witzum: None. S. Marcovina: None. D.J. Rader: None. J. Danesh: None.
- © 2016 by American Heart Association, Inc.