Abstract 838: Heritability Of Oxidized Phospholipids And Lp(a): Studies In Twin Pairs
We have recently demonstrated that Lp(a) is a carrier of oxidized phospholipids (OxPL) and this may confer a novel mechanism of cardiovascular risk. It is well appreciated that Lp(a) is a genetic risk factor with an autosomal dominant penetration. Since circulating measures of OxPL on apoB-100 particles (OxPL/apoB) are strongly associated with Lp(a), we hypothesized that OxPL/apoB levels may also be a genetically determined cardiovascular risk factor. We measured OxPL/apoB and Lp(a) in a series of 396 predominantly healthy monozygotic and dizygotic twins, both to estimate trait heritability (h2) and to determine specific genetic effects on traits. Single nucleotide polymorphism genotyping was also done at adrenergic pathway loci. Haplotypes were inferred from genotypes by likelihood methods. OxPL/apoB was measured by antibody EO6 and Lp(a) by an established ELISA technique. OxPL/apoB levels were strongly correlated with Lp(a) levels (r2=0.71, r=0.93, p<0.0001); this correlation was also high (r=0.84, p<0.0001) in twin pairs. OxPL/apoB and Lp(a) levels were not related to any other cardiovascular risk factors, or to any other demographic, physical, physiologic, biochemical or lipoprotein risk factors. The h2 of OxPL/apoB was 86.8±1.89% and for Lp(a) was 85.3±2.11%, and such h2s were higher than that for other physical, physiologic, inflammatory, and lipid parameters. Twin pair correlations indicated that the Lp(a) and OxPL/apoB traits shared genetic determination (genetic covariance: 0.703±0.040, p=1.3×10−28), though not environmental determination (environmental covariance: 0.056±0.084, p=NS). Lp(a) levels (16.3±0.30 vs. 15.1±0.30 mg/dl, p=0.0059) were higher in subjects carrying the tyrosine hydroxylase G-801C promoter C (minor) allele, which is associated with heritable adrenergic stress responses. OxPL/apoB is a potent heritable cardiovascular risk factor, and even more heritable than traditional risk factors. The fact that OxPL/apoB levels are primarily genetically determined suggests enhanced exposure from birth in those with elevated Lp(a) levels. This may help to explain the enhanced risk for atherothrombosis associated with Lp(a), particularly in younger patients.