Genetic Control of Coordinated Changes in HDL and LDL Size Phenotypes

Abstract

Abstract-We investigated the correlation of high density lipoprotein (HDL) and low density lipoprotein (LDL) particle size distributions in samples from Ͼ1100 participants in the San Antonio Family Heart Study. By use of analyses of individual correlations of each HDL fraction with each LDL fraction, we devised new metrics for particle size phenotype, termed ⌬HDL and ⌬LDL, to optimally reflect the size correlations. Confirming previous studies, we found that the 2 size phenotype variables were positively correlated (rϭ0.51). Quantitative genetic analysis indicated that nearly half (44%) of the variance in ⌬HDL and in ⌬LDL was explained by the additive effects of genes. Bivariate genetic analyses indicated that a positive genetic correlation ( G ϭ0.56) exists between them and suggested that the pleiotropic effects of a gene or group of genes account for Ϸ31% [ie, G 2 ϭ(0.56) 2 ϭ0.31] of the genetic variance in the 2 traits. Triglyceride (TG) levels were negatively related to ⌬HDL and ⌬LDL, with phenotypic correlations of Ϫ0.48 and Ϫ0.58, respectively, and genetic correlations of Ϫ0.45 and Ϫ0.76, respectively, suggesting that genes exert significant pleiotropic effects on the covariation of TGs with each of the size variables. Finally, we evaluated a bivariate model for ⌬HDL and ⌬LDL in which TG level was included as a covariate. This analysis indicated that a small but significant genetic correlation remains for ⌬HDL and ⌬LDL, even after accounting for the effects of TGs. Thus, our study demonstrates that the phenotypic correlation of HDL and LDL sizes results in part from the pleiotropic actions of a set of genes, some of which also influence TG levels and some of which do not. Key Words: LDL size distributions Ⅲ HDL size distributions Ⅲ genetics Ⅲ triglycerides Ⅲ Mexican Americans L ipoprotein particles of differing sizes play distinct roles in lipoprotein metabolism and the process of atherosclerosis. The predominance of small dense LDLs was identified as a risk factor for cardiovascular disease (CVD), 1 and prospective studies now have confirmed this initial observation. 2-4 Several mechanisms have been proposed to explain this association 5 : (1) small dense LDLs are more readily converted to highly atherogenic oxidized LDLs; (2) they more readily bind to surface components in the vessel wall; and (3) their size permits a more efficient infiltration into the vessel wall.There is growing evidence that HDL subpopulations differ in their abilities to protect against CVD. 6,7 However, whether current methods of measuring HDL subpopulations provide a substantial increment in CVD-predictive power is more controversial. For example, 2 studies reported significant associations of small dense HDLs (ie, HDL 3 , separated by electrophoresis and density fractionation) and CVD, but they differed as to whether HDL 3 improved the prediction. 8,9 Using nuclear magnetic resonance methodology, Freedman et al 10 found that lipoprotein subpopulation measures, for HDL and LDL, significantly increased the proportion of variation ...

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