Pleiotropic Genetic Effects on LDL Size, Plasma Triglyceride, and HDL Cholesterol in Families

Abstract

Abstract-The interrelationships among low density lipoprotein (LDL) particle size, plasma triglyceride (TG), and high density lipoprotein cholesterol (HDL-C) are well established and may involve underlying genetic influences. This study evaluated common genetic effects on LDL size, TG, and HDL-C by using data from 85 kindreds participating in the Genetic Epidemiology of Hypertriglyceridemia (GET) Study. A multivariate, maximum likelihood-based approach to quantitative genetic analysis was used to estimate the additive effects of shared genes and shared, unmeasured nongenetic factors on variation in LDL size and in plasma levels of TG and HDL-C. A significant (PϽ0.001) proportion of the variance in each trait was attributable to the additive effects of genes. Maximum-likelihood estimates of heritability were 0.34 for LDL size, 0.41 for TG, and 0.54 for HDL-C. Significant (PϽ0.001) additive genetic correlations ( G ), indicative of the shared additive effects of genes on pairs of traits, were estimated between all 3 trait pairs: for LDL size and TG G ϭϪ0.87, for LDL size and HDL-C G ϭ0.65, and for HDL-C and TG G ϭϪ0.54. A similar pattern of significant environmental correlations between the 3 trait pairs was also observed. These results suggest that a large proportion of the well-documented correlations in LDL size, TG, and HDL-C are likely attributable to the influence of the same gene(s) in these families. That is, the gene(s) that may contribute to decreases in LDL size also contribute significantly to higher plasma levels of TG and lower plasma levels of HDL-C. These relationships may be useful in identifying genes responsible for the associations between these phenotypes and susceptibility to cardiovascular disease in these families.

The genetic architecture of lipoprotein subclasses in Gullah-speaking African American families enriched for type 2 diabetes: The Sea Islands Genetic African American Registry (Project SuGAR)

“…by guest, on May 11, 2018 www.jlr.org Downloaded from mosome 10p11 for large VLDL particle concentration, which as described above has a LOD-1 interval that spans about 6 cM starting at rs959629 and ending at rs1441027.…”

“…When the entire sample was used in the analysis, covariate adjustments were made for diabetes status, age, gender, BMI, and lipid and hypertension medication. triglycerides (TG), and HDL are described in the literature ( 14,15 ), and it is reasonable to expect this type of pleiotropic effect may be observed with the lipoprotein subclasses.…”

“…There were seven pedigrees containing unrelated individuals; these individuals were removed prior to the analysis. After modifying all family relationships that appeared to be inconsistent with the genome scan data, there were a total of 1,196 parent-child, 320 grandparent-child, 36 great grandparentgrandchild, 281 full sibling, 79 half-sibling, 136 avuncular, 34 by guest, on May 11, 2018 www.jlr.org Downloaded from whereas the environmental correlation estimates are shown above the diagonal. The highest genetic correlation estimates are observed between the LDL average particle size and the small LDL particle concentration ( Ϫ 0.94) and between the average VLDL particle size and large VLDL particle concentration ( Ϫ 0.88).…”

Genome-wide scan for quantitative trait loci influencing LDL size and plasma triglyceride in familial hypertriglyceridemia

“…Using a quantitative genetic analysis approach, we have previously demonstrated pleiotropic genetic effects on LDL particle size, TG, and HDL cholesterol levels in the familial forms of hypertriglyceridemia (34). These findings illustrated that the well-established phenotypic correlations between these variables (4) reflect strong, underlying genetic correlations in these types of families.…”

“…Details of recruitment procedures have been published (34). Briefly, a self-administered medical history questionnaire and a fasting blood sample were requested from all living relatives who could be contacted.…”