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ANTAGONISTIC HETEROGENEITY IN GENETICS OF LIPID TRAITS: IMPLICATIONS TO THE CETP LOCUS

ABSTRACT: Abstract Preventive medicine is a promising approach in geroscience to avoid diseases by targeting underlying risk factors. Recently, Cholesteryl Ester Transfer Protein (CETP) was considered a target for decreasing risks of cardio-vascular diseases by increasing high-density lipoprotein cholesterol (HDL-C), although clinical trials failed demonstrating limited understanding of the underlying mechanisms in this locus. We examined in detail the associations of the CETP genetic markers with lipids in seven large-scale cohorts (ARIC, CHS, CARDIA, FHS, HRS, MESA, WHI) comprised of 29,902 Caucasians. Our analyses identified rs1532625 polymorphism demonstrating the strongest association with HDL-C at genome-wide level in this locus; moderate association with total cholesterol (TC) partially mediated by HDL-C; and weak associations with low density lipoprotein cholesterol (LDL-C) and triglycerides (TG). Rs1532625 demonstrated complex antagonistic heterogeneity characterized by positive-direction association with TC and negative-direction associations with LDL-C and TG despite positive pairwise correlations between these three traits. Dissecting this heterogeneity by additive adjustment of the model by TC and HDL-C, significance of the association of rs1532625 with TG and LDL-C increased by 2 and 8 orders of magnitude, respectively. Further analyses identified highly significant interaction of rs1532625 with HDL-C but not with TC, which has positive-direction association with LDL-C and negative with TG. Our results suggest that the association of the rs1532625 minor allele with decreased LDL-C and increased TG can be specific for people with high HDL-C. They corroborate observations of decreased LDL-C concentration and increased blood pressure in recent clinical trials, which can be caused by high TG concentration.

SUBMITTER: Loika Y

PROVIDER: S-EPMC6239387 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Project description:Cardiovascular risk factors and atherosclerosis precursors were examined in 365 Turkish children and adolescents. Study participants were recruited at five different state schools. We tested single and multi-locus effects of six polymorphisms from five candidate genes, chosen based on prior known association with lipid levels in adults, for association with low (?10th percentile) high density lipoprotein cholesterol (HDL-C) and high (?90th percentile) triglycerides (TG), and the related continuous outcomes. We observed an association between CETP variant rs708272 and low HDL-C (allelic p=0.020, genotypic p=0.046), which was supported by an independent analysis, PRAT (PRAT control p=0.027). Sex-stratified logistic regression analysis showed that the B2 allele of rs708272 decreased odds of being in the lower tenth percentile of HDL-C measurements (OR=0.36, p=0.02) in girls; this direction of effect was also seen in boys but was not significant (OR=0.64, p=0.21). Logistic regression analysis also revealed that the T allele of rs6257 (SHBG) decreased odds of being in the top tenth percentile of TG measurements in boys (OR=0.43, p=0.03). Analysis of lipid levels as a continuous trait revealed a significant association between rs708272 (CETP) and LDL-C levels in males (p=0.02) with the B2B2 genotype group having the lowest mean LDL-C; the same direction of effect was also seen in females (p=0.05). An effect was also seen between rs708272 and HDL-C levels in girls (p=0.01), with the B2B2 genotype having the highest mean HDL-C levels. Multi-locus analysis, using quantitative multifactor dimensionality reduction (qMDR) identified the previously mentioned CETP variant as the best single locus model, and overall model, for predicting HDL-C levels in children. This study provides evidence for association between CETP and low HDL-C phenotype in children, but the results appear to be weaker in children than previous results in adults and may also be subject to gender effects.

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ANTAGONISTIC HETEROGENEITY IN GENETICS OF LIPID TRAITS: IMPLICATIONS TO THE CETP LOCUS

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