Genetic determinants of long-term changes in blood lipid concentrations: 10-year follow-up of the GLACIER study

Abstract

Recent genome-wide meta-analyses identified 157 loci associated with cross-sectional lipid traits. Here we tested whether these loci associate (singly and in trait-specific genetic risk scores [GRS]) with longitudinal changes in total cholesterol (TC) and triglyceride (TG) levels in a population-based prospective cohort from Northern Sweden (the GLACIER Study). We sought replication in a southern Swedish cohort (the MDC Study; N = 2,943). GLACIER Study participants (N = 6,064) were genotyped with the MetaboChip array. Up to 3,495 participants had 10-yr follow-up data available in the GLACIER Study. The TC- and TG-specific GRSs were strongly associated with change in lipid levels (β = 0.02 mmol/l per effect allele per decade follow-up, P = 2.0 × 10(-11) for TC; β = 0.02 mmol/l per effect allele per decade follow-up, P = 5.0 × 10(-5) for TG). In individual SNP analysis, one TC locus, apolipoprotein E (APOE) rs4420638 (β = 0.12 mmol/l per effect allele per decade follow-up, P = 2.0 × 10(-5)), and two TG loci, tribbles pseudokinase 1 (TRIB1) rs2954029 (β = 0.09 mmol/l per effect allele per decade follow-up, P = 5.1 × 10(-4)) and apolipoprotein A-I (APOA1) rs6589564 (β = 0.31 mmol/l per effect allele per decade follow-up, P = 1.4 × 10(-8)), remained significantly associated with longitudinal changes for the respective traits after correction for multiple testing. An additional 12 loci were nominally associated with TC or TG changes. In replication analyses, the APOE rs4420638, TRIB1 rs2954029, and APOA1 rs6589564 associations were confirmed (P ≤ 0.001). In summary, trait-specific GRSs are robustly associated with 10-yr changes in lipid levels and three individual SNPs were strongly associated with 10-yr changes in lipid levels.

Figure 1. TC and TG level changes (95% CI) over 10-yr follow-up by wGRS quartiles.

The TC wGRS was robustly associated with TC changes over follow-up (β = 0.02 mmol/l per allele per follow-up, 95% CI =  0.01, 0.03, SE = 0.003, P = 9.8*10⁻¹⁸) (A). The TG wGRS was robustly associated with TG changes over follow-up (β = 0.03 mmol/l per allele per follow-up, 95% CI =  0.02, 0.04, SE = 0.005, P = 6.5*10⁻¹¹) (B).

Figure 2. ROC AUC for high TC (A) and high TG (B) at follow-up.

In ROC analyses we excluded individuals with hyperlipidemia at baseline and compared the predictive accuracy of four models (age, sex and BMI (Model 1), Model 1 + trait specific wGRS (Model 2), Model 1 + traditional risk factors for hyperlipidemia (Model 3) and M1 + trait specific GRS + traditional risk factors for hyperlipidemia (Model 4)) in relation to hyperlipidemia at follow-up.