Abstract
Background and AimThere is a growing evidence that fluctuation in lipid profiles is important in cardiovascular outcomes. We aimed to identify single nucleotide polymorphism (SNP) variants associated with low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) variability in statin-naïve Korean subjects and evaluate their associations with coronary atherosclerosis.MethodsIn statin-naïve subjects from Gene-Environment of Interaction and phenotype cohort, we performed genome-wide association studies of lipid variability; the discovery (first) and replication (second) sets included 4,287 and 1,086 subjects, respectively. Coronary artery calcium (CAC) score and degree of coronary artery stenosis were used as outcome measures. Cholesterol variability was determined by standard deviation and average successive variability, and significant coronary atherosclerosis was defined as CAC score ≥400 or coronary stenosis ≥70%.ResultsMean HDL-C and LDL-C level were 54 ± 12 and 123 ± 30 mg/dL in the first set and 53 ± 12 and 126 ± 29 mg/dL in the second set. APOA5 rs662799 and APOA5 rs2266788 were associated with LDL-C variability and PXDNL rs80056520, ALDH2 rs671, HECTD4 rs2074356, and CETP rs2303790 were SNPs associated for HDL-C variability. APOA5 rs662799 passed Bonferroni correction with p-value of 1.789 × 10−9. Among the SNPs associated with cholesterol variability, rs80056520 and rs2266788 variants were associated with CACS ≥400 and coronary stenosis ≥70% and rs662799 variant was associated with coronary stenosis ≥70%.ConclusionTwo SNPs associated with LDL-C variability (APOA5 rs662799 and rs2266788) and one SNP associated with HDL-C variability (PXDNL rs80056520) were significantly associated with advanced coronary artery stenosis. Combining GWAS results with imaging parameters, our study may provide a deeper understanding of underlying pathogenic basis of the link between lipid variability and coronary atherosclerosis.
Highlights
An increased level of serum cholesterol, and low-density lipoprotein cholesterol (LDL-C), is a well-established risk factor in the development of atherosclerosis and associated cardiovascular diseases (CVDs) [1]
We evaluated the association of genome-wide association studies (GWAS)-derived single nucleotide polymorphism (SNP) responsible for LDL-C and high-density lipoprotein-cholesterol (HDL-C) variability with coronary atherosclerosis assessed by CAC score (CACS) and coronary artery stenosis
The exact mechanism is to be elucidated, our study demonstrated for the first time that individuals with PXDNL SNP rs80056520 had higher HDL-C variability and higher risk of having significant coronary atherosclerosis defined by CACS ≥400 and coronary stenosis ≥70%, compared with their counterparts
Summary
An increased level of serum cholesterol, and low-density lipoprotein cholesterol (LDL-C), is a well-established risk factor in the development of atherosclerosis and associated cardiovascular diseases (CVDs) [1]. It is a very common disorder, affecting 17.6% in Korean population [2], and its prevalence is continuously increasing worldwide. One major limitation addressed in these previous studies was the lack of consideration in the use of lipid-lowering agents, which might be a serious confounding factors influencing both mediator (i.e., lipid variability) and outcome variable (i.e., ASCVD risk) This can introduce other confounders, such as treatment adherence or change in statin dose, making it difficult to prove causality in trying to analyze the effect of lipid variability. We aimed to identify single nucleotide polymorphism (SNP) variants associated with low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) variability in statin-naïve Korean subjects and evaluate their associations with coronary atherosclerosis
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