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Background and Aim  There 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.    Methods  In 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%.    Results  Mean 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%.    Conclusion  Two 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.

Genetic Determinants of Visit-to-Visit Lipid Variability: Genome-Wide Association Study in Statin-Naïve Korean Population