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

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.

Association of body mass index and PXDNL gene variants with acute primary angle closure in southern Chinese population

“…We, for the first time, identified significant association of PXDNL variants rs16916207 and rs11985241 with APAC ( Table 4 and Supplementary Table 3 ). PXDNL is an associated gene between the obese individuals and never-overweight controls [ 14 ], and associated with high-density lipoprotein-cholesterol variability [ 37 ], suggesting that PXDNL could be related to the weight. Our genotype-phenotype correlation analysis showed that the APAC subjects carrying the risk alleles of rs11985241 and rs16916207 variants had significantly lower weight than those carrying the protective allele ( Fig.…”

Visit-to-visit variability of metabolic parameters and progression of atherosclerosis in computed tomography: follow up of an asymptomatic cohort

“…Genetic variants may contribute the link of lipid variability and coronary artery stenosis. In a recent study of statin-naive Koreans, some single nucleotide polymorphisms (SNPs) related to LDL-cholesterol variability or HDL-cholesterol variability were found to be associated with advanced coronary artery stenosis ( 16 ). It is also unknown whether the same mechanism causes higher variability of LDL-cholesterol, HDL-cholesterol, and triglycerides, indicating that variability of one lipid measurement did not correlate well with the variability of the others in the Treating to New Targets (TNT) trial ( 8 ).…”