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

Jun-Bean Park; Eunsoon Shin; Jong-Eun Lee; Seung Jae Lee; Heesun Lee; Su-Yeon Choi; Eun Kyung Choe; Seung Ho Choi; Hyo Eun Park

doi:10.3389/fcvm.2022.811657

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

Front Cardiovasc Med. 2022 Jan 31:9:811657. doi: 10.3389/fcvm.2022.811657. eCollection 2022.

Authors

Jun-Bean Park¹, Eunsoon Shin², Jong-Eun Lee², Seung Jae Lee², Heesun Lee³, Su-Yeon Choi³, Eun Kyung Choe⁴, Seung Ho Choi⁵, Hyo Eun Park³

Affiliations

¹ Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.
² DNA Link, Inc., Seoul, South Korea.
³ Division of Cardiology, Department of Internal Medicine, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, South Korea.
⁴ Department of Surgery, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, South Korea.
⁵ Division of Pulmonology, Department of Internal Medicine, Healthcare System Gangnam Center, Seoul National University Hospital, Seoul, South Korea.

Abstract

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.

Keywords: Apo A5; cholesterol variability; coronary artery calcium; coronary artery stenosis; genome wide association study.