Epigenetic aging and lipid traits with a generational gradient in a Korean population with independent replication

DNA methylation in peripheral blood is associated with blood lipid levels, but the studies that established these associations were conducted predominantly in European-ancestry populations, and East Asian data remain sparse. Our primary aim was to determine whether established lipid–methylation loci transfer to a Korean population; our secondary aim was to characterize how lipid-specific epigenetic signatures relate to biological aging across clock generations. An epigenome-wide association study (EWAS) of lipid traits (total cholesterol, log-transformed triglyceride [TG], high-density lipoprotein [HDL], and low-density lipoprotein) and hypertriglyceridemia was conducted using peripheral whole-blood leukocyte DNA from 1,527 Korean adults (discovery), with replication in two non-overlapping Korean Genome and Epidemiology Study health examinees (HEXA) subsets ( N = 389 and N = 417) profiled on the Illumina EPIC array. Associations with five epigenetic clocks were evaluated. Mediation analysis compared two alternative causal orderings linking epigenetic aging, methylation, and lipids. Robustness was assessed by sensitivity analyses including surrogate variable adjustment, fixed-effect meta-analysis, and methylation risk scores. We identified 1,081 differentially methylated positions associated with logTG (Bacon-corrected false discovery rate < 0.05) and seven associated with HDL. All five CHARGE consortium CpGs ( CPT1A , TXNIP , ABCG1 , SREBF1 , and DHCR24 ) were confirmed in both replication subsets by meta-analysis ( P = 2.2 × 10 −3 –2.6 × 10 –17 ). Across the wider discovery set, 89.8% of CpGs were directionally concordant in the primary replication subset (binomial P = 3.4 × 10 –170 ), although only 24 reached individual meta-analysis significance. A generational gradient in age acceleration–TG associations was observed; DunedinPACE showed the broadest associations across lipid traits (logTG P = 4.0 × 10 −7 ). ABCG1 methylation accounted for 63% of the DunedinPACE–TG association, an estimate that was essentially unchanged when the causal ordering was reversed. A five-CpG methylation risk score explained 23.6% of additional TG variance in the discovery set, 16.1% in HEXA-I, and 5.9% in HEXA-II. This Korean EWAS supports the conservation of core lipid–methylation loci across ancestries, implicates ABCG1 on the axis linking accelerated aging to dyslipidemia, and describes a generational gradient in clock–lipid associations. Because both replication subsets came from the same cohort program and methylation was measured in blood, generalization to other populations and tissues requires further study.