Regular exercise modifies the effects of 12 LDL-C SNPs on cardiovascular disease risk: KoGES

Cardiovascular disease risk is significantly driven by dyslipidemia, making it a crucial target for clinical management; however, the translation of low-density lipoprotein cholesterol (LDL-C)-related genetic susceptibility into clinical events is complex. Although regular physical activity improves cardiometabolic health, its effects on LDL-C concentrations are often modest. The present study investigated whether habitual exercise modifies the clinical expression of established LDL-C-associated genetic variants and their association with both cardiovascular and cerebrovascular outcomes among individuals with dyslipidemia. Data from 20,748 adults with dyslipidemia from the Korea Genome and Epidemiology Study (KoGES) were analyzed. Twelve LDL-C-associated single-nucleotide polymorphisms (SNPs), which were validated across independent Korean cohorts, were utilised to assess genetic risk. Associations with LDL-C levels and clinical outcomes (specifically including overall cardiovascular and cerebrovascular disease, coronary artery disease, and ischemic stroke) were evaluated by using multivariable regression and propensity score matching to minimise self-selection bias. Gene-exercise interactions were assessed by using multiplicative interaction terms. All of the selected SNPs demonstrated robust, directionally consistent associations with LDL-C levels regardless of exercise status. Exercise was associated with improved high-density lipoprotein cholesterol and triglyceride levels but did not substantially alter LDL-C concentrations. Notably, significant gene-exercise interactions for ischemic stroke were identified at the DHODH/HP (interaction odds ratio [OR] = 0.65, P = 0.029) and HPR (interaction OR = 0.65, P = 0.026) loci. These interaction signals remained directionally consistent in the propensity score-matched cohort, thus suggesting that exercise could attenuate genetic stroke risk through nonlipid pathways. Although these findings did not persist after stringent Bonferroni correction, they provide exploratory evidence of locus-specific interplay. Although the genetic architecture of LDL-C appears to be stable across physical activity strata, habitual exercise may modify the clinical manifestations of LDL-related genetic susceptibility, particularly regarding ischemic stroke. These findings suggest that regular exercise reduces cerebrovascular risk even in the presence of inherited lipid-related risk. By highlighting the active buffering effect of lifestyle modifications against genetic vulnerability, these results provide actionable evidence for precision prevention strategies, thereby fundamentally supporting broader public health initiatives to reduce the burden of noncommunicable diseases and foster long-term health and well-being.