Genetic Influence of CCDC63 Polymorphisms on Alcohol-Induced Dyslipidemia in a Korean Cohort

While chronic alcohol consumption is an established risk factor for lipid metabolic dysregulation, the underlying genetic mediators remain largely elusive. This study investigated the synergistic impact of <i>CCDC63</i> (coiled-coil domain containing 63) polymorphisms and alcohol intake on dyslipidemia risk within a Korean cohort. Leveraging data from the KARE study (<i>N</i> = 6655; 4327 dyslipidemia cases vs. 2328 controls), we analyzed SNPs across the <i>CCDC63</i> locus via Affymetrix SNP Array 5.0. Logistic regression, adjusted for age and sex, was performed to evaluate genotype-phenotype association and gene-environment interactions induced by alcohol exposure duration. Three intronic variants (rs10849915, rs11065756, and rs2238149) were significantly associated with dyslipidemia (OR ≥ 1.15, <i>p</i> < 0.005). Notably, stratified analysis revealed a clear gene-environment interaction. In ever-drinkers, the G-allele of rs10849915 was significantly associated with a higher risk of dyslipidemia (OR = 1.23, <i>p</i> < 0.05), significantly lower γ-GTP levels (β = -8.08), and reduced HDL (β = -1.42). However, no such genetic associations were observed in the non-drinking group (<i>p</i> > 0.05 for all traits). Our findings demonstrate that <i>CCDC63</i> variants specifically modulate lipid metabolism and hepatic enzyme levels in an alcohol-dependent manner. The paradoxical association-lower γ-GTP yet higher dyslipidemia risk in drinkers-suggests that <i>CCDC63</i> plays a critical role in the complex interplay between alcohol exposure and systemic lipid homeostasis.