Genetic Influence of <em>CCDC63</em> 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 CCDC63 (Coiled-Coil Domain Containing 63) polymorphisms and alcohol intake on dyslipidemia risk within a Korean cohort. Leveraging data from the KARE study (n=6,655; 4,327 dyslipidemia cases vs. 2,328 controls), we analyzed SNPs across the CCDC63 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 by alcohol exposure duration. Three intronic variants (rs10849915, rs11065756, and rs2238149) were significantly associated with dyslipidemia (OR ≥1.15, P &lt;0.005). Notably, stratified analysis revealed a clear gene–environment interaction. In current drinkers, the G-allele of rs10849915 was significantly associated with a higher risk of dyslipidemia (OR = 1.23, P &lt;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 (P &gt; 0.05 for all traits). Our findings demonstrate that CCDC63 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 CCDC63 plays a critical role in the complex interplay between alcohol exposure and systemic lipid homeostasis.