Functional genomic analysis reveals HAVCR1 as the key regulator of 5q33.3 locus linked to hyperlipidemia.

Hyperlipidemia is a major risk factor for atherosclerosis and other serious cardiovascular diseases, yet it often presents without obvious symptoms in the absence of comorbidities, complicating early detection and management. Given the high heritability of lipid traits, genome-wide association studies (GWASs) have identified numerous loci associated with serum lipids; however, pinpointing the causal variants remains a challenge. Here, we investigated the 5q33.3 locus and identified HAVCR1 as a likely effector gene influencing lipid metabolism. By integrating functional genomics and experimental validation, we identified two non-linked variants, rs6882076 and rs17573010, that modulate HAVCR1 via allele-specific binding by IRF2 and GATA4, respectively. rs6882076 was refined from prior GWAS findings, while rs17573010 emerged from ancestry-specific analysis. These findings highlight the complexity of genetic regulation across populations and establish a mechanistic link between lipid metabolism and inflammation, offering insights into the genetic basis of hyperlipidemia and its potential translational relevance.