Single-nucleotide polymorphisms near the ILRUN gene are genome-wide primarily associated with coronary artery disease (CAD) and plasma lipid traits. However, the biological basis of this association remains unknown. This study aimed to investigate the role of ILRUN in lipoprotein and plasma lipid metabolism. Common population-level natural genetic variation with small effect sizes can reveal pathways and targets modulating plasma lipid levels with profound biological and clinical importance. Unbiased genome-wide association studies with follow-up functional validation studies allow the opportunity to identify novel players in regulating lipid metabolism and cardiovascular disease risk.

Liver transcriptome analysis revealed altered transcription of genes, particularly peroxisome proliferator-activated receptors (PPARα). The livers from Ilrun-deficient mice had increased PPARα protein. Human ILRUN binds to ubiquitinated proteins, including PPARα, and the ubiquitin-associated–like the domain of ILRUN was found to be required for its interaction with PPARα. Our results also provide functional evidence that ILRUN may be the casual gene underlying the observed genetic associations with plasma lipids at 6p21 in humans.

In conclusion, the functional link between ILRUN and lipid metabolism was investigated, inspired by human genetic studies. Future studies on the precise molecular mechanisms of liver ILRUN function may uncover new pathways in regulating lipid metabolism and point toward promising approaches for treating dyslipidemia and associated cardiovascular diseases.