Long-chain polyunsaturated fatty acids (LC-PUFAs) influence human health in several areas, including cardiovascular disease, diabetes, fatty liver disease, and cancer. ELOVL2 encodes one of the key enzymes in the in vivo synthesis of LC-PUFAs from their precursors. Variants near ELOVL2 have repeatedly been associated with levels of LC-PUFA-derived metabolites in genome-wide association studies (GWAS), but the mechanisms behind these observations remain poorly defined. In this study, we found that rs953413, located in the first intron of ELOVL2, lies within a functional FOXA and HNF4α cooperative binding site. The G allele of rs953413 increases binding of FOXA1/FOXA2 and HNF4α to an evolutionarily conserved enhancer element, conferring allele-specific upregulation of the rs953413-associated gene ELOVL2. The expression of ELOVL2 was significantly downregulated by both FOXA1 and HNF4α knockdown and CRISPR/Cas9-mediated direct mutation to the enhancer element. Our results suggest that rs953413 regulates LC-PUFAs metabolism by altering ELOVL2 expression through FOXA1/FOXA2 and HNF4α cooperation.

长链多不饱和脂肪酸（LC-PUFA）在几个领域影响人类健康，包括心血管疾病，糖尿病，脂肪肝疾病和癌症。ELOVL2编码从前体体内合成LC-PUFA的关键酶之一。在全基因组关联研究（GWAS）中，ELOVL2附近的变体已与LC-PUFA衍生的代谢物水平反复相关，但这些观察结果背后的机制仍不清楚。在这项研究中，我们发现位于ELOVL2第一个内含子的rs953413，位于功能性FOXA和HNF4α合作结合位点内。rs953413的G等位基因增加了FOXA1 / FOXA2和HNF4α与进化上保守的增强子的结合，赋予rs953413相关基因ELOVL2等位基因特异性上调。ELOVL2的表达被FOXA1和HNF4α敲低以及CRISPR / Cas9介导的增强子直接突变显着下调。我们的结果表明，rs953413通过通过FOXA1 / FOXA2和HNF4α的合作来改变ELOVL2的表达来调节LC-PUFAs的代谢。