rs953413 Regulates Polyunsaturated Fatty Acid Metabolism by Modulating ELOVL2 Expression

Pan, GangUppsala universitet,Medicinsk genetik och genomik,Science for Life Laboratory, SciLifeLab (författare)

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.

Cavalli, MarcoUppsala universitet,Medicinsk genetik och genomik,Science for Life Laboratory, SciLifeLab(Swepub:uu)marca978 (författare)
Carlsson, BjörnAstraZeneca, Res & Early Dev, Cardiovasc Renal & Metab, BioPharmaceut R&D, Gothenburg, Sweden (författare)
Skrtic, StankoAstraZeneca AB, Pharmaceut Technol & Dev, Gothenburg, Sweden;Sahlgrens Univ Hosp, Dept Med, Gothenburg, Sweden (författare)
Kumar, ChanchalAstraZeneca, BioPharmaceut R&D, Translat Sci & Expt Med, Res & Early Dev,Cardiovasc Renal & Metab CVRM, Gothenburg, Sweden;Karolinska Inst, AstraZeneca Integrated CardioMetab Ctr KI AZ ICMC, Dept Med, Huddinge, Sweden (författare)
Wadelius, Claes,1955-Uppsala universitet,Science for Life Laboratory, SciLifeLab,Medicinsk genetik och genomik(Swepub:uu)claeswad (författare)
Uppsala universitetMedicinsk genetik och genomik (creator_code:org_t)

Av författaren/redakt...: Pan, Gang; Cavalli, Marco; Carlsson, Björn; Skrtic, Stanko; Kumar, Chanchal; Wadelius, Claes, ...

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