An APOA5 3' UTR variant associated with plasma triglycerides triggers APOA5 downregulation by creating a functional miR-485-5p binding site - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue American Journal of Human Genetics Année : 2014

An APOA5 3' UTR variant associated with plasma triglycerides triggers APOA5 downregulation by creating a functional miR-485-5p binding site

S. Charriere
C. Marcais
  • Fonction : Auteur
M. Di Filippo
  • Fonction : Auteur
A. Sassolas
  • Fonction : Auteur
M. Delay
  • Fonction : Auteur
A. Jalabert
Etienne Lefai
S. Rome
  • Fonction : Auteur
  • PersonId : 1195256
  • IdHAL : sophie-rome
P. Moulin
  • Fonction : Auteur

Résumé

APOA5 c.*158C\textgreaterT (rs2266788), located in the 3' UTR, belongs to APOA5 haplotype 2 (APOA5*2), which is strongly associated with plasma triglyceride levels and modulates the occurrence of both moderate and severe hypertriglyceridemia. Individuals with APOA5*2 display reduced APOA5 expression at the posttranscriptional level. However, the functionality of this haplotype remains unclear. We hypothesized that the hypertriglyceridemic effects of APOA5*2 could involve miRNA regulation in the APOA5 3' UTR. Bioinformatic studies have identified the creation of a potential miRNA binding site for liver-expressed miR-485-5p (MIRN485-5p) in the mutant APOA5 3' UTR with the c.*158C allele. In human embryonic kidney 293T (HEK293T) cells cotransfected with an APOA5 3' UTR luciferase reporter vector and a miR485-5p precursor, c.*158C allele expression was significantly decreased. Moreover, in HuH-7 cells endogenously expressing miR-485-5p, we observed that luciferase activity was significantly lower in the presence of the c.*158C allele than in the presence of the c.*158T allele, which was completely reversed by a miR-485-5p inhibitor. We demonstrated that the rare c.*158C APOA5 allele creates a functional target site for liver-expressed miR-485-5p. Therefore, we propose that the well-documented hypertriglyceridemic effect of APOA5*2 involves an APOA5 posttranscriptional downregulation mediated by miR-485-5p.

Dates et versions

hal-01859007 , version 1 (21-08-2018)

Identifiants

Citer

Cyrielle Caussy, S. Charriere, C. Marcais, M. Di Filippo, A. Sassolas, et al.. An APOA5 3' UTR variant associated with plasma triglycerides triggers APOA5 downregulation by creating a functional miR-485-5p binding site. American Journal of Human Genetics, 2014, 94 (1), pp.129-34. ⟨10.1016/j.ajhg.2013.12.001⟩. ⟨hal-01859007⟩
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