An Intronic Risk SNP rs12454712 for Central Obesity Acts As an Allele-Specific Enhancer To Regulate <i>BCL2</i> Expression.

Abstract

Genome-wide association studies (GWAS) have reproducibly associated the single nucleotide polymorphism (SNP) rs12454712 with waist-to-hip ratio adjusted for BMI (WHRadjBMI), but the functional role underlying this intronic variant is unknown. Integrative genomic and epigenomic analyses supported rs12454712 as a functional independent variant. We further demonstrated that rs12454712 acted as an allele-specific enhancer regulating expression of its located gene <i>BCL2</i> by using dual-luciferase reporter assays and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9. Specifically, the rs12454712-C allele can bind transcription factor ZNF329, which efficiently elevates the enhancer activity and increases <i>BCL2</i> expression. Knocking down Bcl2 in 3T3-L1 cells led to the downregulation of adipogenic differentiation marker genes and increased cell apoptosis. A significant negative correlation between <i>BCL2</i> expression in subcutaneous adipose tissues and obesity was observed. Our findings illustrate the molecular mechanisms behind the intronic SNP rs12454712 for central obesity, which would be a potential and promising target for developing appropriate therapies.