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

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