A common variant in 11q23.3 associated with hyperlipidemia is mediated by the binding and regulation of GATA4

• Published in: Npj genomic medicine Vol. 7; no. 1; p. 4
• Main Authors: Chou, Wen-Cheng, Chen, Wei-Ting, Shen, Chen-Yang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19-01-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/1647/2017; 631/208/205; 692/308/174; 692/53/2423; 692/699/2743/2037; Alleles; Association analysis; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Chromosome 11; Gene Function; Gene Therapy; Genetic analysis; Genetic diversity; Genomes; Genotypes; Hepatocytes; Homeostasis; Human Genetics; Hyperlipidemia; Internal Medicine; Phenotypes; Phenylephrine; Statistical analysis
• ISSN: 2056-7944; 2056-7944
• DOI: 10.1038/s41525-021-00279-5

Large-scale genome-wide associations comprising multiple studies have identified hundreds of genetic loci commonly associated with hyperlipidemia-related phenotypes. However, single large cohort remains necessary in aiming to investigate ethnicity-specific genetic risks and mechanical insights. A community-based cohort comprising 23,988 samples that included both genotype and biochemical information was assembled for the genome-wide association analysis (GWAS) of hyperlipidemia. The analysis identified fifty genetic variants (
P
 < 5 × 10
−8
) on five different chromosomes, and a subsequent validation analysis confirmed the significance of the lead variants. Integrated analysis combined with cell-based experiments of the most statistically significant locus in 11q23.3 revealed rs651821 (
P
 = 4.52 × 10
−76
) as the functional variant. We showed transcription factor GATA4 preferentially binds the T allele of rs651821, the protective allele for hyperlipidemia, which promoted
APOA5
expression in liver cells and individuals with the TT genotype of rs651821. As GATA4-APOA5 axis maintains triglyceride homeostasis, GATA4 activation by phenylephrine implies synergism for lowering triglyceride levels in hyperlipidemia patients. Our study demonstrates that rs651821 mediates
APOA5
activation via allele-specific regulation by GATA4. We suggest elevating GATA4 activity could provide a therapeutic potential for treating the development of hyperlipidemia.