Functional Genetic Variant in ATG5 Gene Promoter in Acute Myocardial Infarction

Area of Science:

• Cardiovascular Biology
• Genetics
• Molecular Biology

Background:

• Coronary artery disease (CAD), including acute myocardial infarction (AMI), is linked to inflammation and metabolic dysfunction, often driven by atherosclerosis.
• Dysfunctional autophagy, a cellular process, is implicated in abnormal lipid metabolism and inflammation, with prior studies noting altered autophagic activity in AMI patients.
• Autophagy-related protein 5 (ATG5) is crucial for autophagy, prompting investigation into its potential role in CAD and AMI pathogenesis.

Purpose of the Study:

• To investigate the genetic and functional significance of the ATG5 gene promoter in the context of coronary artery disease and AMI.
• To identify and characterize genetic variants within the ATG5 gene promoter in patients with AMI and healthy controls.

Main Methods:

• Genomic analysis of the ATG5 gene promoter in a cohort of 378 AMI patients and 386 ethnic-matched healthy controls.
• Identification and characterization of genetic variants, including single-nucleotide polymorphisms (SNPs) and deletion variants.
• Functional assessment of promoter activity using cultured cell lines (HEK-293 and H9c2) and electrophoretic mobility shift assays (EMSA).

Main Results:

• Fifteen genetic variants, including 6 SNPs in the ATG5 gene promoter, were identified.
• A novel deletion variant (g.106326168_70delTCT) and an SNP (rs190825454) were found in one AMI patient but not in controls.
• The identified deletion variant significantly reduced ATG5 gene promoter transcriptional activity (P < 0.01) and altered transcription factor binding, while other variants had no significant effect.

Conclusions:

• A rare genetic variant in the ATG5 gene promoter may impair its transcriptional activity and influence ATG5 levels.
• This variant could represent a novel, albeit rare, genetic risk factor contributing to the development of acute myocardial infarction.
• Further research is warranted to elucidate the precise mechanisms by which ATG5 gene variants impact cardiovascular health.