Functional genetic variants in the SIRT5 gene promoter in acute myocardial infarction

Area of Science:

• Genetics
• Cardiovascular Disease
• Mitochondrial Biology

Background:

• Coronary artery disease (CAD), including acute myocardial infarction (AMI), is a complex condition with largely unknown genetic underpinnings.
• Mitochondrial sirtuins (SIRT3, SIRT4, SIRT5) are key regulators of cellular metabolism and stress response.
• Low-frequency and rare genetic variants are increasingly recognized as potential contributors to complex diseases.

Purpose of the Study:

• To investigate the role of DNA sequence variants (DSVs) and single nucleotide polymorphisms (SNPs) in the SIRT5 gene promoter in the development of AMI.
• To determine if identified variants affect SIRT5 gene expression and its potential contribution to AMI pathogenesis.

Main Methods:

• Genetic analysis of the SIRT5 gene promoter in a cohort of AMI patients and healthy controls.
• Functional analysis using reporter gene assays in HEK-293 and H9c2 cell lines to assess promoter activity.
• Electrophoretic mobility shift assays (EMSA) to evaluate the impact of SNPs on transcription factor binding.

Main Results:

• Eleven DSVs and SNPs were identified in the SIRT5 gene promoter region.
• Two novel heterozygous DSVs and three heterozygous SNPs were exclusively found in AMI patients.
• These specific DSVs and SNPs significantly reduced SIRT5 promoter activity in cellular models (P < 0.05).
• SNPs were shown to alter transcription factor binding, while DSVs and SNPs found in controls did not significantly affect promoter activity.

Conclusions:

• Specific DSVs and SNPs in the SIRT5 gene promoter are associated with AMI.
• These variants may contribute to AMI development by altering SIRT5 expression levels.
• SIRT5 gene promoter variants represent a potential risk factor for AMI.