The rs2238296 polymorphism of the mitochondrial DNA polymerase gamma gene and postinfarction left ventricular remodeling in patients with heart failure
Authors: Kuzheleva Elena K.E.A , Garganeeva Alla G.A.A , Aleksandrenko Victoria A.V.A , Tukish Olga T.U.V , Andreev Sergey A.S.L , Shipulin Vladimir S.V.M , Golubenko Maria G.M.V 
Published: October 2021

Abstract

Introduction
Mitochondria carry out respiratory function in cells, ensuring the operation of the electron transport chain and the production of ATP. The internal environment of mitochondria, including mitochondrial DNA (mtDNA), is susceptible to free radicals. DNA polymerase gamma mediates mtDNA replication. Mutations in the POLG1 gene cause, in particular, mtDNA depletion syndrome. This leads to mitochondrial dysfunction and reduces oxidative stress resistance, which is one of the main pathological factors in myocardial infarction (MI).

Purpose
To evaluate the association between rs2238296 polymorphism of the POLG1 gene and the features of left ventricular remodeling after MI in patients with chronic heart failure (CHF).

Methods
A total of 153 patients with CHF and history of myocardial infarction were enrolled in the study. According to echocardiography data, 56 patients (36.6%) were diagnosed with left ventricular aneurysm. Thus, the first group consisted of patients with postinfarction left ventricular aneurysm (n=56), the second group consisted of patients without left ventricular aneurysm (n=97). Genotyping of the rs2238296 polymorphism of the POLG1 gene (substitution of T for C) located in the first intron of the gene was performed using polymerase chain reaction (PCR), cleavage of PCR products with MspI restriction enzyme, and electrophoretic detection of the results.

Results
Groups of patients were comparable of gender (92,9% and 87,6% men, p=0.3) and age (57 [50; 60] and 55 [50; 60.5] years, p=0,8). The anamnesis of arterial hypertension (83.9% and 88.7%, p=0,3), diabetes mellitus (14.3% and 19.6%, p=0,4) and stroke (8.9% and 8.3%, p=0,9) in both group of patients was comparable too. Patients of the first group had a significantly lower left ventricular ejection fraction (43 [30; 53.5]% and 54.5 (44; 64)%, p&lt;0.001). In addition, clinical severity of CHF was higher in the first group, but the differences did not reach statistical significance. Thus, NYHA functional class III-IV was diagnosed in 60.7% of patients in group 1 and in 49.5% in group 2 (p=0.2). It was found that haplotype TT of the POLG1 gene rs2238296 polymorphism occurred equally often in the study groups (29.6% and 34.7%, p=0.5). TC was found with frequency 40.7% in patients with aneurism and 52.6% in patients without aneurism (p=0.2). Haplotype CC was found in almost every third patient with left ventricular aneurysm (29.6%), and only in 12.6% of cases in the group without aneurysm (OR 2.3; 95% CI 1.1–5.3, p=0.01). The studied polymorphism is located in the intron, but it can be localized in the region associated with the regulation of gene expression, or linked to a functionally significant polymorphism in another region of the gene.

Conclusion
The CC genotype of the POLG1 gene rs2238296 polymorphism is associated with an increased risk of developing left ventricular aneurysm after MI in patients with CHF.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): State assignment No. AAAA-A20-120041090007-8 (10.04.2020)