Abstract
•The incidence of IDH2 gene mutations is high in myocardial infarction patients.•Missense IDH2 variants are associated with decreased IDH2 enzyme activity.•Missense IDH2 variants are associated with lipid peroxides accumulation.•IDH2 genetic variation is a novel potential risk factor for myocardial infarction.
Mitochondrial isocitrate dehydrogenase (IDH2) is a major contributor to cellular redox control. The aim of this study was to preliminary link IDH2 genetic variations to redox imbalance, atherogenesis and risk of acute myocardial infarction (AMI).
This case-control study included 120 AMI patients and 120 healthy controls. IDH2 genetic variations were tested using direct sequencing. IDH2 enzyme activity was measured spectrophotometrically. Malondialdehyde (MDA) and Oxidized low density lipoproteins (ox-LDL) concentrations, as biomarkers of oxidative stress, were quantitated using ELISA.
Four missense heterozygous mutations were detected within IDH2 gene. The variant forms of the enzyme showed a markedly reduced enzymatic activity (2.22 ± 0.56 mU/mL in wild type compared to 0.65 ± 0.35 mU/mL in mutant enzyme). IDH2 enzyme activity correlated negatively with MDA and ox-LDL concentrations (r = −80.875 and −0.891 respectively). There was a strong association between IDH2 mutations and elevated MDA and ox-LDL (rpb = 0.764 and 0.652, both p < 0.001). After adjustment of other risk factors, IDH2 genetic variations showed to be an independent risk factor for AMI (ß=1.792, p = 0.019).
The study proved that IDH2 genetic variations lead to impaired enzyme activity, redox imbalance, accumulation of lipid-peroxides and coronary atherogenesis. However, because such gene association has not been studied before, further studies are recommended.