New markers of atherosclerosis: a threshold level of heteroplasmy in mtDNA mutations

Sazonova, Margarita A.; Рыжкова, А.И.; Sinyov, Vasily V.; Galitsyna, Elena V.; Orekhova, Varvara A.; Melnichenko, Alexandra А.; Orekhov, Alexander N.; Ravani, A.; Sobenin, Igor A.

doi:10.20517/2574-1209.2017.16

Cited by 17 publications

(33 citation statements)

References 40 publications

(63 reference statements)

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“…On the opposite, the latest findings on the role of mitochondrial DNA variation in individual predisposition to atherosclerosis provide a growing body of evidence and the expectation of the breakthrough in understanding of molecular mechanisms and pathways of atherogenesis [14,15] . Heteroplasmic mtDNA mutations represent a promising molecular biomarker of genetic susceptibility to atherosclerosis and related pathologies [16][17][18][19] . In our study, we have demonstrated that several atherosclerosis-associated mutations of mitochondrial DNA taken together as a mutation burden of mitochondrial genome possess their own explanatory power and give a significant increase atop of assessment of conventional risk factors.…”

Section: Discussionmentioning

confidence: 99%

Profiling of risk of subclinical atherosclerosis: possible interplay of genetic and environmental factors as the update of conventional approach

Sobenin¹,

Myasoedova²,

Kirichenko³

et al. 2019

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Aim:To explore whether geographical location, genetic and environmental factors are associated with carotid atherosclerosis in high-risk individuals. Methods:In Moscow 470 apparently healthy, asymptomatic volunteer subjects with a high cardiovascular disease risk were recruited to participate in a cross-sectional study. Carotid intima-media thickness (cIMT), a validated biomarker for present and future cardiovascular disease risk, was assessed by means of high resolution ultrasound scans in subjects. Results:The total burden of conventional cardiovascular risk factors explained 21% of the cIMT variability; the mutational burden of mitochondrial genome defined by heteroplasmic mutations m.652delG, m.3256C>T, m.13513G>A, m.14459G>A, and m.15059G>A independently explained 23% variability; the combination of conventional and genetic risk factors increased explanatory level to 36%. Further exploratory statistical analyses showed air pollution as an independent risk factor for cIMT. Conclusion:In our study we confirmed and expanded the existence of a European geographic gradient of atherosclerosis risk and its association with cardiovascular disease risk. Geographical, environmental (particularly, air pollution) -and genetic risk factors (particularly, mutant variants of mitochondrial genome) may interplay in the formation of susceptibility to atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Profiling of risk of subclinical atherosclerosis: possible interplay of genetic and environmental factors as the update of conventional approach

Sobenin¹,

Myasoedova²,

Kirichenko³

et al. 2019

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“…For pyrosequencing the following primer sequences were used [24,26,[28][29][30] : 1. For m.652insG The heteroplasmy level of mtDNA mutations was analyzed using a quantitative method developed on the basis of pyrosequencing technology by our laboratory [24][25][26]38,39] . The statistical analysis was performed using SPSS 22.0 software package [40] .…”

Section: Methodsmentioning

confidence: 99%

“…Each mitochondria contains several copies of the mitochondrial genome. Therefore, during the analysis of DNA samples from the study participants it is necessary to determine the heteroplasmy level of each investigated mitochondrial genome mutation (ratio of mtDNA molecules containing the mutation to the total number of mtDNA molecules) [24][25][26][27][28] . It differs significantly from SNP analysis of the nuclear genome, where it is necessary to identify homozygous and heterozygous individuals according to this SNP.…”

Section: Introductionmentioning

confidence: 99%

MtDNA mutations linked with left ventricular hypertrophy

Sinyov¹,

Рыжкова²,

Sazonova³

et al. 2019

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Aim: In left ventricular hypertrophy (LVH), the heart muscle thickens. One third of individuals with LVH never complain of heart problems. However, such patients have a high risk of sudden death. LVH can be caused by arterial atherosclerotic lesions. The linkage of mtDNA mutations 652insG, m.5178C>A, m.3336T>C, m.14459G>A, 652delG, m.14846G>A, m.1555A>G, m.15059G>A, m.3256C>T, m.12315G>A and m.13513G>A with atherosclerosis was described earlier by our laboratory. The aim of the study was to analyze the linkage of these mtDNA mutations with LVH. Methods: DNA from white blood cells was isolated using a phenol-chloroform method. PCR-fragments of DNA contained the region of the investigated mutations. The heteroplasmy level of mtDNA mutations was analyzed using a pyrosequencing-based method developed by our laboratory. Results: We investigated two groups of individuals. One hundred and ninety-four patients with LVH. Two hundred and ten were conventionally healthy. It was found that mtDNA mutation m.5178C>A was significantly associated with LVH. Single nucleotide replacement m.1555A>G was associated with LVH at the level of significance P ≤ 0.1. At the same time m.12315G>A and m.3336T>C were significantly associated with the absence of this pathology. Single nucleotide replacement m.14459G>A was associated with the absence of LVH at the significance level P ≤ 0.1. Conclusion: MtDNA mutations m.5178C>A and m.1555A>G can be used for molecular genetic assessment of the predisposition of individuals to the occurrence of left ventricular hypertrophy. They can also be used for the family analysis of this pathology. Mutations m.12315G>A, m.3336T>C and m.14459G>A can be used in the development of LVH gene therapy methods.

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“…Currently, subcellular therapy is being developed mainly for cancer cells, but we believe that such approaches are applicable to cardiology, in particular, for atherosclerotic diseases. For instance, some pro-atherogenic mitochondrial DNA mutations associated with atherosclerosis can lead to mitochondrial dysfunction [3] . Some photo-sensitizing agents accumulate selectively in mitochondria making the photodynamic targeting efficient enough.…”

Section: Dear Editormentioning

confidence: 99%