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Risk of Multiple Sclerosis: Analysis of Interactions between Variants of Nuclear and Mitochondrial Genomes

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Abstract

There is increasing evidence that the interaction of the mitochondrial and nuclear genomes substantially affects the risk of neurodegenerative diseases. The role of mitonuclear interactions in the development of multiple sclerosis, a severe chronic neurodegenerative disease of a polygenic nature, is poorly understood. In this work, we analyzed the association of multiple sclerosis with two-component mitonuclear combinations that include each of seven polymorphic variants of the nuclear genome localized in the region of the UCP2, and KIF1B genes and in the PVT1 locus (MYC, PVT1, and MIR1208 genes) and each of ten polymorphisms of the mitochondrial genome, as well as individual genetic variants that make up these combinations. Association of the individual components of these combinations with multiple sclerosis was also evaluated. 507 patients with multiple sclerosis and 321 healthy individuals were enrolled in the study, all participants were ethnic Russians. Two mitonuclear combinations associated with multiple sclerosis were identified: the UCP2 (rs660339) *A + MT-ATP6 (rs193303045) *G combination was characterized by p-value = 0.015 and OR = 1.39 [95% CI 1.05-1.87], and the PVT1 (rs2114358) *G + MT-ND1 (rs1599988) *C combination – by p-value = 0.012 and OR = 1.77 [95% CI 1.10-2.84]. Only one of the individual components of these combinations, allele rs660339 *A of the nuclear gene UCP2 encoding uncoupling protein 2 of the mitochondrial anion carrier family, was independently associated with multiple sclerosis (p = 0.028; OR = 1.36 [95% CI 1.01–1.84]). This study expands the current understanding of the role of mitonuclear interactions and variance of nuclear genes, whose products function in mitochondria, and in risk of MS.

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Funding

This work was carried out within the State Assignment AAAA-A19-119042590026-5 and with the financial support of the Russian Foundation for Basic Research within scientific project no. 19-315-51003.

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Authors and Affiliations

  1. Pirogov Russian National Research Medical University, 117997, Moscow, Russia

    M. S. Kozin, I. S. Kiselev, N. M. Baulina, G. V. Pavlova, A. N. Boyko, O. G. Kulakova & O. O. Favorova

  2. Sirius University of Science and Technology, 354340, Sochi, Russia

    M. S. Kozin, I. S. Kiselev, N. M. Baulina & G. V. Pavlova

Authors
  1. M. S. Kozin
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  2. I. S. Kiselev
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  3. N. M. Baulina
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  4. G. V. Pavlova
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  5. A. N. Boyko
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  6. O. G. Kulakova
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  7. O. O. Favorova
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Correspondence to M. S. Kozin.

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Conflict of interests. The authors declare that there is no conflicts of interest.

All procedures used in this paper are in accordance with the ethical standards of the institutional committee on research ethics and the 1964 Declaration of Helsinki and its subsequent amendments or comparable standards of ethics. Written informed consent was obtained from all participants to participate in the experiments.

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Abbreviations: CI, confidence interval; lncRNA, long noncoding RNA; PCR, polymerase chain reaction; PCR-RFLP, PCR with subsequent analysis of restriction fragment length polymorphism; OR, odds ratio; MS, multiple sclerosis; CNS, central nervous system; ETC, mitochondrial electron transport chain; GWAS, Genome Wide Association Study; LD, linkage disequilibrium; SNP, single nucleotide polymorphism; SF, synergy factor.

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Kozin, M.S., Kiselev, I.S., Baulina, N.M. et al. Risk of Multiple Sclerosis: Analysis of Interactions between Variants of Nuclear and Mitochondrial Genomes. Mol Biol 55, 839–846 (2021). https://doi.org/10.1134/S0026893321050071

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