Kozin M S, Kiselev I S, Baulina N M, Pavlova G V, Boyko A N, Kulakova O G, Favorova O O
Pirogov Russian National Research Medical University, Moscow, 117997 Russia.
Sirius University of Science and Technology, Sochi, 354340 Russia.
Mol Biol (Mosk). 2021 Nov-Dec;55(6):956-964. doi: 10.31857/S0026898421060070.
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 often 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)С 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 rs660339A 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.
越来越多的证据表明，线粒体基因组与核基因组的相互作用会显著影响神经退行性疾病的风险。线粒体-核相互作用在多发性硬化症（一种具有多基因性质的严重慢性神经退行性疾病）发展中的作用尚不清楚。在这项研究中，我们分析了多发性硬化症与两组分线粒体-核组合之间的关联，这些组合包括位于UCP2、KIF1B基因区域以及PVT1基因座（MYC、PVT1和MIR1208基因）中的核基因组的七个多态性变体中的每一个，以及线粒体基因组的十个多态性，以及构成这些组合的个体遗传变体。还评估了这些组合的各个组成部分与多发性硬化症的关联。本研究纳入了507例多发性硬化症患者和321名健康个体，所有参与者均为俄罗斯族。确定了两种与多发性硬化症相关的线粒体-核组合：UCP2（rs660339）*A + MT-ATP6（rs193303045）*G组合的p值 = 0.015，OR = 1.39 [95% CI 1.05 - 1.87]，以及PVT1（rs2114358）*G + MT-ND1（rs1599988）С组合的p值 = 0.012，OR = 1.77 [95% CI 1.10 - 2.84]。这些组合中只有一个个体成分，即编码线粒体阴离子载体家族解偶联蛋白2的核基因UCP2的等位基因rs660339A，与多发性硬化症独立相关（p = 0.028；OR = 1.36 [95% CI 1.01 - 1.84]）。这项研究扩展了目前对线粒体-核相互作用以及核基因变异作用的理解，这些核基因的产物在线粒体中发挥作用，并与多发性硬化症的风险相关。
