Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by the autoimmune inflammation, demyelination, and neurodegeneration. This complex disease develops in genetically predisposed individuals under adverse environmental factors. To date, a large number of MS-associated polymorphic loci of the nuclear genome have been identified; however, their total variability can explain only about 48% of the observed inheritance of MS. Polymorphic variants of the mitochondrial genome and interactions of mitochondrial and nuclear genes (mitonuclear interactions) may be the possible sources of the “missing heritability”. We analyzed the association with MS of 10 mitochondrial DNA polymorphisms (m.1719, m.4216, m.4580, m.4917, m.7028, m.9055, m.10398, m.12308, m.13368, m.13708) in DNA of 540 MS patients and 406 healthy individuals. The allele m.9055*G was the only mitochondrial variant associated with MS (P_f = 0.027). To evaluate interactions of mitochondrial and nuclear genomes, we searched for biallelic combinations containing one of 10 mitochondrial variants and one of 35 variants of immune-related nuclear genes. Carriership of mitochondrial variants m.4216, m.4580, or m.13708 in biallelic combinations with variants of nuclear genes IL7R, CLEC16A, CD6, CD86 or PVT1 was associated with MS (P_f = 0.0036–0.00030). We identified epistatic interaction between components of a combination (m.13708*A + PVT1 rs4410871*T). The existence of epistatic biallelic combination can reflect the genuine mitonuclear epistasis.

多发性硬化症（MS）是中枢神经系统的慢性疾病，其特征是自身免疫性炎症，脱髓鞘和神经变性。这种复杂的疾病在不利的环境因素中在遗传易感人群中发展。迄今为止，已经鉴定了核基因组的大量与MS相关的多态性位点。但是，它们的总变异性只能解释观察到的MS遗传的约48％。线粒体基因组的多态性变异以及线粒体和核基因的相互作用（线粒体相互作用）可能是“遗传力缺失”的可能来源。我们分析了与线粒体10种DNA多态性（m.1719，m.4216，m.4580，m.4917，m.7028，m.9055，m.10398，m.12308，m.13368，m。540名MS患者和406名健康个体的DNA中含有13708个样本）。m.9055 * G等位基因是唯一与MS相关的线粒体变体（P _f  = 0.027）。为了评估线粒体和核基因组的相互作用，我们搜索了双等位基因组合，其中包含免疫相关核基因的10个线粒体变体之一和35个变体之一。线粒体的Carriership变体m.4216，与核基因的变体的等位基因组合m.4580，或m.13708 IL7R，CLEC16A，CD6，CD86或PVT1用MS（相关联的P _˚F  = 0.0036-0.00030）。我们确定了组合（m.13708 * A + PVT1 rs4410871 * T）组件之间的上位相互作用 。上位性双等位基因组合的存在可以反映真正的微核上位。