Kozin M S, Kulakova O G, Kiselev I S, Balanovsky O P, Boyko A N, Favorova O O
Pirogov Russian National Research Medical University, Ostrovitjanova Str. 1, Moscow, 117997, Russia.
National Medical Research Center of Cardiology, 3rd Cherepkovskaya Str., 15a, Moscow, 121552 , Russia.
Acta Naturae. 2018 Oct-Dec;10(4):79-86.
For the first time in the history of ethnic Russians, an association analysis the development of multiple sclerosis (MS) was performed for the mitochondrial haplogroups H, J, K, and U, as well as for the individual mitochondrial DNA (mtDNA) polymorphisms discriminating these haplogroups (m.1719G > A, m. 7028C > T, m.9055G > A, m.10398A > G, m.12308A > G). A total of 283 unrelated patients with the relapsing-remitting form of MS and 290 healthy controls were enrolled in the study. Association of haplogroup J with MS was observed (P = 0.0055, OR = 2.00 [95% CI 1.21-3.41]). After gender stratification, the association remained significant in women (P = 0.0083, OR = 2.20 [95% CI 1.19-4.03]). A multilocus analysis of the association between combinations of mtDNA haplogroups with variants of 38 nuclear immune-related genes and MS risk was carried out. MS-associated biallelic combinations of haplogroup J with the alleles CCL5 rs2107538A, PVT1 rs2114358G, TNFSF14 rs1077667C, and IL4 rs2243250C, which were not associated with MS individually, were identified. For the combination of haplogroup J and the CCL5A allele (P = 0.00043, OR = 5.47 [95% CI 1.85-16.15]), a epistatic (synergistic) interaction between the components was established using two statistical criteria: the PFLINT value in the Fisher-like interaction numeric test and the synergy factor, SF (PFLINT = 0.025, SF = 4.32 [95% CI 1.20-15.60]). The combination of haplogroup J and the PVT1G allele is characterized by PFLINT = 0.084; SF = 3.05 [95% CI 1.00-9.31] and can also be epistatic. Thus, interaction between nuclear and mitochondrial genome components in the risk of developing MS was demonstrated for the first time.
在俄罗斯族裔的历史上，首次针对线粒体单倍群H、J、K和U以及区分这些单倍群的个体线粒体DNA（mtDNA）多态性（m.1719G > A、m.7028C > T、m.9055G > A、m.10398A > G、m.12308A > G）进行了多发性硬化症（MS）发病的关联分析。该研究共纳入了283例复发缓解型MS的非亲缘患者和290例健康对照。观察到单倍群J与MS存在关联（P = 0.0055，OR = 2.00 [95% CI 1.21 - 3.41]）。按性别分层后，该关联在女性中仍具有显著性（P = 0.0083，OR = 2.20 [95% CI 1.19 - 4.03]）。对mtDNA单倍群组合与38个核免疫相关基因变体及MS风险之间的关联进行了多位点分析。确定了单倍群J与等位基因CCL5 rs2107538A、PVT1 rs2114358G、TNFSF14 rs1077667C和IL4 rs2243250C的MS相关双等位基因组合，这些等位基因单独与MS无关联。对于单倍群J和CCL5A等位基因的组合（P = 0.00043，OR = 5.47 [95% CI 1.85 - 16.15]），使用两种统计标准在各成分之间建立了上位性（协同）相互作用：费舍尔样相互作用数值检验中的PFLINT值和协同因子SF（PFLINT = 0.025，SF = 4.32 [95% CI 1.20 - 15.60]）。单倍群J和PVT1G等位基因的组合特征为PFLINT = 0.084；SF = 3.05 [95% CI 1.00 - 9.31]，也可能具有上位性。因此，首次证明了核基因组和线粒体基因组成分在MS发病风险中的相互作用。
