Variants of Mitochondrial Genome and Risk of Multiple Sclerosis Development in Russians

For the first time in the history of ethnic Russians, an association analysis the development of multi-ple 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–as-sociated biallelic combinations of haplogroup J with the alleles CCL5 rs2107538*A, PVT1 rs2114358*G, TNFSF14rs1077667*C, and IL4 rs2243250*C, which were not associated with MS individually, were identified. For the combination of haplogroup J and the CCL5*A allele (P = 0.00043, o‎r = 5.47 [95% CI 1.85–16.15]), a epistatic (syn-ergistic) 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 PVT1*G 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.