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Variants of MicroRNA Genes: Gender-Specific Associations with Multiple Sclerosis Risk and Severity
Ivan Kiselev1, Vitalina Bashinskaya2,3, Olga Kulakova4,5
1Dep. of Molecular Biology and Medical biotechnology, Pirogov Russian National Research Medical University, Moscow 117997, Russia. kiselev.ivan.1991@gmail.com.
Abstract:
Multiple sclerosis (MS) is an autoimmune neuro-inflammatory disease arising from complex interactions of genetic, epigenetic, and environmental factors. Variations in genes of some microRNAs--key post-transcriptional regulators of many genes--can influence microRNAs expression/function and contribute to MS via expression changes of protein-coding target mRNA genes. We performed an association study of polymorphous variants of MIR146A rs2910164, MIR196A2 rs11614913, MIR499A rs3746444 MIR223 rs1044165 and their combinations with MS risk and severity. 561 unrelated patients with bout-onset MS and 441 healthy volunteers were enrolled in the study. We observed associations of MS risk with allele MIR223*T and combination (MIR223*T + MIR146A*G/G) carriage in the entire groups and in women at Bonferroni-corrected significance level (pcorr < 0.05). Besides, MIR146A*G/G association with MS was observed in women with nominal significance (pf = 0.025). No MS associations were found in men. A more severe MS course (MSSS value > 3.5) was associated with the carriage of MIR499A*C/T and, less reliably, of MIR499A*C (pcorr = 0.006 and pcorr = 0.024, respectively) and with the carriage of combinations (MIR499A*C/T + MIR196A2*C) and (MIR499A*C + MIR196A2*C) (pcorr = 0.00078 and pcorr = 0.0059, respectively). These associations also showed gender specificity, as they were not significant in men and substantially reinforced in women. The strongest association with MS severity was observed in women for combination (MIR499A*C/T + MIR196A2*C): pcorr = 4.43 × 10(-6) and OR = 3.23 (CI: 1.99-5.26).
Insights
Specific microRNA gene variants are linked to multiple sclerosis (MS) risk and severity, particularly in women. These findings highlight potential genetic factors influencing MS development and progression.
Area of Science:
- Neuroimmunology
- Genetics
- Molecular Biology
Background:
- Multiple sclerosis (MS) is an autoimmune neuroinflammatory disease influenced by genetic and environmental factors.
- MicroRNAs (miRNAs) are key gene regulators; their variations can impact gene expression and contribute to diseases like MS.
- Polymorphisms in miRNA genes may alter miRNA function, affecting target messenger RNA (mRNA) levels and disease susceptibility.
Purpose of the Study:
- To investigate the association of specific microRNA gene variants (MIR146A, MIR196A2, MIR499A, MIR223) and their combinations with the risk and severity of multiple sclerosis.
- To explore potential gender-specific effects of these microRNA variants on MS risk and disease course.
Main Methods:
- A case-control association study was conducted involving 561 patients with bout-onset MS and 441 healthy controls.
- Genotyping was performed for single nucleotide polymorphisms (SNPs) in MIR146A (rs2910164), MIR196A2 (rs11614913), MIR499A (rs3746444), and MIR223 (rs1044165).
- Statistical analyses, including Bonferroni correction, were used to assess associations between genotypes, MS risk, and MS severity scores (MSSS), with subgroup analyses for gender.
Main Results:
- MS risk was associated with MIR223*T allele and a combination of MIR223*T and MIR146A*G/G genotypes, particularly in women.
- The MIR146A*G/G genotype showed a nominal association with MS in women.
- MS severity was significantly associated with MIR499A*C/T and MIR499A*C genotypes, and combinations involving MIR499A and MIR196A2, with the strongest association observed in women for the (MIR499A*C/T + MIR196A2*C) combination.
Conclusions:
- Specific microRNA gene variants, notably in MIR223 and MIR146A, are associated with increased multiple sclerosis risk, especially in women.
- MicroRNA variants in MIR499A and MIR196A2 are linked to a more severe disease course in MS patients, with a pronounced effect in women.
- These findings suggest a significant role for microRNA genetic variations in the pathogenesis and progression of multiple sclerosis, with notable gender-specific influences.
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