Variants of MicroRNA Genes: Gender-Specific Associations with Multiple Sclerosis Risk and Severity

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).

Associations ofmicroRNAsingle nucleotide polymorphisms and disease risk and pathophysiology

“…Many studies have suggested that rs3746444 is correlated with the incidence and risk of many cancers in Asian populations , including prostate cancer (PCa) , squamous cell carcinoma of the head and neck (SCCHN) , and breast cancer , while the relationship between rs3746444 and non‐HBV‐related hepatocellular carcinoma (HCC) has not been discovered . rs3746444 may be involved in inflammatory AD, such as rheumatoid arthritis (RA) , Behcet's disease (BD) , and multiple sclerosis (MS) , by regulating various inflammatory factors. The T allele of rs3746444 was a risk factor in an Iranian population compared with the C allele, while it was a protective factor in Mediterranean populations, and Yang et al found it had no effect in an Asian population for RA .…”

Processo epigenéticos envolvidos na fisiopatologia da esclerose múltipla com ênfase na função dos miRNAs

“…De acordo com Kiselev et al, (2015), os miRNAs são pequenas sequências de RNA de fita simples com tamanho entre 19-24 nucleotídeos. Atualmente estão depositadas no miRBase (http://www.mirbase.org/) mais de 1800 miRNAs humanos que foram descobertos.…”

“…Segundo Kiselev et al (2015) a presença de diferentes miRNAs foi demostrada de forma alterada em pacientes com esclerose múltipla.…”

Les microARN

“…Deux théories qui s'opposent l'une à l'autre, émergent. La première considère la dérégulation des miARN comme un des facteurs responsables de l'apparition de la SEP. À l'appui de cette théorie, la mise en évidence récente de l'association entre SEP et certains variants génétiques de miARN [9,10]. La seconde théorie suppose que la dérégulation des miARN serait une conséquence d'un dérèglement préalable de la réponse neuro-immune.…”

“…Au début des années 2000, l'importance des miARN a été décrite dans diffé-rents contextes pathologiques (le diabète [6] (➜), les maladies cardiovasculaires [7,58] (➜) et le cancer [8]). Plusieurs équipes se sont alors intéres-sées à l'expression des miARN chez les patients atteints de SEP. D'autres ont étudié les polymorphismes des gènes codant ces miARN : des polymorphismes mononucléo-tidiques (ou SNP pour single nucleotide polymorphism) associés à la SEP ont ainsi été découverts dans certains gènes de miARN [9,10]. Parallèlement, un vaste réseau de miARN, dont l'expression est modifiée chez les patients atteints de SEP, a été mis en évidence, princiconséquence, des recommandations récentes ont proposé de regrouper la PPMS et la SPMS en une seule entité, dénommée « maladie progressive ».…”