IL12B gene polymorphisms have sex-specific effects in relapsing–remitting multiple sclerosis
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IL-12-family cytokines play a pivotal role in neuroinflammation and neurodegeneration in relapsing–remitting multiple sclerosis (RRMS). The aim of the study was to evaluate whether two polymorphisms in IL12B gene, rs17860508 and rs3212227, are associated with RRMS, and to define their function effect on serum level of IL-12p40 and IL-23 and degree of disability in RRMS cases. In total 156 Bulgarian patients with Expanded Disability Status Scale score ranging from 1.0 to 3.5 in remission of the disease and 379 controls were genotyped by polymerase chain reaction-based methods. The IL-12p40 and IL-23 serum levels were determined by enzyme-linked immunosorbent assay. We have found substantially higher IL-12p40 and IL-23 serum levels in cases than in controls (p < 0.01) in a sex-dependent manner. Women with RRMS had significantly higher IL-12р40 and IL-23 than men. Gender-stratified association analyses showed a significant impact of rs3212227 polymorphism on RRMS susceptibility in men. The carriers of rs3212227*CC-genotype (OR 3.390, 95% CI 1.007–11.545, p = 0.023) and haplotype rs17860508*2-allele/rs3212227*C-allele (OR 3.740; 95% CI 1.36–10.32, p = 0.007), showed higher risk of RRMS in men, in contrast to women. In women, both IL12B polymorphisms influencing the course, rather than genetic predisposition of RRMS. The rs17860508*22-genotype was associated with significantly lower disability (OR 0.208; 95% CI 0.055–0.725; pc = 0.01) and lower IL-23 serum levels (p = 0.0345), while rs3212227*AA-genotype was associated with early onset of the disease (OR 2.368; 95% CI 1.007–5.608; p = 0.03). Our results suggest that sex-specific effects of IL12B polymorphisms, rs17860508 and rs3212227, on genetic predisposition and disease course of RRMS, is probably mediated by their gender-dependent functional effect on IL-12p40-containing cytokines.
Keywordsrs17860508 rs3212227 IL-23 IL-12p40 Multiple sclerosis EDSS
This work was supported by the Medical University of Plovdiv, Bulgaria under research grant HO-02/2014 and Trakia University, Medical Faculty, Stara Zagora, Bulgaria under research Grant no. 2/2017.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
The study was designed and performed in agreement with the Declaration of Helsinki and was approved by the University Ethics Committee of Medical University of Plovdiv (protocol no. 3/26.06.2014).
Informed consent was obtained from all individual participants included in the study.
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