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.
- 3.Trenova AG, Slavov GS, Manova MG, Draganaova-Filipova MN, Mateva NG, Miteva LD, Stanilova SA (2017) Alterations in serum levels of IL-17 in contrast to TNF-alpha correspond to disease-modifying treatment in relapsing–remitting multiple sclerosis. Scand J Clin Lab Investig 77:283–288. https://doi.org/10.1080/00365513.2017.1303843 CrossRefGoogle Scholar
- 4.Reale M, de Angelis F, di Nicola M, Capello E, di Ioia M, Gd L, Lugaresi A, Tata AM (2012) Relation between pro-inflammatory cytokines and acetylcholine levels in relapsing–remitting multiple sclerosis patients. Int J Mol Sci 13:12656–12664. https://doi.org/10.3390/ijms131012656 CrossRefGoogle Scholar
- 6.Shajarian M, Alsahebfosoul F, Etemadifar M, Sedaghat N, Shahbazi M, Firouzabadi FP, Dezashibi HM (2015) IL-23 plasma level measurement in relapsing remitting multiple sclerosis (RRMS) patients compared to healthy subjects. Immunol Investig 44:36–44. https://doi.org/10.3109/08820139.2014.930477 CrossRefGoogle Scholar
- 7.D’Angelo C, Reale M, Costantini E, Di Nicola M, Porfilio I, de Andrés C, Fernández-Paredes L, Sánchez-Ramón S, Pasquali L (2018) Profiling of canonical and non-traditional cytokine levels in interferon-β-treated relapsing–remitting-multiple sclerosis patients. Front Immunol 9:1240. https://doi.org/10.3389/fimmu.2018.01240 CrossRefGoogle Scholar
- 10.Bonin S, Zanotta N, Sartori A, Bratina A, Manganotti P, Trevisan G, Comar M (2018) Cerebrospinal fluid cytokine expression profile in multiple sclerosis and chronic inflammatory demyelinating polyneuropathy. Immunol Investig 47:135–145. https://doi.org/10.1080/08820139.2017.1405978 CrossRefGoogle Scholar
- 12.Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH, Ustekinumab MS Investigators (2008) Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing–remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomized, dose-ranging study. Lancet Neurol 7:796–804. https://doi.org/10.1016/S1474-4422(08)70173-X CrossRefGoogle Scholar
- 20.Javan MR, Shahraki S, Safa A, Zamani MR, Salmaninejad A, Aslani S (2017) An interleukin 12 B single nucleotide polymorphism increases IL-12p40 production and is associated with increased disease susceptibility in patients with relapsing–remitting multiple sclerosis. Neurol Res 39:435–441. https://doi.org/10.1080/01616412.2017.1301623 CrossRefGoogle Scholar
- 21.Shokrgozar MA, Sarial S, Amirzargar A, Shokri F, Rezaei N, Arjang Z, Radfar J, Yousefi-Behzadi M, Ali Sahraian M, Lotfi J (2009) IL-2, IFNgamma, and IL-12 gene polymorphisms and susceptibility to multiple sclerosis. J Clin Immunol 29:747–751. https://doi.org/10.1007/s10875-009-9310-z CrossRefGoogle Scholar
- 22.Forte GI, Ragonese P, Salemi G, Scola L, Candore G, D’Amelio M, Crivello A, Di Benedetto N, Nuzzo D, Giacalone A, Lio D, Caruso C (2006) Search for genetic factors associated with susceptibility to multiple sclerosis. Ann N Y Acad Sci 1067:264–269. https://doi.org/10.1196/annals.1354.034 CrossRefGoogle Scholar