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The aim of this study was to evaluate the possible association of IL12B gene polymorphisms with serum levels of IL-12p40, IL-23 and genetic susceptibility to rheumatoid arthritis (RA) in the Bulgarian population. Genotyping for IL12Bpro (rs17860508) and IL12B A/C - 3' UTR (rs3212227) polymorphisms was performed by polymerase chain reaction (PCR)-based methods in 125 RA patients and 239 healthy controls. The IL-23 and IL-12p40 serum levels were measured by enzyme-linked immunosorbent assay (ELISA). An association was established between the rs17860508 polymorphism and RA susceptibility in Bulgarian population with an increased frequency of rs17860508 minor allele-2 and homozygous genotype-22 in RA patients. The rs17860508 risk RA genotype-22 was also significantly correlated to elevated serum IL-23 in RA patients. Although, there was no association between the rs3212227 and genetic predisposition to RA, significantly increased serum levels of both Il-12p40 and IL-23 were observed in RA patients with the rs3212227 AA genotype. Furthermore, the distribution of haplotypes and genotype combination in our cohort indicated increased RA risk in individuals carrying the rs17860508/rs3212227 2/A haplotype or 2.2/AC+CC combination, while 1/A haplotype or 1.1/AA combination may be protective for RA. In conclusion, our study demonstrates a functional effect of IL12B polymorphisms on IL-12p40 and IL-23 cytokine levels in RA patients and suggests a leading role for IL12B rs17860508 in the genetic predisposition to RA, while IL12B rs3212227 significantly modify the RA risk in Bulgarian population.

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; p c  = 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.