Association of variants in the IL12B gene with leprosy and tuberculosis

Abstract

There is a great range in outcomes after mycobacterial infections, and this is probably due to individual variation in immune responses. One of the key cytokine regulators of the immune response is interleukin (IL-) 12. The IL12B gene encodes the p40 chain of both IL-12 and IL-23 and it has two major variant sites at which different alleles are associated with increased levels of gene expression and with susceptibility to a range of immune-related diseases. We hypothesized that IL12B variants associated with increased expression would be as associated with susceptibility to persistent mycobacterial infection. We tested this hypothesis by genotyping Indian subjects, having either leprosy or tuberculosis (TB), as well as ethnically matched controls. Subjects with leprosy were less likely to have the 3'UTR genotype associated with lower IL12B expression (P= 0.001). Subjects with TB were not only more likely to have the high-expressing IL12B promoter genotype (P= 0.01) but also more likely to have this in the same haplotype with the high expressing 3'UTR allele (P= 0.0009). These results suggest these infectious diseases may be improved by modulating IL-l2p40 production.

IL12B polymorphisms are linked but not associated with Plasmodium falciparum parasitemia: a familial study in Burkina Faso

“…Our results also indicate that two known cisregulatory element polymorphisms, IL12Bpro and IL12B 3 0 UTR, did not strongly influence parasitemia, despite the associations between IL-12 levels and P. falciparum parasitemia, 19 between IL12Bpro and cerebral malaria 6 and the association of several diseases related to immune responses with IL12Bpro and IL12B 3 0 UTR. 20,22,23,31 Since IL12B polymorphisms may interact, such that different haplotypes exhibit different IL-12 levels, 23 we also evaluated the association of parasitemia with haplotypes, including the IL12Bpro-IL12B 3 0 UTR haplotypes; we detected the association of parasitemia with neither haplotypes based on the seven polymorphisms identified nor with IL12Bpro-IL12B 3 0 UTR haplotypes. This suggests that parasitemia is not influenced by genetic variation in IL12B, including IL12Bpro and IL12B 3 0 UTR polymorphisms.…”

“…6 Furthermore, a stronger association was found between cerebral malaria and an haplotype based on IL12Bpro and one polymorphism in the 3 0 untranslated region (UTR) of IL12B (rs3212227). 6 Interestingly, the IL12B 3 0 UTR polymorphism has been associated with several diseases related to immune responses, 22,23 and with variation in the production of IL-12. 22 To our knowledge, this was the only report of an association between IL12B and human malaria.…”

Innate Immune Gene Polymorphisms in Tuberculosis

“…Discrepant results have been reported among various populations regarding the link between TB and IL-12 polymorphisms (especially for IL-12B, the gene encoding the IL12p40 subunit). Several IL-12B polymorphisms in the introns, promoter, or 3=-UTR were found to be associated with TB in some studies (83,151,236) but not others (132,173,201). An IL-12B 3=-UTR SNP (rs3212227) was identified as a risk factor for pulmonary TB in populations of African origin in a confirmation study (152).…”

Association Between IL12A rs568408, IL12B rs3212227 and IL-12 Receptor rs383483 Polymorphisms and Risk of Pulmonary Tuberculosis

“…In contrast to our findings, Morris et al (20) revealed an association between IL12B rs3212227 and PTB risk in Guinea-Bissau and African-Americans population. Morahan et al (21) showed that the distribution of 3' UTR genotype of IL12B gene was different between the TB patients and control groups, besides they demonstrated a positive correlation between the expression of IL-12 and this polymorphism. They suggested that this polymorphism can cause increased IL-12 expression.…”