ABSTRACT
Interleukin-23 (IL-23) has been associated with atherosclerosis in both humans and animal models with contradictory results. This cytokine is conformed by an α p19 (encoded by IL-23A gene) and a ß p40 subunit (encoded by IL-12B gene). The aim of this study was to evaluate the association of two polymorphisms located within (rs11171806) or near (rs2066808) of the IL-23A gene with the presence of premature coronary artery disease (CAD) and with cardiometabolic parameters. The rs2066808 and rs11171806 polymorphisms were determined in 2249 Mexican individuals (1160 with premature CAD and 1089 healthy controls). Under recessive and codominant 2 models, adjusted by confounding variables, the rs2066808 polymorphism could increase the genetic risk of premature CAD (odds ratio [OR] = 4.567, 95% confidence interval [CI]: 1.03-20.24, Precessive = 0.046 and OR = 4.606, 95% CI: 1.039-20.43, Pcodominant2 = 0.044). The association of the polymorphisms with cardiovascular risk factors was evaluated separately in premature CAD patients and healthy controls. In patients, the rs2066808 polymorphism could decrease the genetic risk of hyperinsulinemia, insulin resistance, and hypoalphalipoproteinemia, and increase the genetic risk of hyperuricemia, whereas the rs11171806 polymorphism could decrease the genetic risk of hyperinsulinemia and insulin resistance. In healthy controls, the rs11171806 polymorphism could decrease the genetic risk of hyperinsulinemia. These findings suggest that the rs2066808 polymorphism located near the IL-23A gene could increase the genetic risk of premature CAD and both studied polymorphisms could be associated with some cardiometabolic parameters in premature CAD patients and in healthy controls.
Subject(s)
Coronary Artery Disease/genetics , Interleukin-23 Subunit p19/genetics , Polymorphism, Single Nucleotide , Adult , Case-Control Studies , Female , Gene Frequency , Genetic Predisposition to Disease , Haplotypes , Humans , Male , Mexico , Middle AgedABSTRACT
BACKGROUND: Psoriatic arthritis (PsA) is a chronic skin and joint condition that considerably affects patient quality of life. Several studies have demonstrated different associations of genetic polymorphisms in the pathogenic process of PsA. Therefore, we conducted a meta-analysis to estimate the effect of polymorphisms in the cytokines TNF, IL12B, IL23A, and IL23R on PsA risk. METHODS: We screened 1,097 abstracts and identified 14 relevant studies published between January 2007 and December 2017. A systematic search was conducted in PubMed, Web of Knowledge and Scopus databases. Meta-analyses were performed for the comparisons of alleles and multiple genetic models. RESULTS: Among the cytokines studied, we found 17 polymorphisms that were the most investigated. The association to PsA was observed in the presence of polymorphisms: TNF-238 G > A (rs361525), -308 G > A (rs1800629), and -857 C > T (rs1799724); IL12B C > G (rs6887695) and A > C (rs3212227); IL23A A > G (rs2066808) and IL23R G > A (rs11209026). CONCLUSION: Our findings suggest that these variant cytokine genes may strongly influence the immunological response of PsA.
Subject(s)
Arthritis, Psoriatic/genetics , Interleukin-12 Subunit p40/genetics , Interleukin-23 Subunit p19/genetics , Receptors, Interleukin/genetics , Tumor Necrosis Factor-alpha/genetics , Arthritis, Psoriatic/immunology , Genetic Predisposition to Disease/genetics , Humans , Polymorphism, Single NucleotideABSTRACT
The Interleukin 23 (IL-23) has a central role in autoimmunity. Allelic variants of p19 subunit of IL-23 (IL23A) and IL-23 receptor (IL23R) genes and increased IL-23 serum concentrations were associated with autoimmune diseases. We therefore searched for variants of IL23A and IL23R that could predispose to Type 1 diabetes (T1D). The coding regions and boundary intron sequences of IL23A were sequenced. Variants of IL23A and of IL23R were also genotyped. Pancreatic and extrapancreatic autoantibodies and IL-23 serum levels were determined. The cohort involved 370 patients with T1D and 351 healthy control subjects. We observed only one coding IL23A variant (rs11171806 G>A) out of the 6 described in databases. As the G alleles of rs11171806 and rs2066808 variants of IL23A gene were in strong linkage disequilibrium (D'=-0.825 for controls, p<2.0 × 10(-6) and D'=-0.902, p<2.0 × 10(-17) for patients), further analyses were performed with the haplotypes. The GG haplotype was more frequent in controls (16.7%) than in T1D patients (9.5%), conferring a protection to T1D (OR=0.53; pc=0.0003). No association was found between IL23A allelic variants with age at diagnosis of diabetes, C-peptide levels or frequency of autoantibodies. IL23R variants (rs10889677 and rs11209026) frequency and IL-23 serum concentrations were similar between groups. The GG haplotype of lL23A variants (rs11171806 and rs2066808) was protective against T1D. IL23R variants (rs11209026 and rs10889677) were not associated with T1D. IL-23 serum concentrations did not differ between groups.
Subject(s)
Diabetes Mellitus, Type 1/genetics , Interleukin-23 Subunit p19/blood , Interleukin-23 Subunit p19/genetics , Receptors, Interleukin/genetics , Adult , Alleles , Autoantibodies/blood , Base Sequence , Brazil , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/metabolism , Female , Gene Frequency , Genetic Predisposition to Disease , Genetic Variation , Genotype , Humans , Interleukin-23 Subunit p19/metabolism , Linkage Disequilibrium , Male , Polymorphism, Single Nucleotide , Receptors, Interleukin/metabolism , Sequence Analysis, DNA , Young AdultABSTRACT
The maturation state of dendritic cells (DC) is regarded as a control point for the induction of peripheral tolerance or autoimmunity. Experimental autoimmune orchitis (EAO) serves as a model to investigate inflammatory-based testicular impairment, which ranks as a significant cause of male infertility. This work aimed to determine whether DC enrichment occurs organotypically in testicular draining lymph nodes (TLN) compared with LN draining the site of immunization (ILN) and thus contributes to the pathogenesis of autoimmune orchitis. In this regard, we quantified and characterized the DC from TLN and ILN in rats with EAO. Flow cytometric analysis showed a significant increase in the percentage of DC (OX62+) only in TLN from EAO rats compared with normal (N) and adjuvant control (C) groups. The number of DC from ILN and TLN expressing CD80, CD86 and major histocompatibility complex (MHC) II was comparable among N, C and experimental (E) groups at 30 and 50 days after the first immunization. However, TLN DC from EAO rats (50 days) showed an increase in mean fluorescence intensity for MHC II compared with N, C and E groups (30 days). The mRNA expression level of IL-10 and IL-12p35 was significantly upregulated in enriched DC fraction from TLN in EAO rats with no significant changes observed in ILN DC. The expression of IL-23p19 mRNA remained unchanged. Functional data, using proliferation assays showed that EAO-DC from TLN, but not from ILN, significantly enhanced the proliferation of naïve T cells compared with C-DC. In summary, our data suggest that the DC in TLN from orchitis rats are mature, present antigens to T cells and stimulate an autoimmune response against testicular antigens, thus causing immunological infertility.