Associations between interleukin-10 polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis

The aim of this study was to determine whether the interleukin-10 (IL-10) polymorphisms confer susceptibility to rheumatoid arthritis (RA). A meta-analysis was conducted on the associations between the IL-10 −1082 G/A, −592 C/A, −892 C/T and IL-10.R polymorphisms and RA using; (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) the additive model. A total of 16 studies (19 comparisons) involving 2647 RA patients and 3383 controls were considered in the meta-analysis. Meta-analysis of the IL-10 −1082 G/A polymorphism showed no association with RA in the study subjects, or in European or Asian subjects. However, meta-analysis of the −1082 G allele in 4 studies in Hardy–Weinberg equilibrium showed a significant association with RA (OR = 1.217, 95% CI = 1.027–1.442, P = 0.0236). In contrast, meta-analysis of the C allele, the CC genotype, and of the CC versus the AA genotype of the IL-10 −592 C/A polymorphism showed significant associations with RA. The overall ORs of the associations between the C allele and RA were 0.684 and 0.758 (95% CI = 0.494–0.946, P = 0.022; 95% CI = 0.475–1.210, P = 0.045) in all study subjects and Asians. Meta-analysis of the CC + CT versus TT genotype and of the CC versus TT genotype of the IL-10 −892 C/T polymorphism revealed significant associations with RA. The overall OR of the association between the C allele carrier and RA was 0.552 (95% CI = 0.375–0.812, P = 0.003). No association was found between the IL10.R2 alleles and RA. This meta-analysis suggests that the IL-10 −592 C/A polymorphism confers susceptibility to RA in Asians and that the IL-10 −1082 G/A and −892 C/T polymorphisms are associated with RA susceptibility. These findings suggest the IL-10 genes confer susceptibility to RA.     

Associations between interleukin-23 receptor polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis

The aim of this study was to determine whether interleukin-23 receptor (IL-23R) polymorphisms confer susceptibility to rheumatoid arthritis (RA). A meta-analysis was conducted on the associations between the IL-23R rs1343151, rs10489629, rs7517847, rs11209026, rs1004819, and rs2201841 polymorphisms and RA using (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) the additive model. A total of 13 studies from eight articles involving 10,016 RA patients and 11,967 controls were considered in the meta-analysis. Meta-analysis identified a significant association between RA and the A allele of the rs1343151 polymorphism in the overall population (OR?=?1.110, 95?% CI?=?1.056–1.168, p?=?4.7?×?10^?6). Stratification by ethnicity identified a significant association between this polymorphism and RA in Europeans (OR?=?1.105, 95?% CI?=?1.049–1.163, p?=?1.4?×?10^?5). An association was also found between RA and the A allele carrier of the rs1343151 polymorphism in Europeans (OR?=?1.135, 95?% CI?=?1.058–1.217, p?=?4.0?×?10^?5). Meta-analysis revealed a significant association between RA and the A allele of the rs10489629 polymorphism in the overall population (OR?=?1.079, 95?% CI?=?1.029–1.131, p?=?0.002) and in Europeans (OR?=?1.092, 95?% CI?=?1.038–1.149, p?=?0.001). Meta-analyses of recessive, dominant, and additive models showed the same pattern as the meta-analysis of the A allele of the rs10489629 polymorphism, that is, a significant association with RA in Europeans. However, no association was found between the IL-23R rs7517847, rs11209026, rs1004819, and rs2201841 polymorphisms and RA susceptibility. This meta-analysis shows that the IL-23R rs1343151 and rs10489629 polymorphisms are associated with the development of RA in Europeans. These findings suggest that the IL-23R genes confer susceptibility to RA in the European population, but further study of this association is required in other ethnic groups.     

Age-related changes in arthritis susceptibility and severity in a murine model of rheumatoid arthritis

Background

Rheumatoid arthritis (RA) most often begins in females in the fourth-fifth decade of their life, suggesting that the aging of the immune system (immunosenescence) has a major role in this disease. Therefore, in the present study, we sought to investigate the effect of age on arthritis susceptibility in BALB/c mice using the proteoglycan (PG)-induced arthritis (PGIA) model of RA.

Results

We have found that young, 1-month-old female BALB/c mice are resistant to the induction of PGIA, but with aging they become susceptible. PG-induced T cell responses decline with age, whereas there is a shift toward Th1 cytokines. An age-dependent decrease in T cell number is associated with an increased ratio of the memory phenotype, and lower CD28 expression. Antigen-presenting cells shifted from macrophages and myeloid dendritic cells in young mice toward B cells in older mice. The regulatory/activated T cell ratio decreases in older mice after PG injections indicating impaired regulation of the immune response.

Conclusion

We conclude that immunosenescence could alter arthritis susceptibility in a very complex manner including both adaptive and innate immunities, and it cannot be determined by a single trait. Cumulative alterations in immunoregulatory functions closely resemble human disease, which makes this systemic autoimmune arthritis model of RA even more valuable.     

High interleukin-4 expression and interleukin-4 gene polymorphisms are associated with susceptibility to human paracoccidioidomycosis

Paracoccidioidomycosis (PCM) is caused by dimorphic fungi fromtheParacoccidioides brasiliensis complex. Previous studies havedemonstrated that the severity of disease is associated with a T-helper 2 immuneresponse characterised by high interleukin (IL)-4 production. In the present study weanalysed two polymorphisms in the IL-4 gene (-590 C/T and intron-3microsatellite) in 76 patients with PCM and 73 control subjects from an endemic area.The production of IL-4 by peripheral blood mononuclear cells after antigen orphytohaemagglutinin stimulation was determined by ELISA. A significant correlationwas observed between the RP2/RP2 intron-3 genotype and infection withParacoccidioides sp. (p = 0.011), whereas the RP1/RP1 genotypewas correlated with resistance. No significant correlation was observed forthe IL-4 promoter polymorphism. Furthermore, the low IL-4expression observed in the control group compared with patients was associated withthe RP1/RP1 genotype. These results suggest that IL-4polymorphismsmight be associated with the ability of the host to control Paracoccidioidessp. infection. The relevance of this polymorphism is supported by theobservation that patients with disease produce high levels of IL-4 following mitogenor antigen stimulation. The IL-4 gene is located in the cytokinecluster region of chromosome 5 where other polymorphisms have also beendescribed.     

Itch gene polymorphisms in healthy population and in patients affected by rheumatoid arthritis and atopic dermatitis

Itch is a HECT-containing E3 ligase that induces proteasomal degradation of many proteins. Two targets of Itch, JunB and Notch, have been found involved in the activation of T-helper cells. It has been proposed that alterations in pathways leading to Th1 and Th2 differentiations could be involved in inflammatory diseases and in autoimmune disorders respectively. Moreover knockout mice for Itch gene displayed inflammatory immune responses and constant itching of the skin. The aim of this work was to screen the putative functional regions of Itch in order to investigate if gene polymorphisms are present in healthy population and if they are differently represented in patients affected by rheumatoid arthritis or atopic dermatitis. Genomic DNA purified from blood samples of 100 healthy volunteers, 25 atopic dermatitis, and 45 rheumatoid arthritis patients were analysed by sequencing. We found 8 substitutions in the functional regions of Itch, but we could not find significant differences between patients and healthy subjects, suggesting a critical role for Itch in the biology of the cell and that Itch could be involved in these disorders through a complex network of interactions in the proteasomal pathways.     

NO role of NOS2A susceptibility polymorphisms in rheumatoid arthritis

Nitric oxide has been described as a trigger for the synthesis of proinflammatory mediators and as a cytotoxic molecule with a pivotal role in apoptosis at the joints of rheumatoid arthritis (RA) patients. Polymorphisms in the NOS2A gene, which codes for the inducible nitric oxide synthase [(i)NOS], have been tested for association with several autoimmune diseases such as Crohn’s disease or type 1 diabetes. Moreover, the existence of correlated levels of (i)NOS protein and synovial cell apoptosis in RA patients, pointed to NOS2A as a good candidate gene involved in RA predisposition. The role of NOS2A was studied in 405 Spanish RA patients and in 398 ethnically matched healthy controls, through the analysis of five SNPs: two at the NOS2A promoter (rs2779251 and 2779248), other two exonic markers (Asp³⁴⁶Asp (rs1137933) and Ser⁶⁰⁸Leu (rs22518)) and the last one located at intron 7 (rs3729508). We also included other two widely-used promoter polymorphisms: the insertion/deletion (TAAA/-) and the (CCTTT)n microsatellite. No individual association of each single-marker or haplotype was found with RA susceptibility. Our data show the low linkage disequilibrium between these NOS2A SNPs and the alleles of the (CCTTT)n microsatellite, corroborating in a Spanish population the observation previously described in British and Gambian population. The present data do not support a causative role of NOS2A polymorphisms in RA predisposition.     

Influence of BLK polymorphisms on the risk of rheumatoid arthritis

B cell lymphocyte kinase (BLK) encodes a member of the Src kinase family and thus may influence the proliferation and differentiation of cells. A single nucleotide polymorphism (SNP) located in the first intron of BLK has shown that the risk C allele of rs2248932 is associated with lower levels of messenger RNA expression of BLK. We hypothesized that this polymorphism may contribute to rheumatoid arthritis (RA) susceptibility. We studied BLK rs2248932 T/C gene polymorphisms in 329 patients with RA and 697 controls in a Chinese population. Genotyping was done using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). When the BLK rs2248932 TT homozygote genotype was used as the reference group, the CC genotype was associated with a significantly increased risk of RA. In the recessive model, when the BLK rs2248932 TT/TC genotypes were used as the reference group, the CC homozygote genotype was associated with a significantly increased susceptibility to RA. In stratification analyses, a significantly increased risk for RA associated with the BLK rs2248932 CC genotype was evident among younger patients, CRP-negative patients and anti-CCP-positive patients compared with the BLK rs2248932 TT/TC genotype. The risk was also significantly evident among RF-positive patients, patients with lower ESR levels, patients with lower or higher DAS28 score and patients with a lower functional class. These findings suggested that the functional SNP BLK rs2248932 T/C variant allele was associated with RA development. However, our results were obtained from a moderate-sized sample, and therefore this is a preliminary conclusion. Validation in a larger study from a more diverse ethnic population is needed to confirm these findings.     

Association of interferon-gamma and interleukin-4 gene polymorphisms with susceptibility to brucellosis in Iranian patients

Activation of macrophages and their antimicrobial activities by interferon-gamma (IFN-gamma) plays a crucial role in controlling Brucella infection. Interleukin-4 (IL-4) antagonizes the macrophage activity effects of IFN-gamma and thus inhibits cell-mediated immune reactions. Given that the production of IFN-gamma and IL-4 are under genetic control, we investigated the relationship between these two cytokine gene polymorphisms and the susceptibility to brucellosis. Hundred and ninety-five patients with brucellosis and 91 healthy animal husbandmen who owned infected animals and consumed their contaminated dairy products were selected to participate in this study. All individuals were genotyped for IFN-gamma and IL-4 gene polymorphisms at positions +874 and -590, respectively. Results showed that IFN-gammaAA genotype was significantly more prevalent (P =0.03) and IL-4CC genotype was significantly less frequent (P =0.034) in the patient group compared to the control group. Also, the frequency of IFN-gamma/IL-4 combination of genotype (IFN-gammaTT/IL-4CC) and allele (IFN-gammaT/IL-4C) were significantly higher in the controls than in the patients (P =0.033 and P =0.0035, respectively). Data suggest that individuals who have IFN-gammaAA genotype are more susceptible, and those who carry IL-4CC genotype are more resistant to brucellosis. We also suggest that individuals who carry IFN-gammaT/IL-4C or IFN-gammaTT/IL-4CC can be more resistant to Brucella infection.     

Association of single nucleotide polymorphisms (SNPs) of PADI4 gene with rheumatoid arthritis (RA) in Indian population

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting ~ 1% of the population worldwide. The genome wide association studies on RA patients revealed linkage with 1p36 locus containing peptidyl arginine deiminase 4 (PADI4) genes. Case-control association studies and mRNA stability assays reported the association of PADI4 gene with RA in Korean and Japanese populations. However, such association was not found in Spanish population. Differences in the association of PADI4 with RA in different populations prompted the present study in Indian population. Anti-CCP antibodies, RF antibody, disease activity scores at 28 joints (DAS28) and mutations in three exons of PADI4 were investigated in RA patients and control group. Among the patients anti-CCP antibody levels were found to be associated with high DAS28 values (r = 0.4526, P < 0.0001). Polymorphism in exon-4 (padi4_104, [rs1748033]) of PADI4 showed significant association of 'C' allele with RA in the study population (P = 0.0008). Polymorphism in exon-3 (padi4_92, [rs874881]) also exhibited moderate association with the disease (P = 0.075). However, no association of the disease was found with the SNPs padi4_89 [rs11203366] and padi4_90 [rs11203367] in exon-2 of PADI4.     

Interleukin-18 gene polymorphisms and rheumatoid arthritis: A meta-analysis

Interleukin-18 (IL-18) is a member of the IL-1 superfamily that enhances both innate and acquired immune responses. IL-18 is highly expressed in sera, synovial fluids and synovial tissues of patients with RA, and these IL-18 levels are correlated with RA disease activity, indicating an important role of IL-18 in the pathogenesis of RA. Several studies have examined the association of IL-18 gene polymorphisms with RA, but these studies have shown inconclusive and controversial results. To verify the association between IL-18 gene polymorphism and susceptibility to RA, we conducted a meta-analysis of all relevant reports cited in MEDLINE/PubMed before October 2012. A meta-analysis on the association between the IL-18 rs1946518 SNP and RA was performed for 2944 patients with RA and 2377 controls from 7 published studies and a meta-analysis on the association between the IL-18 rs187238 SNP and RA was performed for 1319 patients with RA and 1211 controls from 5 published studies. In addition, 2 studies involving 1873 RA patients and 1092 controls were considered in the meta-analysis of the association between the IL-18 rs360722 SNP and RA. No significant association was found between two IL-18 SNPs (rs1946518 and rs187238) and RA susceptibility in all subjects. In subgroup analysis stratified by ethnicity, there was still no significant association between these two IL-18 SNPs and RA susceptibility. However, the frequency of the T allele at rs360722 was found to be significantly lower in patients with RA compared with controls, although this finding was based on only 2 studies. The results of our meta-analysis suggest that IL-18 rs360722 SNP is only associated with RA susceptibility. However, due to only two studies included in our meta-analysis, large-scale well designed studies should be considered in future studies to confirm the exact role of IL-18 rs360722 SNP in RA susceptibility.     

Association of common polymorphisms in known susceptibility genes with rheumatoid arthritis in a Slovak population using osteoarthritis patients as controls

Introduction  

Both genetic and environmental factors contribute to rheumatoid arthritis (RA), a common and complex autoimmune disease. As well as the major susceptibility gene HLA-DRB1, recent genome-wide and candidate-gene studies reported additional evidence for association of single nucleotide polymorphism (SNP) markers in the PTPN22, STAT4, OLIG3/TNFAIP3 and TRAF1/C5 loci with RA. This study was initiated to investigate the association between defined genetic markers and RA in a Slovak population. In contrast to recent studies, we included intensively-characterized osteoarthritis (OA) patients as controls.     

Interferon-gamma and interleukin-4 single nucleotide gene polymorphisms in Paracoccidioidomycosis

The gene polymorphisms interferon-gamma (IFN-γ) +874 T/A and interleukin (IL)-4 −590 C/T have been associated with the altered production of cytokines. Therefore, they might be indicative of the occurrence of Paracoccidioidomycosis (PCM) caused by Paracoccidioides brasiliensis. The analysis of single nucleotide polymorphism (SNP) at position +874 IFN-γ showed an increase occurrence of A/T genotype in both PCM patients and healthy individuals as control (HIC) (56% and 45%, respectively), while the allelic distribution showed 82% of A allele in the patients and 80% in the controls. The SNP of −590 IL-4 showed that C/T genotype was significantly (p < 0.05) more prevalent (39%) in PCM group compared to the HIC group (19%), while IL-4 C/C genotype was significantly less frequent (59%) in the patient group compared to the control group (81%). Otherwise, 41% of PCM patients and 19% of HIC individuals carried the IL-4 T allele. Stimulation of peripheral blood mononuclear cells (PBMC) from PCM patients with cell extract antigenic preparations (PbAg) as well as secreted and surface antigens (MEXO) of P. brasiliensis evidenced that there is no difference in the IFN-γ production related to A and T alleles between PCM and HIC individuals. However, with IL-4 production, PCM patients classified as C phenotype showed two times more IL-4 production than PCM patients classified as T phenotype and HIC controls. In conclusion, our results suggest that functional genetic variants in the IL-4 promoter could influence the production of IL-4 in PCM.     

Role of vitamin D receptor gene polymorphisms and serum 25-hydroxyvitamin D level in Egyptian female patients with systemic lupus erythematosus

Recently, several studies have demonstrated the role of vitamin D receptor (VDR) polymorphisms in the development of systemic lupus erythematosus (SLE). We aimed to evaluate VDR (ApaI, BsmI, and FokI) gene polymorphisms and haplotypes as a risk factors and/or activity markers for SLE, and whether they influence 25-hydroxyvitamin (25(OH) D) level. One hundred and seven SLE patients and 129 controls were enrolled in this study. Disease activity in SLE patients was assessed using Disease Activity Index. Polymorphisms of VDR gene were detected using polymerase chain reaction restriction fragment length polymorphism. Serum 25(OH) D levels were measured using ELISA. We found that ApaI AA genotype, BsmI B allele, Bb, BB genotypes, FokI F allele and FF genotype frequencies of VDR were increased in SLE group. There were significant associations of VDR ApaI AA, BsmI BB, and FokI FF genotypes with lupus nephritis and higher SLE activity scores. Moreover, serum 25(OH) D levels were increased in SLE patients carrying FokI ff genotype compared with patients carrying FF genotype. VDR haplotypes aBF and ABF were associated with SLE risk. The ABF haplotype was associated with higher SLE activity scores and lower serum 25(OH) D concentrations. We observed that the presence of leuko/lymphopenia, renal disorders, higher SLE activity scores and higher anti-dsDNA levels were accompanied by a significant decrease of serum 25(OH)D concentrations. We concluded that The VDR genes polymorphisms, haplotypes, and decreased 25(OH) D levels were associated with risk and more activity scores of SLE.     

Molecular screening and association study of IL15 gene polymorphisms in rheumatoid arthritis

Interleukin 15 (IL-15) is a pleiotropic pro-inflammatory cytokine known to play a relevant role in rheumatoid arthritis (RA) pathogenesis. In this study we aimed to investigate for the first time the contribution of IL15 gene to RA susceptibility. We screened 13 single nucleotide polymorphisms (SNPs) localised within IL15 regulatory regions (promoter, 5' UTR region and 3' UTR region) in a total of 420 individuals, who were genotyped by direct sequencing of PCR products. In addition, an association study of these IL15 SNPs was conducted in three independent case-control cohorts of Spanish Caucasian origin, including a total of 645 RA patients and 656 healthy controls. The presence of the 13 selected IL15 SNPs in our population was confirmed and no new genetic variants were found. The distribution of the IL15 selected SNPs in RA patients and controls showed no statistically significant deviation in any of the populations studied. Additionally, we performed a haplotype analysis that revealed three IL15 haplotype blocks. None of the haplotype blocks was associated with RA susceptibility or severity in the three cohorts analysed. Our results suggest that the IL15 gene polymorphisms do not appear to play a major role in RA genetic predisposition in our population.     

Impact of glutathione-S-transferase gene polymorphisms on enzyme activity, lung function and bronchial asthma susceptibility in Egyptian children

Background

Asthma is a complex multifactorial disease with an obvious genetic predisposition. Polymorphisms of the glutathione-S-transferase (GST) genes are known risk factors for some environmentally-related diseases. The aim of the present study was to investigate the role of polymorphisms in the GSTT1, GSTM1 and GSTP1 genes and asthma susceptibility in Egyptian children, and to analyze their effect on GST activity and lung function.

Methods

GSTT1 and GSTM1 gene polymorphism was genotyped using the multiplex polymerase chain reaction (PCR) and GSTP1 ILe105Val polymorphism was determined using PCR-restriction fragment length polymorphism (PCR-RFLP) in 168 healthy and 126 asthmatic children (82 atopic and 44 nonatopic). Also GST enzyme activity and lung function were evaluated.

Results

Asthmatic children had a significant higher prevalence of the GSTM1 null (P = 0.003) and significant lower prevalence of GSTP1 Val/Val genotypes (P = 0.02) than control group. Lung function was significantly decreased in GSTM1 null genotype and GSTP1 Ile/Ile genotype. GSTP1 Val/Val genotypes and GSTM1 null genotype had a significant decrease in plasma GST activity.

Conclusions

GST genes polymorphisms may play an important role in pathogenesis and susceptibility to asthma in children.     

Association of MHC and rheumatoid arthritis: HLA polymorphisms in phenotypic variants of rheumatoid arthritis

Genes in the human leukocyte antigen (HLA) region remain the most powerful disease risk genes in rheumatoid arthritis (RA). Several allelic variants of HLA-DRB1 genes have been associated with RA, supporting a role for T-cell receptor-HLA-antigen interactions in the pathologic process. Disease-associated HLA-DRB1 alleles are similar but not identical and certain allelic variants are preferentially enriched in patient populations with defined clinical characteristics. Also, a gene dosing effect of HLA-DRB1 alleles has been suggested by the accumulation of patients with two RA-associated alleles, especially in patient subsets with a severe disease course. Therefore, polymorphisms in HLA genes are being explored as tools to dissect the clinical heterogeneity of the rheumatoid syndrome. Besides HLA polymorphisms, other risk genes will be helpful in defining genotypic profiles correlating with disease phenotypes. One such phenotype is the type of synovial lesion generated by the patient. HLA genes in conjunction with other genetic determinants may predispose patients to a certain pathway of synovial inflammation. Also, patients may or may not develop extraarticular manifestations, which are critical in determining morbidity and mortality. HLA genes, complemented by other RA risk genes, are likely involved in shaping the T-cell repertoire, including the emergence of an unusual T-cell population characterized by the potential of vascular injury, such as seen in extraarticular RA.