Genetic Polymorphism (rs329498) in the Pellino-1 Gene as Possible Predisposal Factor for Systemic Lupus Erythematosus in a Chinese Population

Objective: The purpose of this study was to analyze the association of two single nucleotide polymorphisms (SNPs) in Peli-1 gene with systemic lupus erythematosus (SLE) in a Chinese population.

Methods: We conducted a case–control study and a total of 738 SLE patients and 827 healthy controls were finally recruited. Peli-1 rs329498 and rs10496105 polymorphisms were specified from genomic DNA using TaqMan genotyping assay on Fluidigm 192.24 system.

Results: Allele contrast showed the minor allele C was associated with decreased risk for SLE when compared with the A allele (OR = 0.851, 95% CI = 0.737–0.983, p = 0.028). Significant difference was observed in genotype distribution of rs329498 polymorphism between lupus nephritis (LN) patients and non-LN patients (χ² = 8.18, p = 0.017). Furthermore, we also found a decreased frequency of the minor allele C in LN patients (29.2%) than in non-LN patients (37.7%) (χ² = 8.67, p = 0.003). Moreover, a significant difference was also detected under a dominant model with regard to the distribution of genotype frequencies between LN patients and non-LN patients (CC + AC vs. AA: OR = 0.632, 95% CI = 0.451–0.884, p = 0.007). Clinical features analysis showed a significant difference in the distribution of genotypic frequencies between patients with malar rash and patients without this feature (χ² = 6.63, p = 0.036). Unfortunately, we failed to find any significant results between Peli-1 gene rs10496105 and SLE susceptibility.

Conclusions: Our observations suggested that Peli-1 gene polymorphism rs329498 might contribute to SLE susceptibility in Chinese Han Population. Likewise, the rs329498 SNP was also associated with the clinical features LN and malar rash in SLE patients.     

Meta-analysis of the association of IL2RA polymorphisms rs2104286 and rs12722489 with multiple sclerosis risk

Background: The interleukin-2 receptor alpha (IL2RA) gene polymorphisms may be implicated in the genetic susceptibility to multiple sclerosis (MS). This meta-analysis aims to evaluate the relationship of the IL2RA polymorphisms rs2104286 and rs12722489 with MS risk in different populations.

Methods: Eligible association studies were identified through search in Pubmed, Medline, Web of Science, and Scopus (end of search: August 2017). Summary odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models. All statistical analyses were two-sided.

Results: Eleven studies including 8608 cases and 9061 controls evaluated rs2104286. The results demonstrated that the A allele of rs2104286 was associated with increased risk of MS in Caucasians (OR = 1.19, 95%CI: 1.13–1.25, p < 0.001) and Asians (OR = 1.25, 95%CI: 1.01–1.55, p = 0.041), respectively. Concerning rs12722489, six studies with 4259 cases and 5420 controls were eligible. We found that the C allele of rs12722489 was associated with elevated MS risk in Caucasians (OR = 1.20, 95% CI: 1.12–1.29, p < 0.001) but not in Asians (OR = 1.10, 95%CI: 0.75–1.63, p = 0.629). Statistical evidence from the Egger and Begg tests showed absence of publication bias. Sensitivity analysis showed that the results were stable.

Conclusion: Our meta-analysis suggests that the rs2104286 A allele is associated with increased MS risk in both Caucasians and Asians, whereas the rs12722489 C allele is associated with elevated MS risk in Caucasians but not in Asians.     

Association of FAM167A-BLK rs2736340 Polymorphism with Susceptibility to Autoimmune Diseases: A Meta-Analysis

Objective: The purpose of this study is to evaluate the correlation between family with sequence similarity 167A-B lymphoid tyrosine kinase (FAM167A-BLK) rs2736340 polymorphism and autoimmune diseases.

Methods: Databases including PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature database (CBM) and Chinese database, Wan Fang database were used in searching eligible studies from January 1, 1966 to October 2, 2015. The odds ratios (ORs) and their 95% confidence intervals (CIs) were pooled to estimate the strength of the association.

Results: A total of 25 studies with 30,217 patients and 44,754 controls were included in the meta-analysis. The overall results showed FAM167A-BLK rs2736340 T allele was a risk allele for autoimmune diseases (OR 1.36, 95% CI 1.28–1.44, p < 0.001). In the subgroup by ethnicities, the results suggested T allele was an increased risk in North America, Europe, and Asia (OR 1.33, 95% CI 1.10–1.60, p = 0.004; OR 1.26, 95% CI 1.22–1.31, p < 0.001; and OR 1.46, 95% CI 1.40–1563, p < 0.001, respectively), but not in Africa. Subgroup analysis in different genetic models (recessive, dominant, and additive) revealed significant association between rs2736340 and autoimmune diseases in Asia and North America, but not the recessive model in Europe or Africa, or the additive model in Africa. Stratification analysis by diseases suggested FAM167A-BLK rs2736340 had a positive association with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and Kawasaki disease, primary Sjogren’s syndrome (pSS), primary antiphosholipid syndrome (APS), and myositis.

Conclusion: The current meta-analysis suggested that FAM167A-BLK rs2736340 polymorphism is associated with several autoimmune diseases.     

Matrix Metalloproteinase-9 rs17576 Gene Polymorphism and Behçet’s Disease: Is There an Association?

Background: Clinical studies have reported a significant association between matrix metalloproteinases (MMP), particularly (MMP-9), and inflammatory diseases including Behçet’s disease (BD).

Purpose: To study the relationship between MMP-9 rs17576 gene polymorphism and the development of BD, and its relation to disease activity among Egyptian patients.

Methods: A total of 100 BD patients and 100 healthy control volunteers were genotyped for MMP-9 rs17576 polymorphism with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), followed by the confirmation of our results in random subgroups using direct DNA sequencing technique.

Results: The frequency of the GG genotype and G allele was significantly higher in BD patients as compared to the normal controls (p = 0.011, OR 8.61; p = 0.03, OR 1.65, respectively). There was no significant association between the MMP-9 rs17576 polymorphism and the clinical outcomes of BD.

Conclusion: our study suggests a significant association of the MMP-9 rs17576 A/G polymorphism with increased risk of BD development in Egyptian patients.     

Complex role of IL-23R polymorphisms on ankylosing spondylitis: a meta-analysis

Background: The aim of the meta-analysis was to evaluate the association between 10 widely studied polymorphisms of interleukin-23 receptor gene (IL-23R) and ankylosing spondylitis (AS).

Methods: A comprehensive literature search, screening of eligible articles and data extraction was performed independently by two investigators. Further meta-analysis was conducted with STATA 12.0 software (Stata Corp.; College Station, TX, USA). The association between IL-23R polymorphisms and AS was evaluated by odds ratio (OR) and 95% confidence intervals (95% CI).

Results: Twenty-five case–control studies with 8431 cases and 8972 controls were included in this meta-analysis. Quantitative meta-analysis revealed that minor allele frequency (MAF) of rs1004819, rs1495965, and rs2201841 was significantly higher in the AS group (p value < .001, < .001, = .010, respectively). MAF of rs10489629, rs11209026, rs11465804, and rs1343151was significantly lower in the AS group (p value = .002, < .001, = .032, < .001, respectively). However, there is no significant difference between these two groups in rs10889677, rs11209032, and rs7517847 frequency (p value = .128, .237, .131, respectively).

Conclusions: The present study indicates that minor allele carriers of rs1004819, rs1495965, and rs2201841 are susceptible to AS. Conversely, minor alleles of rs10489629, rs11209026, rs11465804, and rs1343151 have protective effect on AS.     

Contribution of Toll-Like Receptor 9 Gene Single-Nucleotide Polymorphism to Systemic Lupus Erythematosus in Egyptian Patients

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease, with multiple genetic and environmental factors involved in its etiology. The toll-like receptor 9 (TLR9) gene has been reported to have important roles in the development and progression of SLE. In this case-control study, the effect of TLR9 polymorphism on susceptibility to SLE was investigated in Egyptian patients.

Methods: We studied the distribution of the TLR9 rs352139 (G + 1174A) single nucleotide polymorphism (SNP) by allele-specific polymerase chain reaction (PCR) in 104 Egyptian patients with SLE and 108 age-, sex-, and ethnically matched controls.

Results: There was no statistically significant difference in the distribution of the AA genotype and alleles between SLE patients and the control group in our study; however, the GA heterozygous patients were three times more likely to develop SLE (P < 0.001). A significant association was detected between TLR9 genotypes and some of the disease manifestations as myositis (p = 0.032), psychosis (p = 0.014), photosensitivity (p = 0.002), and pleurisy (p = <0.001). Moreover, we observed a significant association between the TLR9 AA and GA genotypes and the presence of antinuclear antibodies (ANA) (p = 0.038).

Conclusion: The G + 1174A SNP in the toll receptor 9 gene may contribute to the genetic susceptibility of SLE in Egyptian patients. Also, an influence for this polymorphism on disease manifestations has been elucidated.     

Restoring regulation – IL-2 therapy in systemic lupus erythematosus

Introduction: The pathogenesis of systemic lupus erythematosus (SLE) involves an acquired deficiency of the cytokine IL-2, an essential growth and survival factor for regulatory T cells (Treg), which play an important role in the control of autoimmunity in SLE. In contrast to currently available therapies that broadly suppress the immune system, low-dose IL-2 therapy in SLE aims to compensate the pre-existing IL-2 deficiency and thus to restore a physiological state, where Treg can regain their ability to efficiently counteract autoimmunity.

Areas covered: Here we summarize key findings that led to the development of this novel therapeutic concept and will highlight the key rationales for the clinical translation of low-dose IL-2 therapy in SLE.

Expert commentary: The concept of low-dose IL-2 therapy in SLE has evolved from pathophysiological findings and thus can be considered a selective biological treatment strategy in SLE. Preliminary results from phase I/II studies are promising by proving selective Treg expansion and by providing first evidence for the clinical efficacy of low-dose IL-2 therapy in SLE.     

PTPN22 Single-Nucleotide Polymorphisms in Iranian Patients with Type 1 Diabetes Mellitus

Background: PTPN22 plays a crucial role in regulating the function of various cells of the immune system, particularly T cells. Polymorphisms of the PTPN22 gene have been associated with many autoimmune diseases, including type 1 diabetes (T1D) which is a T-cell-mediated disease.

Objective: The present study was aimed at genotyping of an Iranian population for five polymorphisms of the PTPN22 gene.

Methods: The study population consisted of 99 T1D patients and 100 healthy controls. We genotyped five single-nucleotide polymorphisms (SNPs) (rs12760457, rs1310182, rs1217414, rs33996649, and rs2476601) of the PTPN22 gene.

Results: Regarding the variant rs2476601, genotypes AG and GG were increased and decreased in T1D patients compared with controls, respectively. Further, alleles G and A of this SNP were found to be decreased and increased in T1D patients, respectively (p value = 0.001). However, T1D and control groups did not differ on genotype distribution or allele frequency for other investigated SNPs.

Conclusions: The PTPN22 rs2476601 minor allele (A) was associated with T1D in Iran, accounting for its pathophysiology in autoimmune diseases.     

Evaluation of TLR9 expression on PBMCs and CpG ODN-TLR9 ligation on IFN-α production in SLE patients

Context: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by autoreactive antibodies. Recent findings revealed the importance of innate immune responses, especially Toll-like receptors (TLRs) in the pathogenesis of SLE.

Objective: In this study, the level of TLR9 expression on peripheral blood mononuclear cells (PBMCs) was analyzed. The levels of produced IFN-α were also measured in supernatant of PBMCs from SLE patients and healthy controls after stimulation with CpG ODN2216 which is a plasmocytoid dendritic cell (pDC)-specific TLR9 ligand.

Materials and methods: TLR9 expression was analyzed by real-time polymerase chain reaction (PCR) and flow cytometry in 35 SLE patients and 38 healthy controls and IFN-α concentration was measured in supernatants using enzyme-linked immunosorbent assay (ELISA).

Results: The results showed that the TLR9 expression in the mRNA and the protein level was significantly higher in PBMCs from SLE patients. However, IFN-α concentration in patients and controls significantly increased in response to CpG stimulation but this increase was significantly higher in healthy controls compared with SLE patients. Our results do not show any association between taking hydroxychloroquine and reduction in IFN-α production in SLE patients.

Discussion and conclusions: Regarding the findings of the study, there is the possibility that TLR9 has played a role in SLE pathogenesis, and consequently it implies that TLRs can be considered to be the therapeutic targets for systemic autoimmunity. We may conclude that PBMCs in patients are functionally impaired in response to TLR ligation via innate response stimulating pathogen-associated molecular patterns (PAMPs).     

Lack of Association between MYO9B Gene Polymorphisms and Susceptibility to Coeliac Disease in Caucasians: Evidence from a Meta-Analysis

Objective: Coeliac disease (CD) is a complex disorder influenced by environmental and genetic factors. Recently, a number of studies reported MYO9B gene is associated with CD, but the results are controversial. The aim of this study is to clarify this dispute by means of a meta-analysis.

Methods: The databases of PubMed, Web of Science, and Embase updated to August 2015 were retrieved. Crude odds ratio (OR) and corresponding 95% confidence interval (95%CI) as effect size were calculated by fixed or random effect model according to the heterogeneity.

Results: A total of 8 studies including 2272 cases and 5419 controls were enrolled in this meta-analysis. There was no significant association both in allele and genotype comparisons between the MYO9B (rs2305764, rs2305767, rs1457092) polymorphism and CD in Caucasian populations. No publication bias was detected in this meta-analysis.

Conclusions: This meta-analysis indicates that MYO9B gene polymorphisms might be not associated with CD susceptibility in Caucasians. Further studies are still needed for definitive conclusions.     

Common gene variants interactions related to uric acid transport are associated with knee osteoarthritis susceptibility

Background: The presence of genetic variants in uric acid (UA) transporters can be associated with hyperuricemia, and therefore with an increased risk of monosodium urate (MSU) crystal precipitation. The inflammatory process triggered by these crystals leads to cartilage damage, which, in turn, could promote knee osteoarthritis (KOA).

Objective: To determine whether genetic polymorphisms of the UA transporters and their interactions are associated with KOA.

Materials and Methods: Two hundred forty-three unrelated Mexican-mestizo individuals were recruited for this case-control study. Ninety-three of them were KOA patients but without gout, and one hundred and fifty healthy individuals with no symptoms or signs of KOA were recruited as controls. Forty-one single-nucleotide polymorphisms (SNPs) involved in the UA transporters were genotyped with OpenArray technology in a QuantStudio 12K flex-System with both cases and controls.

Results: After adjusting by age, gender, BMI, and ancestry, significant associations were found for eight SNPs: rs1260326 (GCKR), rs780093 (GCKR), rs17050272 (INHBB), rs1471633 (PDZK1), rs12129861 (PDZK1), rs7193778 (IGF1R), rs17786744 (STC1), and rs1106766 (R3HDM2). With respect to gene–gene interactions, the pairwise interactions of rs112129861 (PDZK1) and rs7193778 (IGF1R); rs17050272 (INHBB) and rs1106766 (R3HDM2); rs1106766 (R3HDM2) and rs780093 (GCKR); rs1260326 (GCKR) and rs17786744 (STC1); and rs17786744 (STC1) and rs1106766 (R3HDM2) make it possible to visualize the synergistic or antagonistic effect of their genotypes or alleles on KOA development.

Conclusions: Our preliminary results show that the common gene variants related to UA transport are associated with KOA in the Mexican population. Further studies must be carried out to corroborate it.     

Systemic inflammatory immune signatures in a patient with CRB1 linked retinal dystrophy

Background: In this report we describe, for the first time, the activation of the peripheral immune compartment in a patient with a CRB1 linked retinal degenerative disease, masquerading as intermediate uveitis.

Methods: To monitor the immune system during systemic immunosuppressive treatment, given for the initial diagnosis of intermediate uveitis, blood samples were taken before and during therapy, for analysis of peripheral blood mononuclear cell-subsets and circulating immune mediators.

Results: The levels of various pro-inflammatory immune mediators (including MIF, TSLP, CCL2/MCP-1, CXCL9, CXCL10, IFN-β, IL-6, IL-17, IL-21, IL-22, and IL-23) were elevated in serum at the first time point, and decreased under immunosuppressive treatment. In parallel, the frequency of activated (CD86+) CD1c+ myeloid dendritic cells in blood was proportional to the central foveal thickness measured by optical coherence tomography.

Conclusions: These observations challenge the current view on the distinct pathophysiology of retinal degenerative and retinal inflammatory conditions in this patient.     

Association between Functional CYP2D6 Polymorphisms and Susceptibility to Autoimmune Diseases: A Meta-Analysis

Objective: This study aimed to explore whether functional CYP2D6 polymorphisms are associated with susceptibility to autoimmune diseases.

Methods: A meta-analysis was conducted on associations between autoimmune diseases and functional CYP2D6*4 1934 A/G and *3 polymorphisms and CYP2D6 phenotypes.

Results: Twelve studies with 1,472 patients and 3,328 controls were included. Autoimmune disease and the CYP2D6 1934 A allele were significantly associated in the overall group, consistent with the Hardy–Weinberg equilibrium (OR = 1.227, 95% CI = 1.071–1.406, p = 0.003); stratification by ethnicity indicated that the CYP2D6 1934 A allele and autoimmune diseases were associated in Caucasians (OR = 1.225, 95% CI = 1.010–1.485, p = 0.039). The CYP2D6*3 allele was also associated with autoimmune diseases in Caucasians (OR = 1.977, 95% CI = 1.125–3.472, p = 0.018). Stratified by autoimmune disease type revealed that the CYP2D6 1934 AA genotype was associated with systemic lupus erythematosus (SLE; OR = 2.007, 95% CI = 1.170–3.442, p = 0.011) and ankylosing spondylitis (AS; OR = 2.317, 95% CI = 1.422–3.774, p = 0.001). The CYP2D6 PM+IM phenotype was significantly associated with autoimmune diseases in Caucasians (OR = 1.526, 95% CI = 1.038–2.246, p = 0.032) and with SLE (OR = 1.778, 95% CI = 1.249–2.532, p = 0.001).

Conclusions: This meta-analysis indicates that CYP2D6*4 and *3 polymorphisms and the CYP2D6 phenotype are associated with susceptibility to autoimmune diseases in Caucasians; particularly, the CYP2D6*4 polymorphism and CYP2D6 PM+IM phenotype are risk factors for SLE development.     

Pregnane X Receptor Polymorphisms and Risk of Inflammatory Bowel Disease: A Meta-Analysis

Background: Pregnane X receptor (PXR) gene polymorphisms have been widely studied in terms of the association with inflammatory bowel disease (IBD), with inconsistent results.

Objective: The present meta-analysis was performed to assess the association between PXR gene polymorphisms and the susceptibility of IBD, Crohn’s disease (CD), and ulcerative colitis (UC).

Methods: PubMed, Wanfang, and CNKI databases were searched for eligible studies before November 1, 2016. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to calculate the various genetic models using either a fixed-effect or a random-effect model. The heterogeneity of the included studies was examined with Cochran Q and I² statistics. Begg’s rank correlation test and Egger’s linear regression test were used to assess the publication bias.

Results: A total of six studies with 4248 cases and 3853 controls were included in this meta-analysis. Three PXR gene polymorphisms were evaluated: rs1523127, rs2276707, and rs6785049. Our analyses of rs1523127, rs2276707, and rs6785049 suggested that PXR gene polymorphism had no obvious influence on the risk of IBD in Caucasians. Subgroup analyses based on disease type showed similar results.

Conclusion: Our meta-analysis revealed that PXR gene polymorphism may not be significantly associated with IBD susceptibility. However, the number of original studies was limited and further studies with large samples are needed to verify the results.

Abbreviations: PXR = pregnane X receptor, IBD = inflammatory bowel disease, CD = Crohn’s disease, UC = ulcerative colitis, ORs = pooled odds ratios, 95% CIs = 95% confidence intervals, NOS = Newcastle–Ottawa scale, HWE = Hardy–Weinberg equilibrium.     

Interferon Regulatory Factor 5 Gene Polymorphisms in Iranian Women with Unexplained Recurrent Pregnancy Loss

Objective: This study aimed to examine the association of three functional IRF5 rs10954213, rs3757385, and rs41298401 polymorphisms with susceptibility to unexplained recurrent pregnancy loss (RPL) among Iranian women from south of Iran.

Methods: 176 women with unexplained RPL and 173 healthy postmenopausal controls were enrolled in this case-control study. Genotyping of the polymorphisms rs10954213 and rs3757385 was carried out using touchdown tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS PCR), and polymorphism rs41298401 was typed using PCR-restriction fragment length polymorphism (PCR-RFLP).

Results: Genotype frequencies were significantly different between RPL cases and controls regarding AG heterozygote genotype of rs10954213, GT genotype of rs3757385, and GG genotype of rs41298401. In addition, allele variants (G for rs10954213, T for rs3757385, and G for rs41298401) showed protective role against RPL, while GG haplotype of two first variants was shown to be a susceptibility factor for the disease.

Conclusion: These data provide the first evidence, to our knowledge, of the protective role of the studied IRF5 gene polymorphisms against unexplained RPL among Iranian women from south of Iran.     

VDR polymorphisms are associated with bone mineral density in post-menopausal Mayan-Mestizo women

Background: Osteoporosis is characterized by low bone mineral density (BMD), which is determined by an interaction of genetic, metabolic and environmental factors.

Aim: To analyse the association between two polymorphisms of VDR as well as their haplotypes with BMD in post-menopausal Maya-Mestizo women.

Subjects and methods: This study comprised 600 post-menopausal Maya-Mestizo women. A structured questionnaire for risk factors was applied and BMD was assessed at the lumbar spine (LS) and total hip (TH) by dual-energy X-ray absorptiometry. DNA was extracted from blood leukocytes. Two single-nucleotide polymorphisms of VDR (rs731236 and rs2228570) were studied using real-time PCR allelic discrimination for genotyping. Differences between the means of the BMDs according to the genotype were analysed with covariance. Haplotype analysis was conducted.

Results: TT genotype of rs731236 of VDR had higher BMD at total hip and femoral neck (FN), and one haplotype formed by the two polymorphisms was associated with only TH-BMD variations. This difference was statistically significant after adjustment for confounders. The genotype of rs2228570 of VDR analysis showed no significant differences with BMD variations.

Conclusion: The results showed that the TT genotype of rs731236 of VDR and one haplotype formed by rs731236 and rs2228570 polymorphisms were associated with higher BMD at TH and FN.     

Macrophage migration inhibitory factor (MIF) inhibitor,Z-590 suppresses cartilage destruction in adjuvant-induced arthritis via inhibition of macrophage inflammatory activation

Background: Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory mediator that is involved in the progression of rheumatoid arthritis (RA). Previously, we demonstrated a small molecule compound 3-[(biphenyl-4-ylcarbonyl) carbamothioyl] amino benzoic acid (Z-590) could inhibit MIF activity with docking-based virtual screening and experimental evaluation.

Methods: The LPS activated RAW264.7 macrophage cells were used to determine the anti-inflammatory effects of Z-590 in vitro. A rat adjuvant-induced arthritis (AIA) model was used to determine the anti-arthritic effects of Z-590 in vivo.

Results: MIF inhibitor Z-590 significantly inhibited the production of NO, TNF-α and IL-6 in LPS-activated RAW 264.7 macrophage cells and markedly inhibited LPS-induced expression of TNF-α, IL-6, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Z-590 also significantly reduced paw edema, serum level of TNF-α, IL-6 and spleen index in the adjuvant-induced arthritis (AIA) rat model. Furthermore, Z-590 markedly ameliorated joint inflammation and articular cartilage damage in AIA rat model.

Conclusion: MIF inhibitor Z-590 possesses potent anti-arthritic activity through suppression of macrophage activation, and could be a potential therapeutic treatment for RA.     

Thymidylate synthase enhancer region: Novel allele in Indians

Background: Thymidylate synthase (TS) is the major target for fluoropyrimidine drugs like 5-Fluorouracil (5-FU). There are polymorphic tandem repeats in the TYMS gene enhancer region (TSER). The number of tandem repeats varies in different populations. The aim of this study was to determine the frequencies of the TSER tandem repeats (rs34743033) and compare the observed frequencies with those of other populations.

Methods: This study genotyped 350 healthy individuals by Polymerase Chain Reaction (PCR).

Results: A novel allele *1 (only a single repeat) was observed in four individuals, the individuals were heterozygous (TSER*1/*2) for TYMS. Another variant rs2853542 affecting the expression of Thymidylate synthase was also analysed. The observed genotype frequencies were compared with frequencies observed in other populations for understanding differences between various population groups. There was a statistically significant difference between Indians and Chinese, Kenyans, Ghanians, African-Americans, Americans of European Ancestry, British, Hungarians, Turkish, Australians and Brazilians.

Conclusion: This study identified a novel single repeat in the TYMS gene which might have an impact on the expression of this gene, which needs to be confirmed by functional studies.     

Elevated Levels of T-helper 17-associated Cytokines in Diabetes Type I Patients: Indicators for Following the Course of Disease

Background: Type 1 diabetes (T1D) is thought to involve chronic inflammation, which is manifested by the activation and expression of different inflammatory mediators. Th1- and Th17-associated cytokines are factors that have been shown to exert profound pro-inflammatory activities and have been implicated in the pathogenesis of T1D in mice and humans.

Objectives: Therefore, the aim of this case control study was to determine the serum level of IL-17, IL-21, IL-27, transforming growth factor beta (TGF-β), and IFN-γ and their reciprocal relationship in Iranian T1D patients.

Patients and Methods: Blood samples were collected from 48 T1D patients and 49 healthy individuals with no history of malignancies or autoimmune disorders based on simple sampling. The serum levels of IL-17, IL-21, IL-27, TGF-β, and IFN-γ were measured by the enzyme linked immunosorbent assay (ELISA).

Results: The serum levels of IL-17 and IL-21 were significantly higher in T1D patients compared to the healthy individuals (p = 0.005 and 0.01, respectively), but interestingly, the opposite was the case for IL-27 (p < 0.0001). However, there were no significant differences in TGF-β and IFN-γ between both groups. In addition, IL-17/IFN-γ and IL-17/IL-27 ratios were higher in patients compared to the control group.

Conclusions: Our results indicated dominant Th17-associated IL-17, suggesting a shift from the Treg and Th1 phenotypes toward the Th17 phenotype. Therefore, it can promote inflammation in β cells in T1D. In addition, it suggests the role of Th17 and Th17/Th1 ratios as a potential contributor to β cells destruction and the Th17/Th1 response ratio may provide a novel biomarker for rapid T1D diagnosis before the destruction of β cells and progression of the disease to the clinical end stages.