<Emphasis Type="Italic">MHC2TA</Emphasis> and <Emphasis Type="Italic">FCRL3</Emphasis> genes are not associated with rheumatoid arthritis in Mexican patients

Rheumatoid arthritis (RA) is a multifactorial disease. A combination of genetic and environmental risk factors contributes to its etiology. Several genes have been reported to be associated with susceptibility to the development of RA. The MHC2TA and FCRL3 genes have been associated previously with RA in Swedish and Japanese populations, respectively. In two recent reports, we show an association between FCRL3 and juvenile rheumatoid arthritis (JRA), and MHC2TA and acute coronary syndrome (ACS) in Mexican population. We assessed the association between three single nucleotide polymorphisms (SNPs) of the MHC2TA (?168G/A; rs3087456, and +16G/C; rs4774) and FCRL3 (?169T/C; rs7528684) genes and rheumatoid arthritis in Mexican population through a genotyping method using allelic discrimination assays with TaqMan probes. Our case–control study included 249 patients with RA and 314 controls. We found no evidence of an association between the MHC2TA ?168G/A and +1614G/C or FCRL3 ?169T/C polymorphisms and RA in this Mexican population. In this cohort of Mexican patients with RA, we observed no association between the MHC2TA or FCRL3 genes and this autoimmune disease.     

<Emphasis Type="Italic">Fas/FasL,Bcl2</Emphasis> and <Emphasis Type="Italic">Caspase</Emphasis>-<Emphasis Type="Italic">8</Emphasis> gene polymorphisms in Chinese patients with rheumatoid arthritis

Apoptosis signals are necessary for maintaining homeostasis and an adequate immune response. Dysregulation of apoptosis-related genes in the immune system has an important impact on autoimmune diseases such as rheumatoid arthritis (RA). Thus, we investigated the association between Fas rs2234767 G/A, FasL rs763110 C/T, Bcl2 rs12454712 T/C, Bcl2 rs17757541 C/G, and Caspase-8 rs1035142 G/T polymorphisms and RA susceptibility in a Chinese population. These five single-nucleotide polymorphisms (SNPs) were studied in a Chinese population consisting of 615 patients with RA and 839 controls. Genotyping was performed using a custom-by-design 48-Plex SNP scan TM kit. Furthermore, we undertook a meta-analysis between FasL rs763110 C/T and RA. This study indicated that Fas rs2234767 and Bcl2 rs17757541 polymorphisms were risk factors for RA. No association was observed between FasL rs763110 C/T, Bcl2 rs12454712 T/C, and Caspase-8 rs1035142 G/T polymorphisms and RA in this study. The results of this meta-analysis suggested no significant association between FasL rs763110 C/T and RA. However, stratification analysis of this meta-analysis indicated that FasL rs763110 C/T increased the risk of Caucasian RA patients. In conclusion, this study demonstrated that Fas rs2234767 G/A and Bcl2 rs17757541 T/C polymorphisms might be associated with an increased risk of RA. This meta-analysis revealed that FasL rs763110 C/T was associated with an increased risk of Caucasian RA patients.     

<Emphasis Type="Italic">C-reactive protein</Emphasis> +1444CT (rs1130864) genetic polymorphism is associated with the susceptibility to systemic lupus erythematosus and C-reactive protein levels

The T rare allele of +1444CT (rs1130864) polymorphism of C-reactive protein (CRP) has been associated with increased CRP levels in some inflammatory conditions, but its role on systemic lupus erythematosus (SLE) susceptibility and on CRP levels in SLE patients remains uncertain. The objective of the study was to evaluate the association between the rs1130864 CRP polymorphism with SLE susceptibility, disease activity, and CRP levels in SLE Brazilian patients. The study enrolled 176 SLE patients and 137 controls. SLE disease activity was assessed using the SLE Disease Activity Index (SLEDAI). The rs1130864 CRP polymorphism was determined using polymerase chain reaction and restriction fragment length polymorphism. SLE patients presented higher body mass index (p = 0.046) and CRP levels (p = 0.017) than controls. The genotype and allele frequencies of patients differed from controls [CC vs. CT = odds ratio (OR) 1.730, 95% confidence interval (CI) 1.068–2.803, p = 0.035; CC vs. TT = OR 3.667, 95% CI 1.410–9.533, p = 0.009; C vs. T = OR 1.883, 95% CI 1.299–2.728, p = 0.001)]. Patients carrying the T allele presented higher CRP levels (p = 0.009), were more frequent Caucasians (p = 0.018), and with no use of immunosuppressive treatment (p = 0.004) than those carrying the C allele. However, the SLEDAI and anti-double-stranded DNA positivity did not differ from those carrying T vs. C allele (p = 0.595 and p = 0.243, respectively). The rs1130864 CRP polymorphism was associated with SLE susceptibility and CRP levels, but not with disease activity, suggesting that this polymorphism may play a role in the pathophysiology of SLE through increasing the CRP that, probably, plays an inflammatory role in SLE pathophysiology.     

Influence of <Emphasis Type="Italic">TNF</Emphasis> and <Emphasis Type="Italic">IL6</Emphasis> gene polymorphisms on the severity of cytopenias in Argentine patients with myelodysplastic syndromes

Myelodysplastic syndromes (MDS) represent a heterogeneous group of hematologic disorders characterized by cytopenia(s) and predisposition to leukemic progression. An immune dysregulation and an aberrant bone marrow microenvironment seem to be key elements in the physiopathological process of MDS. In order to evaluate a possible association between susceptibility and clinic-pathologic features, we genotyped 153 MDS patients for functional cytokine polymorphisms: TNF (?308 G/A), IFNG (+874 A/T and +875 CAn), IL6 (?174 G/C), and TGFB1 (+869 C/T and +915 G/C). The frequency of TNF and IL6 polymorphisms was different between patients and healthy controls (n = 131), suggesting a relatedness to MDS susceptibility in our population. Furthermore, the presence of each or both high-producing genotypes [TNF: p = 0.048, odds ratio (OR): 3.979; IL6: p = 0.001, OR: 6.835; both: p = 0.010, OR: 6.068] and thrombocytopenia at platelet counts of <50,000/μL (p = 0.004, OR: 4.857) were independently associated with an increased risk of manifesting a hemoglobin level of <8 g/dL at diagnosis. In particular, a severe bicytopenia was more frequently observed in patients with the TNF (high)_IL6 (high) combined genotype (p = 0.004, OR: 8.357), who consistently became transfusion dependent earlier (2.9 vs. 34.6 months; p = 0.001); and this likelihood was more evident in patients with lower bone marrow blast counts. The contribution of the remaining functional polymorphisms to the disease phenotype was less relevant. Our results demonstrate that TNF and IL6 gene polymorphisms, as underlying host features, are likely to play a key role in influencing the severity of the cytopenias in MDS and they may be instrumental for tailoring cytokine-target therapies.     

Interactive role of endothelial nitric oxide synthase gene polymorphisms in T2D with CAD and CAD patients of Punjab (North-West India)

Dysregulation of endothelial nitric oxide synthase (eNOS) activity causes the reduction in the production of nitric oxide (NO) which is an early indicator of type 2 diabetes (T2D) and cardiovascular complications. The present study evaluates the association of ?786 T?>?C, 894 G?>?T, and 4a/b polymorphisms of eNOS gene in total of 1223 individuals enrolling 307 coronary artery disease (CAD) cases, 486 T2D cases with (n?=?170) and without (n?=?316) CAD as the secondary macrovascular complication, and 430 healthy controls from Punjab (North-West India). Genotyping of ?786 T?>?C and 894 G?>?T polymorphisms was done with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and the genotyping of 4a/b insertion/deletion polymorphism was done by PCR. The minor allele frequency (MAF) of ?786 T?>?C polymorphism was higher in CAD (21.8 %), T2D + CAD (22.4 %), and T2D cases (18.4 %) as compared to healthy controls (17.6 %). However, in single-locus analysis, no significant results were obtained for eNOS polymorphisms in any of the studied groups. Significant association of C-b-G haplotype with the risk of both CAD [P?=?0.003, odds ratio (OR)?=?1.89 (1.04–3.45)] and T2D [P?=?0.019, OR?=?1.69 (0.92–3.13)] was observed. Diplotype analysis showed that TbG/CbG haplotype combination conferred risk towards CAD and T2D [P?=?0.01, OR?=?2.04 (1.18–3.57); P?=?0.006, OR?=?2.13 (1.22–3.57), respectively]. Furthermore, phenotypic parameters like waist circumference, high-density lipoprotein, and waist to height ratio are significantly associated with 894 G?>?T genotypes among CAD patients. In conclusion, the eNOS polymorphisms did not provide any conclusive result individually; however, their interactive effect gives some insights towards eNOS role in the population of Punjab.     

Associations of <Emphasis Type="Italic">methylenetetrahydrofolate reductase</Emphasis> (<Emphasis Type="Italic">MTHFR</Emphasis>) C677T and A1298C polymorphisms with genetic susceptibility to rheumatoid arthritis: a meta-analysis

The aim of our study was to conduct a meta-analysis to assess whether combined evidence shows associations between C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and genetic susceptibility to rheumatoid arthritis (RA). A total of 11 articles involving 20 comparisons were included, containing 12 comparisons for the MTHFR C677T polymorphism and 8 comparisons for the MTHFR A1298C polymorphism. Significant evidence was detected for the association of RA susceptibility with the MTHFR C677T polymorphism T allele under allelic contrast and dominant model in Asians (T versus C, OR = 1.300, 95 % CI = 1.104–1.531, p = 0.002; TT + CT versus CC, OR = 1.495, 95 % CI = 1.187–1.882, p = 0.001). Significant association between RA susceptibility and the MTHFR A1298C polymorphism A allele under recessive model was found in the overall meta-analysis (AA versus AC + CC, OR = 1.281, 95 % CI = 1.048–1.565, p = 0.016). Our meta-analysis results demonstrate that the MTHFR C677T polymorphism is involved in the genetic susceptibility of RA in Asians, and the MTHFR A1298C polymorphism is associated with genetic susceptibility to RA in the overall population. Given the paucity of studies, especially in non-Asian populations, further studies with larger sample sizes are required to elucidate the role of MTHFR polymorphisms in the genetic basis of RA in different ethnic populations.     

Association between susceptibility to rheumatoid arthritis and <Emphasis Type="Italic">PADI4</Emphasis> polymorphisms: a meta-analysis

The objective of the study was to determine by meta-analysis whether polymorphisms of the gene encoding peptidylarginine deiminase 4 (PADI4) are associated with susceptibility to rheumatoid arthritis (RA). A literature review was conducted to identify data sets that described analyses of genetic association between PADI4 polymorphisms and RA. Data sets were collated and a meta-analysis was performed, with a specific focus on associations within Caucasian and Asian populations. A total of 15,947 RA cases and 22,696 controls that were taken from 28 studies in 24 papers were included in this study. Meta-analysis showed a significant association between allele 2 of the PADI4_94 polymorphism and RA in the overall population (odds ratio [OR]?=?1.155, 95 % confidence interval [CI]?=?1.069–1.249, p?=?2.7?×?10^?5). Stratification by ethnicity revealed an association between PADI4_94 allele 2 and RA in Asians (OR?=?1.273, 95 % CI?=?1.193–1.359, p?<?1.0?×?10^?9), but not in Caucasians (OR?=?1.024, 95 % CI?=?0.973–1.078, p?=?0.358). However, meta-analysis using homozygote contrast showed an association between PADI4_94 allele 2 and RA in both Asians (OR?=?2.311, 95 % CI?=?1.1.858–2.875, p?<?1.0?×?10^?9) and Caucasians (OR?=?1.523, 95 % CI?=?1.157–2.004, p?=?0.008). Meta-analysis also revealed an association between allele 2 of the PADI4_104 polymorphism and RA in both Asians (OR?=?1.547, 95 % CI?=?1.247–1.919, p?=?7.1?×?10^?6) and Caucasians (OR?=?1.096, 95 % CI?=?1.025–1.172, p?=?0.008). Finally, meta-analysis showed an association between allele 2 of the PADI4_92 polymorphism and RA in Asians (OR?=?1.263, 95 % CI?=?1.153–1.384, p?=?5.8?×?10^?8), but not in Caucasians (OR?=?1.123, 95 % CI?=?0.980–1.287, p?=?0.095). Meta-analysis indicated no association between allele 2 of either the PADI4_90 or PADI4_89 polymorphisms and RA in Asians. This meta-analysis revealed that the PADI4_94 and PADI_104 polymorphisms are associated with susceptibility to RA in Asians and Caucasians, and that the PADI4_92 polymorphism is associated with susceptibility to RA in Asians, but not in Caucasians.     

Association between the functional <Emphasis Type="Italic">MHC2TA</Emphasis> −168 A/G polymorphism and susceptibility to rheumatoid arthritis: a meta-analysis

The aim of this study was to determine whether the functional major histocompatibility complex II transactivator (MHC2TA) ?168 A/G polymorphism is associated with susceptibility to rheumatoid arthritis (RA). A meta-analysis was conducted to estimate the association between the MHC2TA?168 A/G polymorphism and RA. A total of 15 comparative studies, which included 14,158 patients and 13,642 controls, were included in the meta-analysis. Based on the meta-analysis, there was no association between RA and the MHC2TA ?168 G allele in the study subjects (OR?=?1.046, 95 % CI?=?0.987–1.108, p?=?0.130) or Caucasians (OR?=?1.027, 95 % CI?=?0.986–1.070, p?=?0.193). However, the country-specific meta-analysis revealed an association between the MHC2TA ?168 G allele and RA in the Swedish population (OR?=?1.131, 95 % CI?=?1.023–1.250, p?=?0.016). A direct comparison between rheumatoid factor (RF)-positive and RF-negative patients revealed that the frequency of the G allele was significantly lower in RF-positive patients (OR?=?0.783, 95 % CI?=?0.628–0.975, p?=?0.029) than in RF-negative patients. This meta-analysis demonstrated that the MHC2TA ?168 A/G polymorphism is not associated with susceptibility to RA in Caucasians.     

Associations between <Emphasis Type="Italic">ERAP1</Emphasis> polymorphisms and susceptibility to ankylosing spondylitis: a meta-analysis

The aim of this study was to determine whether 11 polymorphisms of endoplasmic reticulum aminopeptidase 1 (ERAP1) confer susceptibility to ankylosing spondylitis (AS). The authors conducted meta-analyses on associations between ERAP1 polymorphisms and AS susceptibility by using fixed and random effects models. A total of 19 articles were included in this meta-analysis, which comprised a total of 19,902 AS patients and 39,750 controls. The meta-analysis revealed a significant association between AS and the minor alleles of the rs30187 polymorphism in all study subjects (OR?=?1.255, 95 % CI?=?1.147–1.373, P?=?8.0?×?10^?8). Stratification by ethnicity led to the identification of a significant association between this polymorphism and AS in European patients (OR?=?1.283, 95 % CI?=?1.237–1.331, P?<?1.0?×?10^?9). Meta-analyses of the results for the rs27044, rs10050860, rs2287987, rs17482078, and rs26653 polymorphisms showed the same pattern that was found for rs30187. Interestingly, the rs27037 polymorphism was significantly associated with AS susceptibility in both European and Asian patients. Meta-analysis showed a significant association between AS and the minor alleles of the rs27980 and rs27582 polymorphisms in the East Asian patients (OR?=?0.904, 95 % CI?=?0.818–0.999, P?=?0.047; OR?=?0.871, 95 % CI?=?0.772–0.982, P?=?0.024, respectively) (Table 2). However, these polymorphisms have not been studied in Europeans. This meta-analysis shows that the ERAP1 polymorphisms are associated with the development of AS in Europeans and East Asians.     

<Emphasis Type="Italic">Vegf-A</Emphasis> mRNA transfection as a novel approach to improve mouse and human islet graft revascularisation

Aims/hypothesis

The initial avascular period following islet transplantation seriously compromises graft function and survival. Enhancing graft revascularisation to improve engraftment has been attempted through virus-based delivery of angiogenic triggers, but risks associated with viral vectors have hampered clinical translation. In vitro transcribed mRNA transfection circumvents these risks and may be used for improving islet engraftment.

Methods

Mouse and human pancreatic islet cells were transfected with mRNA encoding the angiogenic growth factor vascular endothelial growth factor A (VEGF-A) before transplantation under the kidney capsule in mice.

Results

At day 7 post transplantation, revascularisation of grafts transfected with Vegf-A (also known as Vegfa) mRNA was significantly higher compared with non-transfected or Gfp mRNA-transfected controls in mouse islet grafts (2.11- and 1.87-fold, respectively) (vessel area/graft area, mean?±?SEM: 0.118?±?0.01 [n?=?3] in Vegf-A mRNA transfected group (VEGF) vs 0.056?±?0.01 [n?=?3] in no RNA [p?<?0.05] vs 0.063?±?0.02 [n?=?4] in Gfp mRNA transfected group (GFP) [p?<?0.05]); EndoC-bH3 grafts (2.85- and 2.48-fold. respectively) (0.085?±?0.02 [n?=?4] in VEGF vs 0.030?±?0.004 [n?=?4] in no RNA [p?<?0.05] vs 0.034?±?0.01 [n?=?5] in GFP [p?<?0.05]); and human islet grafts (3.17- and 3.80-fold, respectively) (0.048?±?0.013 [n?=?3] in VEGF vs 0.015?±?0.0051 [n?=?4] in no RNA [p?<?0.01] vs 0.013?±?0.0046 [n?=?4] in GFP [p?<?0.01]). At day 30 post transplantation, human islet grafts maintained a vascularisation benefit (1.70- and 1.82-fold, respectively) (0.049?±?0.0042 [n?=?8] in VEGF vs 0.029?±?0.0052 [n?=?5] in no RNA [p?<?0.05] vs 0.027?±?0.0056 [n?=?4] in GFP [p?<?0.05]) and a higher beta cell volume (1.64- and 2.26-fold, respectively) (0.0292?±?0.0032 μl [n?=?7] in VEGF vs 0.0178?±?0.0021 μl [n?=?5] in no RNA [p?<?0.01] vs 0.0129?±?0.0012 μl [n?=?4] in GFP [p?<?0.001]).

Conclusions/interpretation

Vegf-A mRNA transfection before transplantation provides a promising and safe strategy to improve engraftment of islets and other cell-based implants.

     

Association between SNPs in <Emphasis Type="Italic">AdipoQ</Emphasis>, +45 T &gt; G and +276 G &gt; T,and adiponectin levels in the Korean Chinese population in Yanbian,China

This study investigated the association between single nucleotide polymorphisms (SNPs) in AdipoQ, +45 T?>?G and +276 G?>?T, and adiponectin levels in the Korean Chinese population in Yanbian, China. A total of 329 subjects were involved in this study, including 178 female and 151 male individuals. All of them are ethnic Koreans living in Yanbian, aged from 31 to 70, and 58 % of them were diagnosed with type 2 diabetes (T2D). Items tested and calculated include total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), body fat percentage (BF%), fasting plasma insulin (FPI), plasma adiponectin (PA), and homeostasis model assessment of insulin resistance (HOMA-IR). SNPs were screened with the method of SNaPshot. P?<?0.05 was defined as the statistically significant threshold. Results include the following: (1) PA levels in the T2D group are much lower than those in the normal group (P?<?0.001); (2) the distribution of genotypes of SNPs +45 T?>?G and +276 G?>?T was determined to be in Hardy-Weinberg equilibrium (P?>?0.05) and complete linkage disequilibrium (|D′|?=?1.0); (3) PA levels in females are much higher than those in males no matter which group they belong to (normal or T2D group) (P?=?0.004 and P?=?0.018); (4) PA levels are higher in the individuals with +45G as a dominant allele than those in individuals with homozygous genotype TT at locus +45 in the normal group (P?=?0.037); and (5) of SNPs +45 T?>?G and +276 G?>?T, no risk factor of genotype or allele was found (P?>?0.05). Three conclusions can be drawn: (1) PA levels are lower in T2D patients than in normal persons; (2) PA levels are higher in females than in males; (3) PA levels are higher for normal individuals with +45G allele than those with homozygous TT genotype at locus +45 in AdipoQ.     

Role of <Emphasis Type="Italic">PPARG</Emphasis> (Pro12Ala) in Malaysian type 2 diabetes mellitus patients

Diabetes is one of the major lifestyle disorders in the world. Asian countries, including Malaysia, contribute with more than 60 % of the world’s diabetic population. The single nucleotide polymorphisms (SNPs) of the peroxisome proliferator-activated receptor gamma (PPARG) have been identified as one of the key regulators of glucose and lipid metabolism that controls the protein synthesis in multiple metabolic, biochemical, and molecular pathways. The aim of this study was to investigate the possible role of PPARG (Pro12Ala) gene polymorphism as a genetic risk factor for type 2 diabetes mellitus (T2DM) patients in Malaysian population. A total of 241 subjects between the age of 35 and 85 years were recruited in this study. Out of the total 241 subjects, 120 were T2DM patients and 121 were healthy individuals. SNP of PPARG (Pro12Ala) was determined by polymerase chain reaction (PCR) and restriction fragment length polymorphisms (RFLPs). The frequencies of wild homozygote (WH), heterozygote (H), and mutant homozygote (MH) among the T2DM patients were (n?=?73) 60.8 %, (n?=?39) 32.5 %, and (n?=?3) 2.5 % compared to (n?=?57) 47 %, (n?=?46) 38 %, and (n?=?16) 13.2 % among the healthy subjects. The mean of Hba1C (%) among normal and diabetic patients with genotypes were different (5.36?±?0.54 vs 7.58?±?1.76), p?<?0.005. SNP of PPARG (Pro12Ala) gene could be a genetic risk factor for insulin resistance and T2DM among Malaysian population.     

The functional <Emphasis Type="Italic">PTPN22</Emphasis> C1858T polymorphism confers risk for rheumatoid arthritis in patients from Central Mexico

Rheumatoid arthritis (RA) is a complex genetic disease. Human leukocyte antigen (HLA) and non-HLA genes are reportedly associated with an increased risk of RA. The protein tyrosine phosphatase non-receptor 22 gene (PTPN22), which encodes the lymphoid tyrosine phosphatase (LYP) protein, is one of the best examples of a non-HLA gene associated with a risk for RA in several populations. The functional PTPN22 C1858T (R620W) non-synonymous polymorphism is widely associated with an increased risk for RA in Europeans and non-Europeans. The aim of this study was to determine if the PTPN22 C1858T polymorphism confers susceptibility to RA in a sample of patients from Mexico. This study included 364 RA patients and 387 non-related controls from Central Mexico. Genotyping of the PTPN22 C1858T (rs2476601) polymorphism was performed using allelic discrimination assays with TaqMan probes. The functional PTPN22 C1858T polymorphism was associated with an increased risk for RA in our study population. The CC vs CT genotype in RA patients versus healthy controls had an odds ratio (OR) of 4.17 (95 % CI 1.79–9.74, p?=?0.00036), while T allele had an OR of 4.06 (95 % CI 1.75–9.41, p?=?0.00043). PTPN22 is a genetic risk factor for developing RA in the Mexican population.     

Analysis of PD-1 and Tim-3 expression on CD4<Superscript>+</Superscript> T cells of patients with rheumatoid arthritis; negative association with DAS28

Expression of T cell immunoglobulin and mucin-domain containing-3 (Tim-3) and programmed cell death-1 (PD-1) was studied on CD4⁺ T cells of patients with rheumatoid arthritis (RA). Association of Tim-3 and PD-1 expression with disease activity of RA patients was also addressed. A total of 37 RA patients and 31 sex- and age-matched healthy controls were included in this study. Disease activity of RA patients was determined by Disease Activity Score of 28 joints scoring system (DAS28). A three-color flow cytometry method was applied to determine the frequency of Tim-3⁺/PD-1⁺/CD4⁺ T cells. To measure the cytokine production, peripheral blood mononuclear cells (PBMCs) were stimulated with PMA/ionomycin. Concentrations of IL-17, IL-10, IFN-γ, and TNF-α were measured in culture supernatants by ELISA. The frequency of PD-1⁺/CD4⁺ and Tim-3⁺/PD-1⁺/CD4⁺ T cells was significantly higher in patients with RA compared to that in controls (p?=?0.0013 and p?=?0.050, respectively). The percentage of Tim-3⁺/CD4⁺ T cells was similar in patients and controls (p?=?0.4498). The RA patients have produced significant higher levels of TNF-α, IL-17, and IFN-γ than those of healthy controls (p?=?0.0121, p?=?0.0417, and p?=?0.0478, respectively). Interestingly, an inverse correlation was found between the frequency of Tim-3⁺/CD4⁺ cells and DAS28 of RA patients (r?=???0.4696, p?=?0.0493). Similarly, the percentage of Tim-3⁺/PD-1⁺/CD4⁺ T cells was also revealed an inverse correlation with DAS28 (r?=???0.5268, p?=?0.0493). Moreover, significant positive correlations were detected between the concentrations of TNF-α (r?=?0.6418, p?=?0.0023) and IL-17 (r?=?0.4683, p?=?0.0373) with disease activity of RA patients. Our results indicate that Tim-3 and PD-1 are involved in immune dysregulation mechanisms of rheumatoid arthritis and could be considered as useful biomarkers for determination of disease activity and progression.     

CTLA-4 +49A/G gene polymorphism and type 1 diabetes mellitus in the Chinese population: a meta-analysis of 2238 subjects

Previous studies reported that cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) +49A/G gene polymorphism is correlated with type 1 diabetes mellitus (T1DM) risk. However, their results remain disputable. This study aims to discuss the relationship between CTLA-4 +49A/G gene polymorphism and T1DM in a Chinese population. The current meta-analysis involved 2238 participants from seven individual studies. The pooled odds ratio (OR) and its corresponding 95 % confidence interval (95 % CI) were assessed by the random- or fixed-effects model. A significant relationship between CTLA-4 +49A/G gene polymorphism and T1DM was detected under allelic (OR: 1.84, 95 % CI: 1.62–2.10, P?<?0.00001), dominant (OR: 1.152, 95 % CI: 1.062–1.249, P?=?0.001), recessive (OR: 1.631, 95 % CI: 1.443–1.844, P?<?0.00001), and additive (OR: 1.292, 95 % CI: 1.224–1.363, P?<?0.00001) genetic models. A significant relationship exists between CTLA-4 +49A/G gene polymorphism and increased T1DM risk in the Chinese population. Individuals having the G allele of CTLA-4 +49A/G gene polymorphism have a higher risk for T1DM in the Chinese population.     

Vitamin A improve Th17 and Treg regulation in systemic lupus erythematosus

The aim of this study was to determine the role of vitamin A in modulating T helper 17 (Th17) and regulatory T cell (Treg) balance in systemic lupus erythematosus (SLE) patients. Sixty-two female SLE patients and sixty-two female controls were measured for vitamin A levels from serum by enzyme-linked immunosorbent assay (ELISA) and percentages of Th17 and Treg from peripheral blood mononuclear cells (PBMC) by flow cytometry. We also performed an in vitro study to evaluate the effects of retinoic acid treatment (0, 0.1, 0.2, and 0.3 μg/ml) in modulating Th17/Treg balance in CD4⁺ T cell culture from hypovitaminosis A SLE patients. Th17 and Treg percentages from cell cultures were measured by flow cytometry. Vitamin A levels in the SLE patients were lower compared to those in the healthy control (46.9?±?43.4 vs. 75.6?±?73.1 ng/ml, p?=?0.015). Vitamin A levels also had a negative correlation to Th17 percentages in the SLE patients (p?=?0.000, R?=??0.642). Th17 percentages in the hypovitaminosis A SLE patients were higher compared to those SLE patients with normal vitamin A levels (10.9?±?5.3 vs. 2.9?±?2.2 %, p?=?0.000). Treatment of 0.3 μg/ml of retinoic acid could increase Treg differentiation (33.9?±?1.6 vs. 21.8?±?1.1 %, p?=?0.000) and decrease Th17 differentiation (27.2?±?2.5 vs. 37.4?±?1.3 %, p?=?0.000). In conclusion, vitamin A has important roles in modulating Th17/Treg balance in the SLE patients shown by the significant decrease of vitamin A levels in the SLE patients which negatively correlate with Th17 population, and treatment of retinoic acid could decrease Th17 and increase Treg percentages in CD4⁺ T cells cultures.     

Clinical and laboratory aspects of dyslipidemia in Brazilian women with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is associated with dyslipidemia, atherosclerosis, and cardiovascular disease. In this study, we investigated the presence of dyslipidemia in Brazilian SLE patients by evaluating their lipid profile and immune status, including the production of autoantibodies and cytokines involved in atherogenesis. Ninety-four female SLE patients participated in this study and, based on their lipid profile, were classified as dyslipidemic or not. All were tested for antinuclear antibodies (ANAs), antiphospholipid antibodies, and autoantibodies to extractable nuclear antigens and double-stranded DNA. Serum levels of apolipoproteins A and B, C3, C4, and C-reactive protein were measured, as well as serum levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-10. Lupus activity was scored according to the Systemic Lupus Erythematosus Disease Activity Index 2000. Sixty-nine patients (73.4%) had dyslipidemia, and the remaining 25 patients (26.6%) were non-dyslipidemic. Lupus activity was correlated with non-high-density lipoprotein cholesterol and triglyceride (TG) levels (non-HDL-C, r?=?0.34 and p?=?0.0043 and r?=?0.46 and p?<?0.0001, respectively). Atherogenic indexes apolipoprotein B/apolipoprotein A and TG:HDL-C ratios were higher in dyslipidemic women, and TG:HDL was correlated with disease activity (r?=?0.40, p?=?0.0007). IL-6, TNF-α, and IL-10 levels were similar between groups; however, a positive correlation between IL-6 and CRP levels was only observed in the group with dyslipidemia (r?=?0.55, p?<?0.0001). Female Brazilian SLE patients present a high prevalence of dyslipidemia and exhibit a higher risk of cardiovascular diseases as compared with female SLE patients without dyslipidemia and healthy individuals.     

Associations of <Emphasis Type="Italic">TIM</Emphasis>-<Emphasis Type="Italic">1</Emphasis> Genetic Polymorphisms with Asthma: A Meta-analysis

Purpose

Recently, the roles of TIM-1 genetic polymorphisms in asthma have been extensively studied, with conflicting results. Therefore, we performed the present meta-analysis to better assess potential associations of TIM-1 genetic polymorphisms with asthma.

Methods

Eligible articles were searched in PubMed, Medline, EMBASE, Google Scholar, and CNKI up to December 2016. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to detect any potential associations between TIM-1 genetic polymorphisms and asthma.

Results

A total of 12 articles including 3120 asthma patients and 2825 control subjects were analyzed. The overall and subgroup analyses revealed that TIM-1-416G>C single nucleotide polymorphism was significantly associated with asthma for the Asian population in the codominant (G/G vs. G/C, p = 0.0003, OR 1.86, 95% CI 1.33–2.60) and dominant (G/G vs. G/C + C/C, p < 0.0001, OR 1.94, 95% CI 1.40–2.69) genetic models. Nevertheless, we failed to detect any significant associations between TIM-1-416G>C single nucleotide polymorphism and asthma in Caucasians. Additionally, according to our analyses, TIM-1 5383_5397 insertion/deletion polymorphism was not correlated with asthma in both Asians and Caucasians.

Conclusions

In conclusion, our findings suggest that TIM-1-416G>C single nucleotide polymorphism is associated with asthma susceptibility for the Asian ethnicity in certain genetic models. However, TIM-1 5383_5397 insertion/deletion polymorphism may not be correlated with the risk of asthma.

     

Non-driver mutations in patients with <Emphasis Type="Italic">JAK2</Emphasis>V617F-mutated polycythemia vera or essential thrombocythemia with long-term molecular follow-up

JAK2V617F monitoring and NGS of non-driver genes was performed in 100 patients with polycythemia vera (PV) or essential thrombocythemia (ET) with long molecular follow-up. Patients who did not progress to myelofibrosis (MF) or acute myeloid leukemia (AML) after more than 10 years (n?=?50) showed a low frequency of mutations at first sample (18%) and an incidence rate of 1.7 new mutations?×?100 person-years. Mutations were detected at first sample in 83% of PV/ET patients who later progressed to AML (n?=?12) with these patients having a rate of 25.6 mutations?×?100 person-years. Presence of mutations at diagnosis was the unique risk factor for acquiring a new genetic event (HR 2.7, 95% CI 1.1–6.8, p?=?0.03) after correction for age, PV diagnosis, and total duration of hydroxyurea (HU) exposure. Patients with additional mutation at first sample showed a higher probability of developing cytopenia under HU therapy and a higher risk of AML (HR 12.2, 95% CI 2.6–57.1, p?=?0.001) with mutations in ASXL1 (p?<?0.0001), TP53 (p?=?0.01), SRSF2 (p?<?0.0001), IDH1/2 (p?<?0.0001), and RUNX1 (p?<?0.0001) being associated with a higher probability of AML. Myelofibrotic transformation was more frequent in patients with additional mutations, especially in SF3B1 (p?=?0.02) and IDH1/2 (p?<?0.0001) although a persistently high or a progressive increase of the JAK2V617F allele burden while receiving cytoreduction was the strongest predictor of MF transformation (HR 10.8, 95% CI 2.4–49.1, p?=?0.002). In conclusion, NGS may be useful to identify a minority of PV and ET patients with high genetic instability and increased risk of AML transformation.     

Reduced folate carrier-1 80G &gt; A gene polymorphism is not associated with methotrexate treatment response in South Indian Tamils with rheumatoid arthritis

Methotrexate (MTX) is the most commonly used disease-modifying drug to treat rheumatoid arthritis (RA). Although there are no reliable molecular markers to predict the treatment response and adverse effects to MTX therapy, the polymorphisms in genes coding for MTX metabolizing enzymes and transporters may play a crucial role. The reduced folate carrier-1 (RFC-1) is a bidirectional anion exchanger which transports MTX and folinic acid. It is reported to influence MTX treatment response and adverse effects in some ethnic populations but not in others. It is also associated with susceptibility to various diseases including systemic lupus erythematosus (SLE). The present study was aimed at investigating the role of RFC-1 80G > A gene polymorphism in association with disease susceptibility, MTX treatment response and the MTX-induced adverse events in the South Indian Tamil patients with rheumatoid arthritis. The RFC-1 80G > A gene polymorphism was investigated in 327 patients with RA and in 322 healthy controls by PCR-RFLP method. It was found that the heterozygous RFC-1 80 GA genotype was associated with protection against RA [p?=?0.02, odds ratio (OR) 0.69, 95 % confidence interval (CI) 0.50–0.95]. However, it was not found to be associated with MTX treatment response. The RFC-1?G allele frequency was higher in patients with adverse effects, but the difference was not statistically significant (p?=?0.08, OR 1.44, 95 % CI 0.97–2.13). RFC-1 80G > A gene polymorphism confers protection for RA. However, it is not associated with MTX treatment response and MTX-induced adverse effects in South Indian Tamil patients with RA.