C3435T Single Nucleotide Polymorphisms Research Articles

Frequency distribution of the methylenetetrahydrofolate reductase polymorphisms in sickle cell hemoglobinopathy-A hospital based study in central India

BackgroundCoexistence of polymorphisms of methylenetetrahydrofolate reductase (MTHFR) with sickle cell gene exerts synergistic effect on complications associated with sickle cell hemoglobinopathy. Therefore, the study was planned to determine the frequency distribution of the MTHFR C677T and A1298C genotypes in children diagnosed with sickle cell disease. MethodsA total of 249 children diagnosed with sickle cell anemia, between age group 5–18 years, were enrolled for the cross sectional study. The demographic and clinical details were entered in a structured questionnaire. Collected blood samples were analyzed for hemoglobin and DNA was extracted for genotypic assay for MTHFR C677T and A1298C single nucleotide polymorphisms (SNPs) by Real-time PCR. ResultsThe study groups comprised of 218 sickle cell trait (SCT) and 31 sickle cell disease (SCD) children. The caste distribution between the two study groups was quite uniform (X231 = 44.21, p = 0.06). Frequencies of homozygous mutants 677TT and 1298CC were 2% and 19.7% respectively. The odds for the variant forms for both SNPs were found to be greater in SCD group. The genotypic and allelic frequencies did not reveal any caste preponderance. The mean age (p = 0.001), weight (p < 0.001), height (p < 0.001), BMI (p < 0.001) and hemoglobin concentrations (p = 0.002) were lower in homozygous 1298CC but not so in 677TT children. A1298C also depicted significant association with BMI and anemia (p < 0.001). ConclusionHomozygous mutant MTHFR variants would be essential genetic markers especially in children with SCD to identify the vulnerable group who frequently get hospitalized for vascular complications.

Association of the methylene-tetrahydrofolate reductase gene rs1801133 C677T variant with serum homocysteine levels, and the severity of coronary artery disease

This study aimed to investigate whether the single nucleotide polymorphism C677T (rs1801133) of the methylene-tetrahydrofolate reductase (MTHFR) gene was associated with the risk of coronary artery disease (CAD) and circulating homocysteine (Hcy) levels in Tunisian population. 310 angiografically diagnosed CAD patients and 210 controls were enrolled in this study. The MTHFR C677T (rs1801133) polymorphism was genotyped, and the Hcy concentrations were measured. The severity of CAD was evaluated using the Gensini scoring system. Compared to the CC genotype, the TT genotype confers a higher risk for CAD severity with an OR = 9.07 and 95% CI = 3.78–21.8. The T allele was the predisposing allele for CAD and that it was probably associated with CAD severity. The area under the ROC curve for Hcy was 0.764 (95% CI 0.660 to 0.868, p = 0.001). The receiver operating characteristics curve (ROC) for Hcy showed its useful prediction of CAD. Hcy levels were not significantly associated with CAD severity expressed by Gensini Score (GS). The MTHFR C677T (rs1801133) polymorphism influences circulating Hcy levels. The MTHFR C677T polymorphism and hyperhomocysteinemia could have an important role in the prediction of the presence and not the severity expressed by GS of CAD.

Association of MTHFR and RFC1 gene polymorphisms with methotrexate efficacy and toxicity in Chinese Han patients with rheumatoid arthritis.

ObjectiveThe objective was to explore the association of methylene tetrahydrofolate reductase (MTHFR) C667T and A1298C and reduced folate carrier 1 (RFC-1) A80G single nucleotide polymorphisms (SNP) with rheumatoid arthritis (RA) and efficacy and toxicity of methotrexate (MTX) treatment in Chinese Han patients in Henan, China.MethodsTwo hundred ninety-six patients with RA were enrolled (cases) and 120 healthy individuals served as controls. The genotypes of MTHFR C667T and A1298C SNP and RFC-1 A80G SNP were detected by restriction fragment length polymorphism-PCR and compared between cases and controls. We analyzed correlations of clinical effect, toxicity, and SNPs after 6 months of MTX treatment.ResultsWe detected no significant differences in MTHFR C677T and A1298C and RFC-1 A80G SNPs between cases and controls. The RFC-1 A80G SNP differed between RA patients with good and poor efficacy after 6 months of MTX, and was an independent factor of MTX efficacy. The MTHFR C677T SNP was differently distributed in the adverse drug reaction (ADR) and non-ADR groups and was an independent factor of MTX toxicity.ConclusionsIn Chinese Han patients with RA, the MTHFR C667T SNP may correlate with MTX toxicity, whereas the RFC-1 A80G SNP may correlate with MTX efficacy rather than toxicity.

P6603The predictive role of T786C single nucleotide polymorphism in endothelial no-synthase gene in late left ventricular remodeling after ST-segment elevation myocardial infarction

Abstract Introduction Endothelial NO-synthase (eNOS) is constitutive enzyme, which is expressed in mature endothelial cells and promotes direct vascular dilatation. Single nucleotide polymorphism (SNP) of T786C in eNOS gene may influence on adverse cardiac remodeling after ST-elevation myocardial infarction (STEMI). Purpose To investigate possible associations between SNP T786C in eNOS gene and adverse cardiac remodeling after STEMI Methods 177 acute STEMI patients treated with primary and facilitate percutaneous coronary intervention that were admitted to intensive care unit of a Therapy National Institute were enrolled in the study. Anthropometry, cardiovascular risk assay, coronary angiography, echocardiography and biomarkers' measure were performed at baseline. The DNA extraction was performed with a commercial kit using real-time polymerase chain reaction PCR. All procedures performed in the study involving human participants were in accordance with the ethical standards and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards and approved by the local ethics committee (Protocol No. 8, 29.08.2016). Written informed consent was obtained from each patient. Results There were correlations between 786CC polymorphism in eNOs gene and adverse cardiac remodeling (r=0.48; p=0.001), LDL cholesterol (r=0.32; p=0.012), type 2 diabetes mellitus (r=0.30; p=0.042), diastolic BP (r=−0.26; p=0.048), unstable angina prior to STEMI (r=0.25; p=0.047) and total quantity of complicated STEMI (r=0.23; p=0.042). Additionally, there were not significant relations between 786CC polymorphism in eNOs gene and multiple coronary vessel injury, STEMI localization, levels of circulating biomarkers of myocardial injury, and amount of damaged coronary arteries. Using univariate and multivariate regressive logistic analysis we found that 786CC genotype of eNOS was independent predictor for late adverse LV remodeling (β-coefficient = 1.57342; odds ratio = 4.8231; 95% confidence interval = 1.5349–15.1552; p=0.0071). Conclusions The polymorphism 786CC in eNOs gene was found as an independent predictor for late adverse cardiac remodeling after STEMI. Acknowledgement/Funding None

MDR1 gene polymorphism correlated with pathological characteristics and prognosis in patients with primary hepatocellular carcinoma receiving interventional therapy.

The aim of this study was to explore the relationship of multidrug resistance gene 1 (MDR1) C1236T and C3435T single nucleotides polymorphisms (SNPs) with hepatocellular carcinoma (HCC) pathological features and prognosis. A total of 143 patients with HCC were treated with transcatheter arterial chemoembolization. Moreover, 251 controls were included in the study. C1236T and C3435T single nucleotide polymorphisms (SNPs) were detected by PCR-RFLP. Association of C1236T and C3435T SNPs with HCC was analyzed subsequently. There was no significant difference in genotypes distribution between HCC group and control group (P>0.05), indicating comparability. Among patients with portal vein tumor thrombus, the CC+CT genotype of C1236T locus was significantly higher than that of TT genotype (P=0.031). The median progression-free survival after interventional therapy for patients with C3435T genotype T (TC+TT) and C genotype (CC) was 36 and 18 months, respectively. CC and TC+TT genotype patients with C1236T loci showed statistically significant differences in tumor size stratification (χ=4.006, P=0.045). When tumor diameter was less than 5 cm, 5-10 cm, and more than 10 cm, the mean survival time of C and T genotypes was decreased gradually. The logistic regression model suggested that lesion size, blood volume value, and permeability surface value were influential factors for response to chemoradiotherapy (all P<0.05). Univariate analysis showed that postoperative chemotherapy, portal vein tumor thrombus, and capsular invasion were correlated with overall survival in patients with HCC. Cox proportional hazard model showed that postoperative chemotherapy, capsule invasion, and portal vein tumor thrombus were independent factors of overall survival after interventional therapy in patients with HCC (all P<0.05). C1236T genotype may predict changes in pathological features of patients with HCC to a certain extent, and C3435T SNP can be used as one of the prognostic factors of HCC. Postoperative chemotherapy and portal vein tumor thrombus are independent factors of overall survival in patients with HCC.

Investigation of Leptin Receptor and eNOS Gene Polymorphisms in Preeclamptic Umbilical Cords

Preeclampsia occurs in the umbilical artery with proteinuria and edema accompanying pregnancy-induced hypertension. Vasoconstriction results in severe complications such as intrauterine growth restriction, preterm birth, fetal death due to decreased uteroplacental blood flow. Preeclampsia may cause perinatal mortality and morbidity and it is one of the most important causes of maternal mortality. The etiology and pathogenesis of preeclampsia, which is present in 7,18% of all pregnancies, has not yet been elucidated. However, it is thought that one of the causes of pathogenesis may be caused by possible changes in the synthesis of endothelial nitric oxide synthase (eNOS) mediated nitric oxide (NO). DNA sequencing studies revealed many single nucleotide polymorphisms (SNPs) in the promoter region, exons and introns of this gene. T-786C SNP is found in the promoter region of the eNOS gene. There are several agents affecting eNOS activity in preeclampsia.

Association of Single Nucleotide Polymorphisms (SNPs) in Genes Encoding for Folate Metabolising Enzymes with Glioma and Meningioma in Indian Population

Background:The association of primary brain tumors with Single Nucleotide polymorphisms (SNPs) in genes of folate metabolising enzymes have been reported to vary among different ethnic population. Here, we have studied the association of SNPs of folate metabolizing genes with the primary brain tumors (glioma and meningioma) in North Indian population.Methods:SNPs of genes coding for folate metabolizing enzymes was carried out in 288 study population from North India [Glioma (n=108), Meningioma (n=76) and healthy-control (n=104)]. The allele-specific polymerase chain reaction (ARMS-PCR) was used to analyse the SNP A1298C of the MTHFR (Methylenetetrahydrofolate-reductase) and the SNP A66G of the methionine synthase reductase (MTRR) genes. The PCR-RLFP (Restriction Fragment Length Polymorphism) was used to analyse the SNP C677T of the Methylene tetrahydrofolate-reductase and the SNP A2756G of the methionine-synthase (MTR) genes. Serum homocysteine, vitamin B12 and folate levels were evaluated in controls/patients serum using Chemiluminescence immunoassay and the levels were correlated with SNPs genotype.Results:The CC genotype of MTHFR A1298C was observed to have reduced risk of having meningioma than AA genotype (odd ratio=0.62, 95%CI 0.32-0.97, p=0.03). Similarly, the AG genotype of MTRR A66G showed reduced risk of glioma than AA genotype (odd ratio=0.56, 95%CI 0.32-0.97, p=0.039). Furthermore, in patients with AA genotype of MTR A2756G and CT genotype of MTHFR C677T showed higher serum homocysteine level than GG genotype (8.6 µmol/L, p=0.048) and CC genotype (11.2µmol/L, p=0.039) respectively.Conclusion:Our findings provide an insight into the risk association of SNPs in MTHFR A1298C and MTRR A66G genes with glioma/meningioma patients. Further studies are needed to evaluate their clinical implications.

Common Methylenetetrahydrofolate Reductase Polymorphisms (A1298C & C677T) in Ectopic Trophoblasts and Methotrexate Treatment Failure in Tubal Pregnancies.

The success rate of methotrexate (MTX) therapy varies among tubal ectopic pregnancies. Common methylenetetrahydrofolate reductase (MTHFR) polymorphisms (C677T&A1298C) have been suggested to alter MTX effect. This study aimed to assess and compare MTX treatment failure rates with respect to MTHFR polymorphisms in trophoblasts of ectopic tubal pregnancies. A retrospective chart review of tubal ectopic pregnancies was conducted and 34 eligible cases were found. Paraffinized blocks of ectopic trophoblastic tissues were retrieved from the archives of pathology department. Common MTHFR polymorphisms were studied on microdissected trophoblastic tissues. Sixteen cases with history of failed MTX therapy (study group) and 18 control cases were compared for their pertinent clinical characteristics and common MTHFR polymorphisms (C677T&A1298) data. In the study group, there were 8 (50%) C677T single nucleotide polymorphisms (SNP) and 9 (56.7%) A1298C SNP. Polymorphism rates were not found to be different between two groups for neither polymorphism (p > 0.05 for both). Number of compound heterozygotes was 3 (18.7%) in study group and 5 (27.7%) in controls (p = 0.693). In addition, MTHFR polymorphism presence seemed to have no effect on interval serum β-hCG concentration change in MTX-fail group (p=0.693). Our data implied that common MTHFR polymorphisms of ectopic trophoblastic tissue are not associated with MTX failure in patients with tubal pregnancies. Additionally, serum β-hCG concentration changes caused by MTX treatment and studied MTHFR polymorphisms are likely independent.

The protein tyrosine phosphatase PTPN22 negatively regulates presentation of immune complex derived antigens

A C1858T single nucleotide polymorphism within PTPN22 (which encodes PTPN22R620W) is associated with an enhanced susceptibility to multiple autoimmune diseases including type 1 diabetes and rheumatoid arthritis. Many of the associated autoimmune diseases have an autoantibody component to their pathology. Fc receptors (FcRs) recognise autoantibodies when they bind to autoantigens and form immune complexes. After immune complex binding and receptor crosslinking, FcRs signal via Src and Syk family kinases, leading to antigen uptake, presentation and cytokine secretion. Ptpn22 encodes a protein tyrosine phosphatase that negatively regulates Src and Syk family kinases proximal to immunoreceptor signalling cascades. We therefore hypothesised that PTPN22 regulates immune complex stimulated FcR responses in dendritic cells (DCs). Bone marrow derived DCs (BMDCs) from wild type (WT) or Ptpn22−/− mice were pulsed with ovalbumin:anti-ovalbumin immune complexes (ova ICs). Co-culture with WT OT-II T cells revealed that ova IC pulsed Ptpn22−/− BMDCs have an enhanced capability to induce T cell proliferation. This was associated with an increased capability of Ptpn22−/− BMDCs to present immune complex derived antigens and to form ova IC dependent DC-T cell conjugates. These findings highlight PTPN22 as a regulator of FcR mediated responses and provide a link between the association of PTPN22R620W with autoantibody associated autoimmune diseases.

Protein tyrosine phosphatase PTPN22 regulates LFA-1 dependent Th1 responses

A missense C1858T single nucleotide polymorphism within PTPN22 is a strong genetic risk factor for the development of multiple autoimmune diseases. PTPN22 encodes a protein tyrosine phosphatase that negatively regulates immuno-receptor proximal Src and Syk family kinases. Notably, PTPN22 negatively regulates kinases downstream of T-cell receptor (TCR) and LFA-1, thereby setting thresholds for T-cell activation. Alterations to the quality of TCR and LFA-1 engagement at the immune synapse and the regulation of downstream signals can have profound effects on the type of effector T-cell response induced. Here we describe how IFNγ+ Th1 responses are potentiated in Ptpn22−/− T-cells and in T-cells from mice expressing Ptpn22R619W (the mouse orthologue of the human genetic variant) as they age, or following repeated immune challenge, and explore the mechanisms contributing to the expansion of Th1 cells. Specifically, we uncover two LFA-1-ICAM dependent mechanisms; one T-cell intrinsic, and one T-cell extrinsic. Firstly, we found that in vitro anti-CD3/LFA-1 induced Th1 responses were enhanced in Ptpn22−/− T-cells compared to WT, whereas anti-CD3/anti-CD28 induced IFNy responses were similar. These data were associated with an enhanced ability of Ptpn22−/− T-cells to engage ICAM-1 at the immune synapse when incubated on planar lipid bilayers, and to form conjugates with dendritic cells. Secondly, we observed a T-cell extrinsic mechanism whereby repeated stimulation of WT OT-II T-cells with LPS and OVA323-339 pulsed Ptpn22−/− bone marrow derived dendritic cells (BMDCs) was sufficient to enhance Th1 cell development compared to WT BMDCs. Furthermore, this response could be reversed by LFA-1 blockade. Our data point to two related but distinct mechanisms by which PTPN22 regulates LFA-1 dependent signals to enhance Th1 development, highlighting how perturbations to PTPN22 function over time to regulate the balance of the immune response.

METHYLENETETRAHYDROFOLATE REDUCTASE C677T GENE POLYMORPHISM AND PROSTATE CANCER RISK

Objective: The single nucleotide polymorphism C677T of the methylenetetrahydrofolate reductase (MTHFR) gene encodes a thermolabile enzyme. This polymorphism was found to be implicated in cancer susceptibility. In this study, we analyzed the distribution of the MTHFR C677T polymorphism in two cohorts; patients and controls native of East of Algeria to explore the possible association between this polymorphism and prostate cancer susceptibility.Methods: Our examination has been conducted in 98 cases and 98 healthy controls. Genotyping was realized by polymerase chain reaction-restriction fragment length polymorphism method.Results: Compared with CC homozygous, the CT heterozygous was found to have a significantly increased risk of prostate cancer (p=0.04; odds ratio [OR]=2.01, 95% confidence interval [CI]: 1.02–3.95). However, no statistically significant difference was observed concerning the TT homozygous (p=0.74; OR=1.25, 95% CI: 0.51–3.04).Conclusion: Our results indicate that the genotype CT is a risk factor for prostate cancer in East of Algeria.

Association of C3435T, C1236T and C4125A Polymorphisms of the MDR-1 Gene in Egyptian Children with Acute Lymphoblastic Leukaemia

Background:P-glycoprotein (P-gp), a membrane transporter encoded by the multidrug resistance-1 (MDR1) gene, influences pharmacokinetics and metabolism of anticancer drugs and contributes to multidrug resistance phenotype in acute lymphoblastic leukemia (ALL). Genetic variation ofMDR1 in ALL patients is increasingly recognized as a factor influencing response to treatment.Aim:To investigate the possible role of MDR-1 gene polymorphisms (C3435T, C1236T and C4125A) as risk factors for the development and clinical outcome of ALL in Egyptian children.Materials and Methods:Genotyping of MDR-1 C3435T, C1236T and C4125A single nucleotide polymorphisms (SNPs) was accomplished using a polymerase chain reaction–restriction fragment length polymorphism (RFLP-PCR) assay with 120 childhood ALL patients and 100 healthy controls.Results:Homozygous T with the C3435T SNP showed a protective effect as compared to homozygous C (OR=0.748) while heterozygous CT correlated with a poor outcome (high risk, drug unresponsiveness, relapse and high percentage of death). Additionally, the T allele of the C1236T SNP showed a significant relation with ALL risk (OR=1.6). However, there were no significant differences in the genotype and allele frequencies of MDR-1 SNPs between patients and controls. Only one genotype (CC) and one allele of MDR-1 (C4125A) were seen. Neither CA/AA genotypes nor A alleles were present in ALL patients and normal controls. TC was the predominant haplotype in both groups, while CT proved to be minor. The cumulative incidence of relapse was higher with the CC genotype of C1236T as compared with TT.Conclusion:From our preliminary data, the CT genotype of C3435T is associated with a poor ALL outcome while the CC genotype of C1236T is related with an increased incidence of relapse. Although our results provide assistance for oncologist choice of individual therapeutic strategy taking the patient genetic repertoire into consideration, further investigations with larger sample size should be conducted to validate our results.

GSTP1, TSER, MTHFR C677T and MTHFR A1298C gene single nucleotide polymorphisms associated with toxicity and survival in patients with colorectal cancer treated with 5‑fluorouracil-based chemotherapy

GSTP1, TSER, MTHFR C677T and MTHFR A1298C gene single nucleotide polymorphisms associated with toxicity and survival in patients with colorectal cancer treated with 5‑fluorouracil-based chemotherapy

Analysis of the influence of the T393C polymorphism of the GNAS gene on the clinical expression of primary hyperparathyroidism

BackgroundThe receptor of parathyroid hormone and parathyroid hormone-related-protein (PTH/PTHrp) is located in the cell membrane of target tissues – kidney and osteoblasts. It is a G protein-coupled-receptor whose Gsα subunit is encoded by the GNAS gene. Our aim was to study whether the single nucleotide polymorphism (SNP) T393C of the GNAS gene is associated with renal stones, bone mineral density (BMD), or bone remodelling markers in primary hyperparathyroidism (PHPT). MethodsAn analysis was made of clinical and biochemical parameters and densitometric values in three areas and their relationship with the T393C SNP of the GNAS gene in 261 patients with primary hyperparathyroidism and in 328 healthy controls. Genotyping was performed using the Custom Taqman® SNP Genotyping assay. ResultsThe genotype frequencies of GNAS T/C 393 were similar in the control and PHPT groups. No association was found between genotypes and clinical expression of PHPT (renal stones and bone fractures). A nonstatistically significant trend was seen to lower BMD in the lumbar spine, femoral neck, and total hip in both PHPT and control C homozygote subjects. ConclusionGenetic susceptibility to PHPT related to the GNAS T393C polymorphism or a major influence in its development and clinical expression were found. A C allele-related susceptibility to lower BMD in trabecular bone in both PHPT and control subjects is not sufficient to suggest a more severe clinical expression of PHPT. This trend may be considered as a basis for further studies with larger sample sizes and complementary functional evaluation.

Analysis of the influence of the T393C polymorphism of the GNAS gene on the clinical expression of primary hyperparathyroidism

BackgroundThe receptor of parathyroid hormone and parathyroid hormone-related-protein (PTH/PTHrp) is located in the cell membrane of target tissues – kidney and osteoblasts. It is a G protein-coupled-receptor whose Gsα subunit is encoded by the GNAS gene. Our aim was to study whether the single nucleotide polymorphism (SNP) T393C of the GNAS gene is associated with renal stones, bone mineral density (BMD), or bone remodelling markers in primary hyperparathyroidism (PHPT). MethodsAn analysis was made of clinical and biochemical parameters and densitometric values in three areas and their relationship with the T393C SNP of the GNAS gene in 261 patients with primary hyperparathyroidism and in 328 healthy controls. Genotyping was performed using the Custom Taqman® SNP Genotyping assay. ResultsThe genotype frequencies of GNAS T/C 393 were similar in the control and PHPT groups. No association was found between genotypes and clinical expression of PHPT (renal stones and bone fractures). A nonstatistically significant trend was seen to lower BMD in the lumbar spine, femoral neck, and total hip in both PHPT and control C homozygote subjects. ConclusionGenetic susceptibility to PHPT related to the GNAS T393C polymorphism or a major influence in its development and clinical expression were found. A C allele-related susceptibility to lower BMD in trabecular bone in both PHPT and control subjects is not sufficient to suggest a more severe clinical expression of PHPT. This trend may be considered as a basis for further studies with larger sample sizes and complementary functional evaluation.

P-149 - C677T single nucleotide polymorphism of methylenetetrahydrofolate reductase gene and colorectal cancer

P-149 - C677T single nucleotide polymorphism of methylenetetrahydrofolate reductase gene and colorectal cancer

Association Between MTHFR C677T Polymorphism and Methotrexate Treatment Outcome in Rheumatoid Arthritis Patients: A Systematic Review and Meta-Analysis.

Methotrexate (MTX) is one of the most widely used disease-modifying antirheumatic drugs for the treatment of rheumatoid arthritis (RA). However, its efficacy in RA patients is variable and unpredictable. Methylene tetrahydrofolate reductase (MTHFR) is an important enzyme in the MTX pathway and is involved in folate metabolism and DNA synthesis. Several studies have examined the association between the MTHFR C677T polymorphism and MTX toxicity and efficacy in RA, but their conclusions remain controversial. We conducted a comprehensive literature search of the PubMed, Embase, and Cochrane Library databases to identify studies reporting an association between the MTHFR C677T single nucleotide polymorphism and MTX response in RA patients. We identified 16 studies reporting MTX efficacy in 2373 RA cases, and 25 studies reporting MTX toxicity in 4063 RA cases. The pooled data analysis indicated that the MTHFR C677T polymorphism was associated with increased toxicity, but not efficacy, of MTX in RA patients. Further stratification based on ethnicity revealed an association between the MTHFR 677TT genotype and overall MTX toxicity in East Asian and Caucasian patient populations. In addition, RA patients with the MTHFR C677T polymorphism who were supplemented with folic acid displayed significantly elevated risk for MTX toxicity. Our study indicated that the MTHFR C677T polymorphism could be used as a predictor of MTX toxicity in RA patients. However, large randomized prospective studies will be required to effectively replicate and validate these findings.

The common, autoimmunity-predisposing 620Arg > Trp variant of PTPN22 modulates macrophage function and morphology

The C1858T single nucleotide polymorphism (SNP) in PTPN22 (protein tyrosine phosphatase nonreceptor 22) leads to the 620 Arg to Trp polymorphism in its encoded human protein LYP. This allelic variant is associated with multiple autoimmune diseases, including type 1 diabetes (T1D), Crohn's disease, rheumatoid arthritis and systemic lupus erythematosus. However, the underlying mechanisms are poorly understood. To study how this polymorphism influences the immune system, we generated a mouse strain with a knock-in of the Trp allele, imitating the human disease-associated variant. We did not find significant difference between the polymorphic and the wild type mice on the proportion of total CD4 T cell, CD8 T cell, NK cell, memory T lymphocyte, macrophage, dendritic cells in both peripheral lymph nodes and spleen. However, macrophages from Trp/Trp mice showed altered morphology and enhanced function, including higher expression of MHCII and B7 molecules and increased phagocytic ability, which further leads to a higher T-cell activation by specific antigen. Our model shows no alteration in immune cell profile by the Trp allele, but brings up macrophages as an important player to consider in explaining the PTPN22 Trp allele effect on autoimmune disease risk.

Endothelial nitric oxide synthase gene single nucleotide polymorphisms and the risk of hypertension: A meta-analysis involving 63,258 subjects

ABSTRACTThe endothelial nitric oxide synthase (eNOS) gene plays an important role in regulating vascular tone and blood pressure. Recently, the eNOS G894T and T-786C single nucleotide polymorphisms (SNPs) were intensively studied with regard to their associations with hypertension. However, the results of these studies were inconsistent. Therefore, we conducted the so far largest meta-analysis to better assess the correlations between eNOS SNPs and hypertension. Eligible articles were searched in PubMed, Medline, Embase, Scopus, and CNKI up to April 2016. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to detect any potential associations between eNOS SNPs and the risk of hypertension. A total of 95 case–control studies involving 29,308 hypertension cases and 33,950 healthy controls were analyzed. The overall meta-analysis results showed that eNOS G894T and T-786C SNPs were both significantly associated with the risk of hypertension, the T allele of G894T SNP (G versus T, P < 0.00001, OR = 0.82, 95% CI 0.76–0.89) and C allele of T-786C SNP (T versus C, P = 0.004, OR = 0.92, 95% CI 0.87–0.97) conferred an increased susceptibility to hypertension. Further subgroup analyses yielded similar positive results for G894T SNP in essential hypertension, gestational hypertension, and Asian ethnicity, and that for T-786C SNP in essential hypertension and Asian population. Overall, our findings suggest that eNOS G894T and T-786C SNPs were both significantly correlated with hypertension. Additionally, the T allele of G894T SNP and C allele of T-786C SNP may serve as potential biological markers for hypertension susceptibility in Asians.

Polymorphisms in the multidrug-resistance 1 gene related to glucocorticoid response in rheumatoid arthritis treatment

A substantial proportion of rheumatoid arthritis (RA)-patients experience an insufficient response to glucocorticoids, an important therapeutic agent in RA. The multidrug-resistance 1 (MDR1) gene product P-glycoprotein (P-gp) is an efflux pump that actively transports substrates, such as glucocorticoids, out of the cell. We investigated if the variation in response might be explained by single-nucleotide polymorphisms (SNPs) in the MDR1 gene. RA-patients treated with intravenous methylprednisolone pulses (n = 18) or oral prednisone/prednisolone (n = 22) were included in a prospective cohort, and clinical response was measured after 5 and 30 days, respectively. The C1236T, G2677A/T, and C3435T SNPs were determined, and the functionality of P-gp was assessed by flow cytometry (Rhodamine efflux assay). Carriage of the G2677A/T SNP was significantly associated with response (OR = 6.18, p = 0.035), the other SNPs showed trends. Stratified for received treatment, the effect was only present in methylprednisolone treated patients. Mutant allele carriage significantly decreased functionality of P-gp in B cells, though had a smaller impact in other PBMC subtypes. Carriage of a MDR1 SNP was related to a response to methylprednisolone in this study, which his suggests that RA-patients carrying wild-type alleles might benefit from P-gp inhibition or administration of glucocorticoid analogues that are non-P-gp substrates.