Association of ANKRD55 Gene Polymorphism with HT: A Protective Factor for Disease Susceptibility.

Purpose: Recent studies have shown that Ankyrin Repeat Domain 55 (ANKRD55) gene polymorphism is a risk factor for multiple autoimmune diseases, but its association with autoimmune thyroid diseases (AITDs) has not been reported. The purpose of this study was to investigate the potential relationship between polymorphism of the ANKRD55 gene and AITDs. Methods: For this study, we enrolled 2050 subjects, consisting of 1220 patients with AITD and 830 healthy subjects. Five loci (rs321776, rs191205, rs7731626, rs415407, and rs159572) of the ANKRD55 gene were genotyped using Multiplex PCR combined with high-throughput sequencing. Results: The results showed that the allele frequencies of rs7731626 and rs159572 loci in HT patients were lower than those in normal controls (P=0.048 and P=0.03, respectively). In different genetic model analyses, rs7731626 and rs159572 were also significantly correlated with HT in allele, dominant and additive models before and after age and sex adjustment. There were no differences in rs321776, rs191205, or rs415407 of the ANKRD55 gene in allele frequency or genotype frequency between AITDs patients and controls. Conclusions: This study for the first time found that rs7731626 and rs159572 of ANKRD55 were significantly correlated with HT, and individuals carrying the A allele at these two loci had a lower probability of developing HT.

Association Between Polymorphisms of IL-23/IL-17 Pathway and Clinical Phenotypes of Autoimmune Thyroid Diseases.

BACKGROUND: Several autoimmune and inflammatory disorders, including autoimmune thyroid diseases (AITD), have been linked to Th17 cells and the IL-23/IL-17 axis. Current data suggest that genetic variation contributes greatly to disease susceptibility to AITD. OBJECTIVES: To study the role of single nucleotide polymorphisms (SNPs) of IL-23/IL-17 pathway in AITD predisposition and test the gene-gene/gene-sex interactions in these loci. METHODS: A total of 1051 patients with AITD, including 657 patients with Graves' disease (GD) and 394 patients with Hashimoto's thyroiditis (HT), and 874 healthy controls were enrolled in this case-control association study. Six SNPs were selected and genotyped by multiplex PCR combined with high-throughput sequencing. Interactions were tested by the general multifactor dimensionality reduction (GMDR) method. RESULTS: Allele C and combinational genotype AC+CC of rs3212227 within IL-23 were significantly associated with GD with goiter (p=0.003 and 0.014, respectively). Allele G and combinational genotype AG+GG of rs4819554 within IL-17RA were significantly related to HT with family history and the severity of HT (p=0.011 and 0.027; p=0.041 and 0.035). Also, allele T and genotype CT+TT of rs9463772 within IL-17F were significantly correlated with the severity of HT (p=0.001 and 0.027, respectively). Moreover, high dimensional gene-sex interaction (IL-23R-IL-23-IL-17RA-IL-17F-sex) was identified in AITD, GD, and HT patients with GMDR analysis. CONCLUSIONS: Our study identified the novel loci and gene-sex interaction in AITD. This evidence, from another perspective, suggests that sex, IL-23/IL-17 pathway, and Th17 cells play an important role in the pathogenesis of AITD.

Psoriasis Susceptibility 1 Candidate 1 (PSORS1C1) Polymorphism is Associated with Autoimmune Thyroid Disease in a Chinese Han Population.

BACKGROUND: Autoimmune thyroid disease (AITD) is an inherited, complex gene- and immune-related disorder that mainly includes Graves' disease (GD) and Hashimoto's thyroiditis (HT). Psoriasis susceptibility 1 candidate 1 (PSORS1C1) is a susceptibility gene associated with many autoimmune diseases, but its role in an individual's predisposition to AITD is unknown. METHODS: This study included 1065 Chinese Han patients with AITD and 943 matched healthy individuals. The rs3130983, rs3778638, rs3815087, and rs4959053 single nucleotide polymorphisms (SNPs) in PSORS1C1 were determined using multiplex polymerase chain reaction technology. RESULTS: Of the four SNPs, only the distribution of the rs3778638 genotypes was different between the AITD (AA, 2.67%; AG, 19.15%; and GG, 78.18%) and control (AA, 1.52%; AG, 22.2%; and GG, 75.87%) groups (P = .046). An association between rs3778683 and GD was observed (p = .039) but not with HT. No linkage disequilibrium was observed for rs3130983, rs3815087, rs3778638, and rs4959053 in PSORS1C1 among the patients with AITD and controls. CONCLUSION: This study suggests the influence of PSORS1C1 rs3778638 on the susceptibility to GDs, supporting this locus as a common autoimmunity risk factor.

Associations between CD160 polymorphisms and autoimmune thyroid disease: a case-control study.

BACKGROUND: Recent researches suggest that the CD160/HVEM/LIGHT/BTLA signaling pathway may contribute to the pathogeneses of autoimmune diseases, but the relationship between CD160 polymorphisms and autoimmune thyroid disease (AITD) has not been reported yet. This study aimed to evaluate the associations between CD160 polymorphisms and AITD. METHODS: A total of 1017 patients with AITD (634 Graves' disease and 383 Hashimoto's thyroiditis) and 856 unrelated healthy controls were recruited into our study. Odds ratios (ORs) with 95% confidence interval (95%CI) were calculated through logistic regression analyses. The CD160 SNPs were detected using Hi-SNP high-throughput genotyping. RESULTS: There was a statistically significant difference between Graves' disease patients and the control group with respect to both the genotype distribution (P = 0.014) and allele frequency of rs744877 (P = 0.034). A significant association of CD160 rs744877 with AITD was observed before adjusted age and gender under a dominant model (OR = 0.79, 95%CI 0.66-0.95; P = 0.013) and an additive model (OR = 0.77, 95%CI 0.64-0.94, P = 0.008), and was also observed after adjusted age and gender under a dominant model (OR = 0.78, 95%CI 0.65-0.95; P = 0.011) and an additive model (OR = 0.76, 95%CI 0.63-0.93, P = 0.007). A significant association of rs744877 with Graves' disease was observed under an allele model (OR = 0.84, 95%CI 0.71-0.98, P = 0.027), a dominant model (OR = 0.74, 95%CI 0.60-0.91; P = 0.005), and an additive model (OR = 0.72, 95%CI 0.58-0.90, P = 0.004). Multivariate logistic regression analyses suggested that the association remained significant after adjustment for age and gender. However, rs744877 was not related to Hashimoto's thyroiditis. Furthermore, CD160 rs3766526 was not significantly related to either Graves' disease or Hashimoto's thyroiditis. CONCLUSION: This is the first identification of the association of CD160 rs744877 with Graves' disease. Our findings add new data to the genetic contribution to Graves' disease susceptibility and support the crucial role of the CD160/HVEM/LIGHT/BTLA pathway in the pathogenesis of Graves' disease.

Hepatic nNOS impaired hepatic insulin sensitivity through the activation of p38 MAPK.

Neuronal nitric oxide synthase (nNOS) interacts with its adaptor protein NOS1AP through its PZD domain in the neurons. Previously, we had reported that NOS1AP enhanced hepatic insulin sensitivity through its PZD-binding domain, which suggested that nNOS might mediate the effect of NOS1AP. This study aimed to examine the role and underlying mechanisms of nNOS in regulating hepatic insulin sensitivity. nNOS co-localized with NOS1AP in mouse liver. The overexpression of NOS1AP in mouse liver decreased the level of phosphorylated nNOS (p-nNOS (Ser1417)), the active form of nNOS. Conversely, the liver-specific deletion of NOS1AP increased the level of p-nNOS (Ser1417). The overexpression of nNOS in the liver of high-fat diet-induced obese mice exacerbated glucose intolerance, enhanced intrahepatic lipid accumulation, decreased glycogen storage, and blunted insulin-induced phosphorylation of IRbeta and Akt in the liver. Similarly, nNOS overexpression increased triglyceride production, decreased glucose utilization, and downregulated insulin-induced expression of p-IRbeta, p-Akt, and p-GSK3beta in the HepG2 cells. In contrast, treatment with Nω-propyl-L-arginine (L-NPA), a selective nNOS inhibitor, improved glucose tolerance and upregulated insulin-induced phosphorylation of IRbeta and Akt in the liver of ob/ob mice. Furthermore, overexpression of nNOS increased p38MAPK phosphorylation in the HepG2 cells. In contrast, inhibition of p38MAPK with SB203580 significantly reversed the nNOS-induced inhibition of insulin-signaling activity (all P < 0.05). This indicated that hepatic nNOS inhibited the insulin-signaling pathway through the activation of p38MAPK. These findings suggest that nNOS is involved in the development of hepatic insulin resistance and that nNOS might be a potential therapeutic target for diabetes.

Resveratrol Attenuates High Glucose-Induced Vascular Endothelial Cell Injury by Activating the E2F3 Pathway.

Type 2 diabetes mellitus (T2DM) is the most common metabolic disease. High glucose-induced macrovascular disease and microangiopathy are major complications of diabetes. E2F3, a member of the E2F transcription factor family, is closely related to cardiovascular diseases. Resveratrol, a nonflavonoid polyphenolic compound widely found in plants, has been shown to have cardiovascular protection. However, there are few studies on whether resveratrol can effectively treat diabetic angiopathy, and the specific mechanism involved needs further study. This study investigated whether E2F3 transcription factors are involved in the process of vascular endothelial injury induced by high glucose and observed its effects on the proliferation of vascular endothelial cells. Then, it analyzed whether resveratrol can inhibit high glucose-induced vascular endothelial cell injury by regulating the E2F3 pathway. We demonstrated that the expression level of the E2F3 transcription factor was significantly inhibited in high glucose state. Resveratrol inhibited high glucose-induced vascular endothelial cell injury by upregulating the E2F3 pathway. High glucose can induce vascular endothelial injury by inhibiting E2F3 gene expression, while resveratrol can inhibit high glucose-induced vascular endothelial injury by activating the E2F3 pathway.

Hepatic nitric oxide synthase 1 adaptor protein regulates glucose homeostasis and hepatic insulin sensitivity in obese mice depending on its PDZ binding domain.

BACKGROUND: NOS1AP is an adaptor protein and its SNP rs12742393 was associated with type 2 diabetes (T2D). However, it remains uncertain whether NOS1AP plays a role in regulation of insulin sensitivity. Hepatic insulin resistance contributed to the development of T2D. Here, our investigation was focused on whether NOS1AP is involved in the regulation of hepatic insulin sensitivity and its underlying mechanisms. METHODS: Liver specific NOS1AP condition knockout (CKO) and NOS1AP overexpression mice were generated and given a high fat diet. SNPs of NOS1AP gene were genotyped in 86 human subjects. FINDINGS: NOS1AP protein is expressed in human and mouse liver. CKO mice exhibited impaired pyruvate, glucose and insulin tolerance, and increased lipid deposits in the liver. Conversely, NOS1AP overexpression in livers of obese mice improved pyruvate and/or glucose, and insulin tolerance, and attenuated liver lipid accumulation. Moreover, hepatocytes from CKO mice exhibited an elevated glucose production and mRNA expressions of Pc and Pck1. Overexpression of NOS1AP potentiated insulin-stimulated activation of IR/Akt in livers from obese mice. The insulin sensitizing effect of NOS1AP could be mimicked by overexpression of C-terminal domain of NOS1AP in ob/ob mice. Furthermore, NOS1AP overexpression in liver significantly inhibited p38 MAPK phosphorylation, and maintained ER homeostasis through p-eIF2a-ATF4-CHOP pathway. Subjects with rsl2742393 of NOS1AP have higher risk to develop hepatic steatosis. INTERPRETATION: Our data demonstrate a novel role of NOS1AP in regulating hepatic insulin sensitivity and p38 MAPK inactivation in obese mice, which makes NOS1AP a potential therapeutic target for the prevention and treatment of T2D. FUND: This work was supported by the National Natural Science Foundation of China (81670707, 31340072) (to C. Wang), and National Basic Research Program of China (Nation 973 Program) (2011CB504001) (to W. Jia).

Aberrant Histone Methylation in Patients with Graves' Disease.

BACKGROUND: Graves' disease (GD) is an organ-specific autoimmune disease. Accumulated data have indicated that aberrant epigenetic modifications are associated with many autoimmune disorders. However, it remains unknown whether histone methylation plays a role in the pathogenesis of GD. In the present study, we aimed to assess histone modification patterns in peripheral blood mononuclear cells (PBMCs) from GD patients. The rate (degree) of H3K4 and H3K9 methylation and the expressions of histone-modifying genes were investigated. METHODS: A total of 68 GD patients and 32 healthy controls were enrolled in this study. Global histone H3K4/H3K9 methylation of PBMCs was evaluated by the EpiQuik™ global histone H3K4/H3K9 methylation assay kit. The expressions of histone methyltransferases (HMTs) and histone demethylases (HDMs) at the mRNA level were determined by real-time quantitative polymerase chain reaction. RESULTS: Global histone H3K9 methylation in PBMCs of GD patients was significantly decreased compared with that in the healthy controls (P=0.007). The expressions of HMTs (SUV39H1 and SUV39H2) at the mRNA level were significantly decreased in PBMCs from GD patients compared with healthy controls (P<0.001), whereas the SETD1A expression at the mRNA level was significantly increased in GD patients compared with healthy controls (P=0.004). In addition, the expressions of HDMs, including JHDM2A and JMJD2A, at the mRNA level were significantly increased in GD patients compared with healthy controls (P<0.001; P=0.007). Moreover, the mRNA expression levels of JARID1A and LSD1 did not significantly differ in GD patients and healthy controls (P>0.05). CONCLUSIONS: These findings firstly suggested that the histone methylation was aberrant in PBMCs of GD patients, which could be possibly attributed to the deregulation of epigenetic modifier genes. Abnormal histone methylation modification may be involved in the pathogenesis of GD.

IRF7 Gene Variations Confer Susceptibility to Autoimmune Thyroid Diseases and Graves' Ophthalmopathy.

The objective of this study was to investigate whether IRF7 polymorphisms are associated with autoimmune thyroid diseases (AITDs). We selected three single nucleotide polymorphisms (SNPs) of IRF7, namely, rs1061501, rs1131665, and rs1061502 for genotyping using PCR-based ligase detection reaction (LDR) method in a total of 1659 participants (592 with Graves' disease, 297 with Hashimoto's thyroiditis, and 770 healthy controls). Gene-disease and genotype-clinical phenotype associations were evaluated for the three SNPs. Our results showed that the AG genotype and the minor allele G frequency of rs1131665 and rs1061502 in AITD patients were both higher than those of the controls (rs1131665: AG genotype: P = 0.017, OR = 1.968; allele G: P = 0.018, OR = 1.946; rs1061502: AG genotype: P = 0.029, OR = 1.866; allele G: P = 0.031, OR = 1.847). Subgroup analysis also showed that the AG genotype and the minor allele G frequency of rs1131665 and rs1061502 in Graves' disease patients were both higher than those of the controls (rs1131665: AG genotype: P = 0.015, OR = 2.074; allele G: P = 0.016, OR = 2.048; rs1061502: AG genotype: P = 0.034, OR = 1.919; allele G: P = 0.035, OR = 1.898). Furthermore, the allele G frequency of rs1061501 was associated with Graves' ophthalmopathy (P = 0.035, OR = 1.396). No significant difference in IRF7 polymorphisms was found between Hashimoto's thyroiditis patients and controls. Our study has revealed for the first time that IRF7 is a susceptibility gene for AITD, especially for Graves' disease and Graves' ophthalmopathy.

Association of single-nucleotide polymorphisms in the IL27 gene with autoimmune thyroid diseases.

Background Accumulating data have shown that interleukin-27 (IL27) polymorphisms are linked to the susceptibility of some autoimmune diseases. We assessed whether there was an association between three single-nucleotide polymorphisms (SNPs) of IL27 gene and autoimmune thyroid diseases (AITDs). Methods Three SNPs (rs153109, rs17855750 and rs181206) of IL27 gene were genotyped by Hi-SNP high-throughput genotyping in 843 patients with AITDs (516 Graves' disease (GD) and 327 Hashimoto's thyroiditis (HT)) and 677 healthy controls in Chinese Han population. Results Compared with controls, rs153109 displayed significant associations with GD in allele and genotype frequencies (P = 0.002 and P = 0.008, respectively) and rs17855750 displayed significant associations with HT in allele frequencies (P = 0.02), whereas no differences in genotype or allele frequencies were found between AITD patients and controls at rs181206. Conclusion Our study, for the first time, showed the significant association of the IL27 gene SNPs with AITD.

Decreased number and impaired function of type 1 regulatory T cells in autoimmune diseases.

Type 1 regulatory T (Tr1) cell is a special type of T regulatory cells with surface molecular markers such as lymphocyte-activation gene 3 and CD49b. A key property of Tr1 cells is the capability to produce high-level interleukin 10 (IL-10) upon activation, in a FOXP3-independent manner. The immunosuppressive function of IL-10 producing Tr1 cells has been extensively studied for many years. Autoimmune diseases (AIDs) are conditions in which the immune system breaks down and starts to attack the body. AIDs include inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis (MS), type 1 diabetes mellitus, Greaves' disease, and so forth. In recent years, more and more studies have documented that the number of Tr1 cells is decreased and the function is inhibited in a variety of AIDs, among which MS is the most widely studied. The protocol for engineering Tr1 cell therapy has been established and is gradually being used in clinical practice in recent years. Tr1 cell therapy has been proven to be safe and effective, but it is mainly involved in myeloid leukemia, graft versus host disease currently. Its therapeutic role in AIDs still needs to be further explored. In this study, we will summarize the research advances of Tr1 cells in AIDs, which will provide useful information for treating AIDs through Tr1 cell therapy in the future.

Dose-response relationship between thyroid stimulating hormone and hypertension risk in euthyroid individuals.

BACKGROUND: The adverse impact of thyroid dysfunction on cardiovascular system is well established, but the relationship between the level of thyroid stimulating hormone (TSH) and the risk of hypertension in euthyroid individuals is still inconclusive. METHODS: We carried out a population-based, cross-sectional study to evaluate the relationship between TSH and hypertension risk in euthyroid individuals, and logistic regression analysis was utilized. In addition, a dose-response meta-analysis of relevant cohort or cross-sectional studies was carried out to further assess the impact of TSH on hypertension risk among euthyroid individuals. RESULTS: A total of 2289 euthyroid individuals without thyroid diseases were recruited in our cross-sectional study. Serum TSH level within the upper reference range was associated with higher risk of hypertension [odds ratio (OR) = 1.29, 95% confidence interval (CI) 1.04-1.61, P = 0.023], and the OR for hypertension was still statistically significant after adjustment for confounding factors (OR = 1.32, 95% CI 1.01-1.72, P = 0.041). Moreover, meta-analysis suggested an obvious dose-response relationship between TSH and hypertension risk in euthyroid individuals, and the OR for hypertension associated with per 1 mIU/l increase in TSH level was 1.09 (95% CI 1.04-1.14, P < 0.001). Meta-analysis also showed that the ß-coefficients of SBP and DBP associated with per 1 mIU/l increase in TSH level were 0.78 (95% CI 0.37-1.18, P < 0.001) and 0.45 (95% CI 0.15-0.76, P = 0.004), respectively. CONCLUSION: The current study provides strong evidence for the dose-response relationship between serum TSH level and hypertension risk in euthyroid individuals. Euthyroid individuals with higher normal TSH level are at higher risk of developing hypertension than those with lower normal TSH level.

The pathogenesis of thyroid autoimmune diseases: New T lymphocytes - Cytokines circuits beyond the Th1-Th2 paradigm.

Autoimmune thyroid disease (AITD) is one of the most common organ-specific autoimmune disorders. It mainly manifests as Hashimoto's thyroiditis (HT) and Graves' disease (GD). HT is characteristic of hypothyroidism resulting from the destruction of the thyroid while GD is characteristic of hyperthyroidism due to excessive production of thyroid hormone induced by thyrotropin receptor-specific stimulatory autoantibodies. T lymphocytes and their secretory cytokines play indispensable roles in modulating immune responses, but their roles are often complex and full of interactions among distinct components of the immune system. Dysfunction of these T cells or aberrant expressions of these cytokines can cause the breakdown of immune tolerance and result in aberrant immune responses during the development of AITDs. This review summarizes recently identified T subsets and related cytokines and their roles in the pathogenesis of AITDs with the hope to provide a better understanding of the precise roles of notably identified T subsets in AITDs and facilitate the discovery of functional molecules or novel immune therapeutic targets for AITDs.

Effect of Levothyroxine on Blood Pressure in Patients With Subclinical Hypothyroidism: A Systematic Review and Meta-Analysis.

Background: Patients with subclinical hypothyroidism (SCH) have elevated blood pressure, but the effect of levothyroxine (LT4) therapy on blood pressure among those patients is still unclear. This study aimed to assess whether LT4 therapy could reduce blood pressure in SCH patients through a systematic review and meta-analysis. Methods: PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science were searched. Randomized controlled trials (RCTs) assessing the effect of LT4 therapy on blood pressure or prospective follow-up studies comparing the blood pressure level before and after LT4 treatment were included, and the mean difference of systolic blood pressure (SBP) or diastolic blood pressure (DBP) was pooled using random-effect meta-analysis. Results: Twenty-nine studies including 10 RCTs and 19 prospective follow-up studies were eligible for the analysis. Meta-analysis of 10 RCTs suggested that LT4 therapy could significantly reduce SBP in SCH patients by 2.48 mmHg (95% CI -4.63 to -0.33, P = 0.024). No heterogeneity was observed among these 10 RCTs (I2 = 0%). Meta-analysis of the 19 prospective follow-up studies found that LT4 therapy significantly decreased SBP and DBP by 4.80 mmHg (95%CI -6.50 to -3.09, P < 0.001) and 2.74 mmHg (95%CI -4.06 to -1.43, P < 0.001), respectively. Conclusion: The findings suggest that LT4 replacement therapy can reduce blood pressure in SCH patients, which needs to be validated in more clinical trials with larger samples.

Key gene co-expression modules and functional pathways involved in the pathogenesis of Graves' disease.

Graves' disease (GD) is a common autoimmune thyroid disease characterized by positive thyroid stimulating hormone receptor antibody. To better understand its molecular pathogenesis, we adopted the weighted gene co-expression network analysis to reveal co-expression modules of key genes involved in the pathogenesis of GD, protein-protein interaction network analysis to identify the hub genes related to GD development and functional analyses to explore their possible functions. Our results showed that 1) a total of 2667 differentially expressed genes in our microarray study and 16 different gene co-expression modules were associated with GD, and 2) the most significant module was associated with the percentage of macrophages, T follicular helper cells and CD4+ memory T cells and mainly enriched in immune regulation and immune response. Overall, our study reveals several key gene co-expression modules and functional pathways involved in GD, which provides some novel insights into the pathogenesis of GD.

Associations of TNFRSF1A Polymorphisms with Autoimmune Thyroid Diseases: A Case-Control Study.

Previous studies have shown associations of polymorphisms in the tumor necrosis factor (TNF) receptor super family member 1A (TNFRSF1A) gene with several groups of inflammatory and autoimmune related diseases, but associations of TNFRSF1A polymorphisms with autoimmune thyroid diseases (AITD), mainly including two sub-types of Hashimoto's thyroiditis (HT) and Graves' disease (GD), in the Chinese Han population is unclear. A case-control study of 1812 subjects (965 AITD patients and 847 unrelated healthy controls) was conducted to assess AITD associations with five single nucleotide polymorphisms (SNPs), including rs4149576, rs4149577, rs4149570, rs1800693, and rs767455 in the TNFRSF1A gene locus. Genotyping was performed and evaluated using the platform of ligase detection reaction. No significant difference was observed in the allele and genotype frequencies between HT or GD patients and controls in any of the five SNPs in the TNFRSF1A gene (all p values >0.05). However, a moderate association of rs4149570 with HT was found after adjusting for age and gender [odds ratio (OR)=1.40, p=0.03]. No obvious difference was found in the haplotype distribution of any of the five SNPs in the TNFRSF1A gene between the AITD patients and controls. These data suggest that these five SNPs in the TNFRSF1A gene are not associated with AITD in the Chinese Han population, but rs4149570 shows a weak association with HT after adjusting for gender and age.

Increased Risk of Thyroid Dysfunction Among Patients With Rheumatoid Arthritis.

Background: Thyroid dysfunction seems to be common among rheumatoid arthritis (RA) patients, but the risk of thyroid dysfunction in RA has not been well-defined. Methods: We performed a case-control study of 65 RA patients and 550 matched non-RA subjects to assess the risk of thyroid dysfunction among Chinese RA patients. A systematic review and meta-analysis was also conducted to comprehensively define the relationship between RA and thyroid dysfunction. Results: The case-control study indicated that the prevalence of thyroid dysfunction was significantly higher in RA patients than controls (OR = 2.89, P < 0.001). Further subgroup analyses revealed positive correlations of RA with hypothyroidism (OR = 2.28, P = 0.006) and hyperthyroidism (OR = 8.95, P < 0.001). Multivariate logistic regression analysis revealed an independent association between RA and thyroid dysfunction (Adjusted OR = 2.89, 95%CI 1.63-5.12, P < 0.001). Meta-analysis of 15 independent studies also showed an obviously increased risk of thyroid dysfunction among RA patients (RR = 2.86, 95%CI 1.78-4.58, P < 0.001). Further subgroup analysis showed RA could obviously increase risk of hyperthyroidism (RR = 2.73, 95%CI 1.29-5.77, P = 0.043) and hypothyroidism (RR = 2.02, 95%CI 1.49-2.74, P < 0.001). Conclusion: Our study provides strong evidence for the increased risk of thyroid dysfunction among RA patients. Screening of thyroid dysfunction may be recommended for RA patients.

Deletion of ß-Arrestin2 in Mice Limited Pancreatic ß-Cell Expansion under Metabolic Stress through Activation of the JNK Pathway.

ß-Arrestin2 (ßarr2) is an adaptor protein that interacts with numerous signaling molecules and regulates insulin sensitivity. We reported previously that ßarr2 was abundantly expressed in mouse pancreatic ß-cells, and loss of ßarr2 leads to impairment of acute- and late-phase insulin secretion. In the present study, we examined the dynamic changes of ß-cell mass in ßarr2-deficient (ßarr2-/-) mice in vivo and explored the underlying mechanisms involved. ßarr2-/- mice with exclusively luciferase overexpression in ß-cells were generated and fed a high-fat diet (HFD). ß-Cell mass was determined by in vivo noninvasive bioluminescence imaging from 4 to 20 wks of age. Proliferation was measured by 5-bromo-2-deoxyuridine (BrdU) incorporation and fluorescence-activated cell sorter analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunoblotting were conducted for gene and protein expression. We found that ß-cell mass was reduced dramatically in ßarr2-/- mice at 12 wks old compared with that of their respective HFD-fed controls. The percentage of BrdU- and Ki67-positive cells reduced in islets from ßarr2-/- mice. Exposure of ßarr2-/- islets to high levels of glucose and free fatty acids (FFAs) exacerbated cell death, which was associated with upregulation of the JNK pathway in these islets. Conversely, overexpression of ßarr2 amplified ß-cell proliferation with a concomitant increase in cyclinD2 expression and a decrease in p21 expression and protected ß-cells from glucose- and FFA-induced cell death through JNK-activation inhibition. In conclusion, ßarr2 plays roles in regulation of pancreatic ß-cell mass through the modulation of cell cycle regulatory genes and the inhibition of JNK activation induced by glucolipotoxity, which implicates a role for ßarr2 in the development of type 2 diabetes.