Pan-cancer integrated analysis of ANKRD1 expression, prognostic value, and potential implications in cancer.

There is substantial evidence demonstrating the crucial role of inflammation in oncogenesis. ANKRD1 has been identified as an anti-inflammatory factor and is related to tumor drug resistance. However, there have been no studies investigating the prognostic value and molecular function of ANKRD1 in pan-cancer. In this study, we utilized the TCGA, GTEx, GSCALite, ENCORI, CTRP, DAVID, AmiGO 2, and KEGG databases as well as R language, to explore and visualize the role of ANKRD1 in tumors. We employed the ROC curve to explore its diagnostic significance, while the Kaplan-Meier survival curve and Cox regression analysis were used to investigate its prognostic value. Additionally, we performed Pearson correlation analysis to evaluate the association between ANKRD1 expression and DNA methylation, immune cell infiltration, immune checkpoints, TMB, MSI, MMR, and GSVA. Our findings indicate that ANKRD1 expression is dysregulated in pan-cancer. The ROC curve revealed that ANKRD1 expression is highly sensitive and specific in diagnosing CHOL, LUAD, LUSC, PAAD, SKCM, and UCS (AUC > 85.0%, P < 0.001). Higher ANKRD1 expression was related to higher overall survival (OS) in LGG, but with lower OS in COAD and STAD (P < 0.001). Moreover, Cox regression and nomogram analyzes suggested that ANKRD1 is an independent factor for COAD, GBM, HNSC, and LUSC. Dysregulation of ANKRD1 expression in pan-cancer involves DNA methylation and microRNA regulation. Using the CTRP database, we discovered that ANKRD1 may influence the half-maximal inhibitory concentration (IC50) of several anti-tumor drugs. ANKRD1 expression showed significant correlations with immune cell infiltration (including cancer-associated fibroblast and M2 macrophages), immune checkpoints, TMB, MSI, and MMR. Furthermore, ANKRD1 is involved in various inflammatory and immune pathways in COAD, GBM, and LUSC, as well as cardiac functions in HNSC. In vitro experiments demonstrated that ANKRD1 promotes migration, and invasion activity, while inhibiting apoptosis in colorectal cancer cell lines (Caco2, SW480). In summary, ANKRD1 represents a potential prognostic biomarker and therapeutic target in human cancers, particularly in COAD.

Emerging roles of SIRT1 activator, SRT2104, in disease treatment.

Silent information regulator 1 (SIRT1) is a NAD+-dependent class III deacetylase that plays important roles in the pathogenesis of numerous diseases, positioning it as a prime candidate for therapeutic intervention. Among its modulators, SRT2104 emerges as the most specific small molecule activator of SIRT1, currently advancing into the clinical translation phase. The primary objective of this review is to evaluate the emerging roles of SRT2104, and to explore its potential as a therapeutic agent in various diseases. In the present review, we systematically summarized the findings from an extensive array of literature sources including the progress of its application in disease treatment and its potential molecular mechanisms by reviewing the literature published in databases such as PubMed, Web of Science, and the World Health Organization International Clinical Trials Registry Platform. We focuses on the strides made in employing SRT2104 for disease treatment, elucidating its potential molecular underpinnings based on preclinical and clinical research data. The findings reveal that SRT2104, as a potent SIRT1 activator, holds considerable therapeutic potential, particularly in modulating metabolic and longevity-related pathways. This review establishes SRT2104 as a leading SIRT1 activator with significant therapeutic promise.

Congenital disorder of glycosylation type Ia in a Chinese family: Function analysis of a novel PMM2 complex heterozygosis mutation.

Congenital disorder of glycosylation type Ia (CDG-Ia) is an autosomal recessive genetic disease caused by a mutation in the phosphomannomutase 2 (PMM2) gene. We have identified a 13-month-old boy who has been diagnosed with CDG-Ia. He displays several characteristic symptoms, including cerebellar hypoplasia, severe developmental retardation, hypothyroidism, impaired liver function, and abnormal serum ferritin levels. Through whole-exome sequencing, we discovered novel complex heterozygous mutations in the PMM2 gene, specifically the c.663C > G (p.F221L) mutation and loss of exon 2. Further analysis revealed that the enzymatic activity of the mutant PMM2 protein was significantly reduced by 44.97% (p < 0.05) compared to the wild-type protein.

The contribution of a novel PHEX gene mutation to X-linked hypophosphatemic rickets: a case report and an analysis of the gene mutation dosage effect in a rat model.

A Chinese family was identified to have two patients with rickets, an adult female and a male child (proband), both exhibiting signs related to X-linked hypophosphatemic rickets (XLH). Gene sequencing analysis revealed a deletion of adenine at position 1985 (c.1985delA) in the PHEX-encoding gene. To investigate the relationship between this mutation and the pathogenicity of XLH, as well as analyze the effects of different dosages of PHEX gene mutations on clinical phenotypes, we developed a rat model carrying the PHEX deletion mutation. The CRISPR/Cas9 gene editing technology was employed to construct the rat model with the PHEX gene mutation (c.1985delA). Through reproductive procedures, five genotypes of rats were obtained: female wild type (X/X), female heterozygous (-/X), female homozygous wild type (-/-), male wild type (X/Y), and male hemizygous (-/Y). The rats with different genotypes underwent analysis of growth, serum biochemical parameters, and bone microstructure. The results demonstrated the successful generation of a stable rat model inheriting the PHEX gene mutation. Compared to the wild-type rats, the mutant rats displayed delayed growth, shorter femurs, and significantly reduced bone mass. Among the female rats, the homozygous individuals exhibited the smallest body size, decreased bone mass, shortest femur length, and severe deformities. Moreover, the mutant rats showed significantly lower blood phosphorus concentration, elevated levels of FGF23 and alkaline phosphatase, and increased expression of phosphorus regulators. In conclusion, the XLH rat model with the PHEX gene mutation dosage demonstrated its impact on growth and development, serum biochemical parameters, and femoral morphology.

Potential Biomarker of Acute Anthracycline-induced Cardiotoxicity Among Children With Acute Lymphoblastic Leukemia: Cardiac Adriamycin-responsive Protein.

ABSTRACT: This study aimed to investigate whether serum cardiac adriamycin-responsive protein (CARP) can serve as a sensitive and specific biomarker of anthracyclines (ANT)-induced cardiotoxicity. Fifty-five children with acute lymphoblastic leukemia were recruited. Before and after the administration of ANT, serum levels of CARP, high-sensitivity troponin T, creatine kinase-MB, and electrocardiogram were measured. Postchemotherapeutic clinical manifestations of cardiotoxicity were also investigated. Adverse cardiac events (ACEs) were graded according to the Common Terminology Criteria for Adverse Events 4.0. Then, the CARP expression was statistically analyzed among different groups. The receiver operating characteristic curve was used to evaluate the efficacy of CARP in predicting acute ANT-induced cardiotoxicity. After ANT chemotherapy, the serum CARP concentration increased in the non-ACEs group but decreased in the ACEs group ( P < 0.05). In addition, not only the serum CARP levels (△CARP) was negatively correlated with the grade of ACEs (R=-0.754, P < 0.0001) but also the extent of QT interval corrected (QTc) prolongation (△QTc; R=-0.5592, P < 0.01). The area under the receiver operating characteristic curve of CARP was 90.94% ( P < 0.0001), and the sensitivity and specificity were 88.64% and 91.67%, respectively, all of which are superior to △high-sensitivity troponin T, △creatine kinase-MB, and △QTc. In conclusion, serum CARP could serve as a novel sensitive and specific biomarker of acute ANT-induced cardiotoxicity, which is negatively associated with ACE grade.

Genetic contribution of synapse-associated protein 97 to cerebellar functional connectivity changes in first-episode schizophrenia.

Our previous study data suggested that the synapse-associated protein 97 (SAP97) rs3915512 polymorphism is significantly related to clinical performance in schizophrenia. The cerebellum exhibits abundant expression of SAP97, which is involved with negative symptoms, cognition and emotion in schizophrenia. As functional dysconnectivity with the cortical-subcortical-cerebellar circuitry has been widely shown in patients with schizophrenia, cortical-subcortical-cerebellar dysconnectivity can therefore be considered a possible intermediate phenotype that connects risk genes with schizophrenia. In this study, resting-state functional magnetic resonance imaging (fMRI) was applied to evaluate whether the SAP97 rs3915512 polymorphism changes cortical/subcortical-cerebellar resting-state functional connectivity (RSFC) in 104 Han Chinese subjects (52 first-episode schizophrenia (FES) patients and 52 matched healthy controls (HCs)). To examine RSFC between cortical/subcortical regions and the cerebellum, a ROI (region of interest)-wise functional connectivity analysis was conducted. The association between abnormal cortical/subcortical-cerebellar connectivity and clinical manifestation was further assessed in FES patients with different genotypes. The interactive effect of disease and genotype on RSFC was found between the frontal gyrus (rectus) and cerebellum. A positive correlation was suggested between RSFC in the cerebellum and the hostility scores in FES patients with the A allele, and no correlation was found in FES patients with the TT genotype. The current findings identified that SAP97 may be involved in the process of mental symptoms in FES patients via cerebellar connectivity depending on the rs3915512 polymorphism genotype.

A syndrome featuring developmental disorder of the nervous system induced by a novel mutation in the TCF20 gene, rarely concurrent immune disorders: a case report.

Background: The expression of TCF20 is the most widespread in brain tissue. TCF20 depletion or mutation can affect the proliferation and differentiation of embryonic neurons, leading to developmental disorder of the central nervous system and subsequent rare syndrome featuring. Case presentation: Here, we report a 3-year-old boy carrying a novel frameshift mutation in TCF20, c.1839_1872del (p.Met613IlefsTer159), resulting in multisystem disease. In addition to symptoms of neurodevelopmental disorder, a large head circumference, special appearance, overgrowth, abnormal testicular descent. Remarkably, previously infrequently reported symptoms of the immune system such as hyperimmunoglobulinemia E (hyper-IgE), immune thrombocytopenic purpura, cows milk protein allergy, and wheezy bronchitis, were observed. Conclusion: This study broadens the mutation spectrum of the TCF20 and the phenotypic spectrum of TCF20-associated disease.

Mesenchymal Stem/Stromal Cells in Asthma Therapy: Mechanisms and Strategies for Enhancement.

Asthma is a complex and heterogeneous disease characterized by chronic airway inflammation, airway hyperresponsiveness, and airway remodeling. Most asthmatic patients are well-established using standard treatment strategies and advanced biologicals. However, a small group of patients who do not respond to biological treatments or are not effectively controlled by available treatment strategies remain a clinical challenge. Therefore, new therapies are urgently needed for poorly controlled asthma. Mesenchymal stem/stromal cells (MSCs) have shown therapeutic potential in relieving airway inflammation and repairing impaired immune balance in preclinical trials owing to their immunomodulatory abilities. Noteworthy, MSCs exerted a therapeutic effect on steroid-resistant asthma with rare side effects in asthmatic models. Nevertheless, adverse factors such as limited obtained number, nutrient and oxygen deprivation in vitro, and cell senescence or apoptosis affected the survival rate and homing efficiency of MSCs, thus limiting the efficacy of MSCs in asthma. In this review, we elaborate on the roles and underlying mechanisms of MSCs in the treatment of asthma from the perspective of their source, immunogenicity, homing, differentiation, and immunomodulatory capacity and summarize strategies to improve their therapeutic effect.

The polymorphisms of miR-146a SNPs are associated with asthma in Southern Chinese Han population.

Asthma, a prevalent disease characterized by innate and adaptive immune responses, has been associated with several risk factors including miR-146a. To better understand the potential impact of miR-146a SNPs on asthma susceptibility and clinical features in Southern Chinese Han population, we conducted a case-control to analyze two functional SNPs (rs2910164 and rs57095329) of the miR-146a (394 patients with asthma and 395 healthy controls). Our findings suggest that the rs2910164 C/G genotype may increase the risk for asthma in females, while the rs57095329 G/G genotype may be involved in the regulation of clinical characteristics of males with asthma. In addition, we demonstrated that the SNPs rs2910164 C/G and rs57095329 A/G variations functionally affected the miR-146a levels in patients with asthma, and may alter structure of miR-146a. Our data are the first to suggest that miR-146a SNPs may be significantly associated with onset asthma in Southern Chinese Han population. Our studies may provide new insight into the potential significance of miR-146a SNPs in asthma.

The roles of sirtuins in ferroptosis.

Ferroptosis represents a novel non-apoptotic form of regulated cell death that is driven by iron-dependent lipid peroxidation and plays vital roles in various diseases including cardiovascular diseases, neurodegenerative disorders and cancers. Plenty of iron metabolism-related proteins, regulators of lipid peroxidation, and oxidative stress-related molecules are engaged in ferroptosis and can regulate this complex biological process. Sirtuins have broad functional significance and are targets of many drugs in the clinic. Recently, a growing number of studies have revealed that sirtuins can participate in the occurrence of ferroptosis by affecting many aspects such as redox balance, iron metabolism, and lipid metabolism. This article reviewed the studies on the roles of sirtuins in ferroptosis and the related molecular mechanisms, highlighting valuable targets for the prevention and treatment of ferroptosis-associated diseases.

miR-181a targets PTEN to mediate the neuronal injury caused by oxygen-glucose deprivation and reoxygenation.

Evidence suggests that the microRNA-181 (miR-181) family performs various roles in the pathophysiology of cerebral ischemia and reperfusion injury (CIRI). MiR-181a has been identified as a critical determinant of neuronal survival. Moreover, the significance of miR-181a in controlling neuronal death after CIRI has received little attention. The objective of this study was to assess the role of miR-181a in neuronal cell injury after CIRI. To mimic the in-vitro and in-vivo CIRI, we developed an oxygen-glucose deficiency/reoxygenation (OGD/R) model in SH-SY5Y cells and a transient middle cerebral artery occlusion model in rats. MiR-181a expression was significantly higher in both in-vivo and in-vitro CIRI models. The overexpression of miR-181a increased cell damage and oxidative stress caused by OGD/R, whereas inhibition of miR-181a reduced both. PTEN has also been found to be a direct miR-181a target. PTEN overexpression reduced cell apoptosis and oxidative stress induced by miR-181a upregulation under an OGD/R condition. Furthermore, we found that the rs322931 A allele was related to increased miR-181a levels in IS peripheral blood and higher susceptibility to IS. The current results offer new insights into the understanding of the molecular pathophysiology of CIRI, as well as possible new treatment candidates.

Direct targeting of DOCK4 by miRNA-181d in oxygen-glucose deprivation/reoxygenation-mediated neuronal injury.

The miRNA-181 (miR-181) family regulates neuronal persistence during cerebral ischemia/reperfusion injury (CI/RI). Since the effect of miR-181d on CI/RI has never been studied, the current work sought to determine the involvement of miR-181d in neuronal apoptosis after brain I/R injury. To replicate in vivo and in vitro CI/RI, a transient middle cerebral artery occlusion (tMCAO) model in rats and an oxygen-glucose deficiency/reoxygenation (OGD/R) model in neuro 2A cells were developed. In both in vivo and in vitro stroke models, the expression of miR-181d was considerably higher. miR-181d suppression reduced apoptosis and oxidative stress in OGD/R-treated neuroblastoma cells, but miR-181d overexpression increased both. Furthermore, it was observed that miR-181d has a direct target in dedicator of cytokinesis 4 (DOCK4). The overexpression of DOCK4 partially overcame cell apoptosis and oxidative stress induced by miR-181d upregulation and OGD/R injury. Furthermore, the DOCK4 rs2074130 mutation was related to lower DOCK4 levels in ischemic stroke (IS) peripheral blood and higher susceptibility to IS. These findings suggest that downregulating miR-181d protects neurons from ischemic damage by targeting DOCK4, implying that the miR-181d/DOCK4 axis might be a novel therapeutic target for IS.

Genetic variations in DOCK4 contribute to schizophrenia susceptibility in a Chinese cohort: A genetic neuroimaging study.

BACKGROUND: Emerging evidence suggests that the DOCK4 gene increases susceptibility to schizophrenia. However, no study has hitherto repeated this association in Chinese, and further investigated the relationship between DOCK4 and clinical symptoms in schizophrenic patients using clinical scales and functional magnetic resonance imaging (fMRI). METHODS: In this study, we genotyped three single nucleotide polymorphisms (SNPs) (rs2074127, rs2217262, and rs2074130) within the DOCK4 gene using a case-control design (including 1289 healthy controls and 1351 patients with schizophrenia). 55 first-episode schizophrenia (FES) patients and 59 healthy participants were divided by the genotypes of rs2074130 into CC and CT+TT groups. We further investigated the association with clinical symptoms and neural characteristics (brain activation/connectivity and nodal network metrics). RESULTS: Our results showed significant associations between all selected SNPs and schizophrenia (all P < 0.05). In patients, letter fluency and motor speed scores of T allele carriers were significantly higher than the CC group (all P < 0.05). Interestingly, greater brain activity, functional connectivity, and betweenness centrality (BC) in language processing and motor coordination were also observed in the corresponding brain zones in patients with the T allele based on a two-way ANCOVA model. Moreover, a potential positive correlation was found between brain activity/connectivity of these brain regions and verbal fluency and motor speed. CONCLUSION: Our findings suggest that the DOCK4 gene may contribute to the onset of schizophrenia and lead to language processing and motor coordination dysfunction in this patient population from China.

Case report: Familial glycogen storage disease type IV caused by novel compound heterozygous mutations in a glycogen branching enzyme 1 gene.

Glycogen storage disease type IV (GSD IV), caused by a mutation in the glycogen branching enzyme 1 (GBE1) gene, is a rare metabolic disorder with an autosomal recessive inheritance that involves the liver, neuromuscular, and cardiac systems. Here, we reported a case of familial GSD IV induced by novel compound heterozygous mutations in GBE1. The proband (at age 1) and her younger brother (at age 10 months) manifested hepatosplenomegaly, liver dysfunction, and growth retardation at onset, followed by progressive disease deterioration to liver cirrhosis with liver failure. During the disease course, the proband presented rare intractable asymptomatic hypoglycemia. The liver pathology was in line with GSD IV. Both cases carried pathogenic compound heterozygous mutations in GBE1 mutations, i.e., a missense mutation (c.271T>A, p. W91R) in exon 2 and a deletion mutation in partial exons 3-7. Both mutations are first reported. The internationally pioneered split-liver transplantation was performed during progression to end-stage liver disease, and the patients had normal liver function and blood glucose after. This study broadens the mutation spectrum of the GBE1 gene and the phenotypic spectrum of GSD IV.

Polymorphisms of Calgranulin Genes and Ischemic Stroke in a Chinese Population.

Background: The S100/calgranulin gene appears to modulate neuroinflammation following cerebral ischemia and could be a valuable biomarker for stroke prognosis, according to growing research. This study aimed at evaluating the correlation between calgranulin gene variants and susceptibility to ischemic stroke (IS) in the Southern Chinese population. Methods: Using an enhanced multi-temperature ligase detection reaction genotyping, 310 IS patients and 324 age-matched healthy controls were genotyped to identify five calgranulin gene variants. Results: According to the obtained results, the S100A8 rs3795391, rs3806232, and S100A12 rs2916191 variants were linked to a higher risk of IS, while the S100A9 rs3014866 variant was associated with a lower risk of IS. Moreover, the T-T-C-A-T, T-T-C-G-T, or C-C-C-G-C haplotypes have been linked to a greater risk of developing IS, according to haplotype analysis. The occurrence of the variant C allele there in S100A8 rs3795391, rs3806232, and S100A12 rs2916191 variants may impart a greater risk of stroke in the LAA subtype, according to further stratification by IS subtypes, while the T allele of the S100A9 rs3014866 variant may be linked to a reduced risk of stroke of all subtypes. Furthermore, patients with the variant C allele of the S100A8 rs3795391, rs3806232, and S100A12 rs2916191 variants presented with increased circulating S100A8 and S100A12 levels and larger infarct volumes relative to those with the major TT genotype. Conclusion: Our findings suggest that calgranulin gene variants are linked to IS susceptibility, implying that the calgranulin gene may be a potential biomarker for IS prevention and personalized treatment.

Isolated steroid-resistant nephrotic syndrome in a Chinese child carrying a de novo mutation in WT1 gene:a case report and literature review.

BACKGROUND: Isolated steroid-resistant nephrotic syndrome (ISRNS) is caused by mutations in the Wilms' tumor-1 (WT1) gene, which encodes glomerular podocytes and podocyte slit diaphragm.We report a novel 8-year-old female patient with ISRNS carrying a de novo missense mutation in WT1 gene and presenting a new type of pathology, have never been reported.We also systematically review previous reports of ISRNS in Chinese children. CASE PRESENTATION: A 8-year-old Chinese patient who had steroid-resistant nephrotic syndrome,responded poorly to immunosuppressant, and had no extrarenal manifestations. The patient had a female phenotype and karyotype of 46, XX. A new type of renal pathology, proliferative sclerosing glomerulonephritis (PSG),and a de novo missense mutation in WT1 gene, c.748C > T (p.R250W),which have not yet been reported, were identified. She was diagnosed with ISRNS.The patient progressed to end-stage renal disease at the age of 10 years,underwent dialysis and kidney transplant. Renal function and urine protein were normal during 4-year follow-up. CONCLUSIONS: WT1 gene testing should be performed to guide treatment for patients with steroid-resistant nephrotic syndrome, especially for isolated cases and female patients.

Correlation Between Angiotensin Receptor Type 1 Polymorphisms and Atherosclerotic Cerebral Infarction Risk.

Background: Emerging evidences suggest that the angiotensin receptor type 1 (AT1R) contributes heavily to the pathogenesis of atherosclerotic cerebral infarction (ACI). Herein, we examined a potential link between AT1R gene polymorphisms and ACI risk among a Southern Han Chinese population. Methods: The rs3772616, rs275645, and rs377262 AT1R polymorphisms were genotyped in 689 ACI patients and 712 healthy controls, using the iMLDR-TM assay. Results: The genotypic and allelic frequencies of AT1R rs3772616 differed tremendously between ACI patients and healthy controls, and the rs3772616 T allele is a risk allele for ACI. However, the rs275645 and rs377262 allelic and genotypic frequency distributions were comparable between ACI patients and controls. In addition, the G-T-T haplotype was linked to an enhanced risk of ACI. We, next, classified our study subjects based on environmental factors and revealed that the rs3772616 T allele was strongly associated with an elevated ACI risk in males, hypertensive individuals, and those over 65 years old. In addition, we observed a marked link between the rs3772616 T allele and enhanced AT1R levels. Conclusion: Based on our research, there is a strong correlation between the AT1R rs3772616 polymorphism and enhanced ACI risk. Hence, the AT1R rs3772616 polymorphism can serve as a potential therapeutic target and bioindicator for ACI development.

LncRNA GAS5 rs145204276 Polymorphism Reduces Renal Cell Carcinoma Susceptibility in Southern Chinese Population.

OBJECTIVE: Recent studies have demonstrated that the long non-coding RNA (lncRNA) GAS5 is closely associated with the onset and progression of several tumor types, including renal cell carcinoma (RCC). This study sought to evaluate the relationship between two functional GAS5 polymorphisms (rs145204276 and rs55829688) and the risk for RCC in the Han Chinese population. METHODS: The rs145204276 and rs55829688 polymorphisms in the GAS5 promoter region were genotyped in 624 RCC patients and 655 age/sex-matched healthy participants. The association between these polymorphisms and RCC risk was then evaluated using odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Additionally, quantitative RT-PCR was used to determine whether these polymorphisms were associated with changes in the levels of expression of GAS5 in 58 RCC patients. RESULTS: There were significant differences in the GAS5 rs145204276 polymorphism genotype and allele frequencies between the RCC patients and controls (adjusted OR = 0.73, 95% CI = 0.61- 0.87, P = 1.8×10-3). When the study participants were stratified based on age, sex, BMI index, and smoking and drinking history, we found that the rs145204276 del allele was associated with a reduced risk for RCC in nondrinkers (P = 3.3×10-3), nonsmokers (P = 3.3×10-3), females (P = 3.8×10-3), and those who were less than 60 years old (P = 3.3×10-3). There was also a significant association between the rs145204276 del allele and elevated expression of GAS5 in RCC patients (P = 0.030). CONCLUSIONS: The results of this study revealed an association between the rs145204276 polymorphism in the GAS5 lncRNA and the risk for the development of RCC, thus representing a potentially viable biomarker for identifying individuals at risk of developing this form of cancer.

Association between the RETN -420C/G polymorphism and type 2 diabetes mellitus susceptibility: A meta-analysis of 23 studies.

Background: The published findings on the link between the resistin (RETN) gene polymorphism and type 2 diabetes mellitus (T2DM) risk are still contradictory. Here, through a meta-analysis, we summarized a more precise evaluation of their connection by synthesizing existing research. Methods: PubMed, Google Scholar, and Web of Science were electronically searched, and all cited sources were manually searched. The heterogeneity of effects was tested and all statistical analyses were performed in Stata 12.0. Results: A total of 23 studies with 10,651 cases and 14,366 controls on RETN -420C/G polymorphism were included. The overall results showed that the association of RETN -420C/G polymorphism and T2DM susceptibility was not significant [for the allelic model: odds ratio (OR) = 0.98, 95% confidence interval (CI) = 0.87-1.10, pheterogeneity <.001; I 2 = 84.6%; for the dominant model: OR = 0.96, 95% CI = 0.80-1.15, pheterogeneity <.001; I 2 = 87.1%; and for the recessive model: OR = 0.96, 95% CI = 0.82-1.12, pheterogeneity <.001; I 2 = 56.9%] but with high heterogeneity across studies (p <.0001). Meta-regression found that the median age of T2DM participants (using age 50 as the cutoff) could be a factor in the observed variation. The RETN -420C/G polymorphism seems to be linked to an increased risk of T2DM in younger individuals [for dominant: OR = 0.84 (95% CI, 0.72-0.98; pheterogeneity <.001; I 2 = 80.9%)] and decreased risk in older people [for dominant: OR = 3.14 (95% CI, 2.35-4.19; pheterogeneity = .98; I 2 = 0.0%)]. Conclusions: Current results found no evidence that the RETN -420C/G variant was linked to T2DM susceptibility, but the patient's age appears to be a potential factor that contributed to high heterogeneity across studies. Additional high-quality and well-designed investigations are required to confirm these results.