Meiling Ou

Global Epidemiology of Dengue Outbreaks in 1990–2015: A Systematic Review and Meta-Analysis

Dengue is an arthropod-borne infectious disease caused by dengue virus (DENV) infection and transmitted by Aedes mosquitoes. Approximately 50–100 million people are infected with DENV each year, resulting in a high economic burden on both governments and individuals. Here, we conducted a systematic review and meta-analysis to summarize information regarding the epidemiology, clinical characteristics, and serotype distribution and risk factors for global dengue outbreaks occurring from 1990 to 2015. We searched the PubMed, Embase and Web of Science databases through December 2016 using the term “dengue outbreak.” In total, 3,853 studies were identified, of which 243 studies describing 262 dengue outbreaks met our inclusion criteria. The majority of outbreak-associated dengue cases were reported in the Western Pacific Region, particularly after the year 2010; these cases were primarily identified in China, Singapore and Malaysia. The pooled mean age of dengue-infected individuals was 30.1 years; of the included patients, 54.5% were male, 23.2% had DHF, 62.0% had secondary infections, and 1.3% died. The mean age of dengue patients reported after 2010 was older than that of patients reported before 2010 (34.0 vs. 27.2 years); however, the proportions of patients who had DHF, had secondary infections and died significantly decreased after 2010. Fever, malaise, headache, and asthenia were the most frequently reported clinical symptoms and signs among dengue patients. In addition, among the identified clinical symptoms and signs, positive tourniquet test (OR = 4.86), ascites (OR = 13.91) and shock (OR = 308.09) were identified as the best predictors of dengue infection, DHF and mortality, respectively (both P < 0.05). The main risk factors for dengue infection, DHF and mortality were living with uncovered water container (OR = 1.65), suffering from hypotension (OR = 6.18) and suffering from diabetes mellitus (OR = 2.53), respectively (all P < 0.05). The serotype distribution varied with time and across WHO regions. Overall, co-infections were reported in 47.7% of the evaluated outbreaks, and the highest pooled mortality rate (2.0%) was identified in DENV-2 dominated outbreaks. Our study emphasizes the necessity of implementing programs focused on targeted prevention, early identification, and effective treatment.

A meta-analysis of interaction between Epstein-Barr virus and HLA-DRB1*1501 on risk of multiple sclerosis

Infection with Epstein-Barr virus (EBV) and HLA-DRB1*1501-positivity is a risk factor for multiple sclerosis (MS), but whether an interaction between these two factors causes MS is unclear. We therefore conducted a meta-analysis on the effect of the interaction between HLA-DRB1*1501 and EBV infection on MS. Searches of PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and the Wanfan databases through February 2015 yielded 5 studies that met the criteria for inclusion in the meta-analysis. EBV infection and HLA-DRB1*1501-positivity were dichotomized. The additive (S) and multiplicative interaction indexes (OR) between EBV infection and HLA-DRB1*1501 and their 95% confidence intervals (95%CI) were calculated for each study and then combined in a meta-analysis. EBV infection was significantly associated with MS (OR = 2.60; 95%CI, 1.48–4.59). HLA-DRB1*1501 was associated with a significantly increased risk of MS (OR, 3.06; 95%CI, 2.30–4.08). An interaction effect between EBV infection and HLA-DRB1*1501 on MS was observed on the additive scale (S, 1.43; 95%CI, 1.05–1.95, P = 0.023), but no interaction effect was observed on the multiplicative scale (OR, 0.86, 95%CI, 0.59–1.26). This meta-analysis provides strong evidence that EBV alone, HLA-DRB1*1501 alone or their interaction is associated with an elevated risks of MS.

Association of polymorphisms in the MyD88, IRAK4 and TRAF6 genes and susceptibility to type 2 diabetes mellitus and diabetic nephropathy in a southern Han Chinese population.

Type 2 diabetes mellitus (T2DM) has been linked to a state of low-grade inflammation resulting from abnormalities in the innate immune pathway. MyD88 is an essential adaptor protein for TLR signaling, which is involved in activating NF-κB through IRAK4 and TRAF6. To investigate the effects of the MyD88, IRAK4 and TRAF6 polymorphisms in the susceptibility of T2DM and diabetic vascular complications, eight SNPs were analyzed in 553 T2DM patients and 553 matched healthy controls. Gene-gene interactions and haplotype associations were also evaluated. We found a significant increased risk of T2DM for the AG genotype of rs6853 in MyD88 gene and the CT genotype of rs4251532 in IRAK4 gene. Significant association was also found between rs16928973 in TRAF6 gene and diabetic nephropathy (DN) under the allelic model. Moreover, the TA haplotype in TRAF6 was negatively associated with DN. No significant gene-gene interactions were found. In conclusion, our results indicate that the polymorphisms in TLR-MyD88-NF-κB signaling pathway confer genetic susceptibility to T2DM and DN.

Association between miR-137 polymorphism and risk of schizophrenia: a meta-analysis

miR-137, a brain-enriched microRNA, is involved in the control of neuronal proliferation, differentiation, and dendritic arborization, all of which are important for proper neurogenesis and relevant to schizophrenia. miR-137 is also known to regulate many genes implicated in schizophrenia risk. Although reports have associated the miR-137 polymorphism rs1625579 with this disease, their results have been inconsistent. The aim of this meta-analysis was to evaluate the relationship between rs1625579 and schizophrenia. Data were obtained from an electronic database, and pooled odds ratios (ORs) with 95% confidence intervals (95%CI) were used to test the association using the RevMan 5.3 software. Twelve case-control studies comprising 11,583 cases and 14,315 controls were included. An estimated lambda value of 0.46 was recorded, suggesting that a codominant model of inheritance was most likely. A statistically significant association was established under allelic (T vs G: OR = 1.15, 95%CI = 1.10-1.21, P < 0.001) and homogeneous codominant models (TT vs GG: OR = 1.32, 95%CI = 1.13-1.54, P < 0.001), but no such relationship was detected using the heterogeneous codominant model (GT vs GG: OR = 1.14, 95%CI = 0.97-1.34, P = 0.11). This meta-analysis demonstrates that the rs1625579 miR-137 genetic variant significantly increases schizophrenia risk.

Interaction between susceptibility loci in cGAS-STING pathway, MHC gene and HPV infection on the risk of cervical precancerous lesions in Chinese population.

Human papillomavirus (HPV) infection is a definite risk factor for cervical cancer. Nevertheless, only some infected individuals actually develop cervical cancer. The cGAS-STING pathway in innate immunity plays an important role in protecting against HPV infection. Chen et al. described that the rs2516448 SNP in the MHC locus may affect susceptibility to cervical cancer, a finding that we attempted to replicate in a Chinese population. To investigate the effects of cGAS, STING and MHC polymorphisms on susceptibility to cervical precancerous lesions, 9 SNPs were analyzed in 164 cervical precancerous lesion cases and 428 controls. Gene-gene and gene-environment interactions were also evaluated. We found a significantly decreased risk of cervical precancerous lesions for the GG genotype of rs311678 in the cGAS gene (ORadjusted = 0.40, 95% CI: 0.16−0.98). Moreover, MDR analysis identified a significant three-locus interaction model, involving HPV infection, age at menarche and rs311678 in cGAS. Additionally, a significant antagonistic interaction between HPV infection and rs311678 was found on an additive scale. In conclusion, our results indicate that the rs311678 polymorphism in the cGAS gene confers genetic susceptibility to cervical precancerous lesions. Moreover, the three-way gene-environment interactions further demonstrate that the rs311678 polymorphism in cGAS can significantly decrease the risk of HPV infection and the elder at menarche.

Meta-Analysis on Associations of RGS1 and IL12A Polymorphisms with Celiac Disease Risk

The pathogenesis of celiac disease (CD) has been related to polymorphisms in the regulator of G-protein signaling 1 (RGS1) and interleukin-12 A (IL12A) genes, but the existing findings are inconsistent. Our aim is to investigate the associations of two single-nucleotide polymorphisms (SNPs) (rs2816316 in RGS1 and rs17810546 in IL12A) with CD risk using meta-analysis. We searched PubMed and Web of Science on RGS1 rs2816316 and IL12A rs17810546 with CD risk. Odds ratio (OR) and 95% confidence interval (CI) of each SNP were estimated. All statistical analyses were performed on Stata 12.0. A total of seven studies were retrieved and analyzed. The available data indicated the minor allele C of rs2816316 was negatively associated with CD (C vs. A: OR = 0.77, 95% CI = 0.74–0.80), and a positive association was found for the minor allele G of rs17810546 (G vs. A: OR = 1.37, 95% CI = 1.31–1.43). The co-dominant model of genotype effect confirmed the significant associations between RGS1 rs2816316/IL12A rs17810546 and CD. No evidence of publication bias was observed. Our meta-analysis supports the associations of RGS1 and IL12A with CD and strongly calls for further studies to better understand the roles of RGS1 and IL12A in the pathogenesis of CD.

Association between IL2/IL21 and SH2B3 polymorphisms and risk of celiac disease: a meta-analysis.

Celiac disease (CD) is a common autoimmune disorder characterized by heightened immunological response to ingested gluten. Certain gene polymorphisms of IL2/IL21 (rs6822844 and rs6840978) and SH2B3 (rs3184504) may influence susceptibility to CD, although the effects remain unclear. We performed a meta-analysis of the associations between rs6822844, rs6840978, and rs3184504 polymorphisms and CD risk. PubMed, EMBASE, and the China National Knowledge Infrastructure were searched. ORs and 95%CIs of each single nucleotide polymorphism (SNP) were estimated using the fixed-effect model if I(2) < 50% in the test of heterogeneity; otherwise, the random-effect model was used. Our meta-analysis included 12,986 CD cases and 28,733 controls from 16 independent samples, and the analysis of each SNP contained a subset of the total. We found that the minor allele T of both rs6822844 (T vs G, OR = 0.72, 95%CI = 0.67-0.78, P < 0.001) and rs6840978 (T vs C, OR = 0.76, 95%CI = 0.71-0.83, P < 0.001) in IL2/IL21 significantly decreased the risk of CD. However, the minor allele A of rs3184504 (A vs G, OR = 1.18, 95%CI = 1.12-1.24, P < 0.001) in SH2B3 significantly increased CD susceptibility. The estimated lambda values were 0.49, 0.50, and 0.53 for rs6822844, rs6840978, and rs3184504, respectively, suggesting that a co-dominant model of genotype effect was most appropriate for the three SNPs. Our results support associations between the three SNPs and CD and provide a strong argument for further research.

Association of LPP and TAGAP Polymorphisms with Celiac Disease Risk: A Meta-Analysis

Background: Lipoma preferred partner (LPP) and T-cell activation Rho GTPase activating protein (TAGAP) polymorphisms might influence the susceptibility to celiac disease. Therefore, we performed a meta-analysis by identifying relevant studies to estimate the risks of these polymorphisms on celiac disease. Methods: The PubMed, Web of Science and Embase databases were searched (up to October 2016) for LPP rs1464510 and TAGAP rs1738074 polymorphisms. Results: This meta-analysis included the same 7 studies for LPP rs1464510 and TAGAP rs1738074. The minor risk A allele at both rs1464510 and rs1738074 carried risks (odds ratios) of 1.26 (95% CI: 1.22–1.30) and 1.17 (95% CI: 1.14–1.21), respectively, which contributed to increased risks in all celiac disease patients by 10.72% and 6.59%, respectively. The estimated lambdas were 0.512 and 0.496, respectively, suggesting that a co-dominant model would be suitable for both gene effects. Conclusions: This meta-analysis provides robust estimates that polymorphisms in LPP and TAGAP genes are potential risk factors for celiac disease in European and American. Prospective studies and more genome-wide association studies (GWAS) are needed to confirm these findings, and some corresponding molecular biology experiments should be carried out to clarify the pathogenic mechanisms of celiac disease.

The effects of TLR3, TRIF and TRAF3 SNPs and interactions with environmental factors on type 2 diabetes mellitus and vascular complications in a Han Chinese population

Toll-like receptor 3 (TLR3) is involved in type I interferon-β (IFN-β) via TIR-domain-containing adapter-inducing interferon-β (TRIF) and Tumor necrosis factor receptor-associated factor 3 (TRAF3), culminating in inflammation and immunity reactions. TLR3 is implicated in insulin resistance and type 2 diabetes mellitus (T2DM). Eight SNPs of these genes were detected in 552 T2DM patients and 552 matched healthy control subjects. Gene-gene and gene-environment interactions and haplotype associations were also evaluated. We identified a 21% increased risk of T2DM for the T allele of rs12435483 in the TRAF3 gene (OR: 1.21; 95% CI: 1.01-1.44; P=0.036). The GA genotype and GA+AA genotype of TRAF3 rs12147254 were found to increase the risk of coronary heart disease (CHD) among T2DM patients (GA vs. GG: OR=4.17, 95% CI: 1.04-16.79, P=0.045; GA+AA vs. GG: OR=3.97, 95% CI: 1.02-15.48, P=0.047). However, the GACGAC haplotype in TRAF3 had a protective effect on T2DM micro-macrovascular complications (OR=0.33, 95% CI: 0.13-0.85, P=0.017). Two-factor (TRAF3 rs12435483 and LDL) and three-factor (TRAF3 rs12435483, BMI and HDL) interactions of the risk of T2DM were identified. In conclusion, the genetic variants in the TLR3-TRIF-TRAF3-INF-β signaling pathway and interactions with some particular environmental factors (LDL, BMI and HDL) may contribute to susceptibility to T2DM and vascular complications in the Han Chinese population.

Interactions between polymorphisms in the 3'untranslated region of the cyclin dependent kinase 6 gene and the human papillomavirus infection, and risk of cervical precancerous lesions

The human papillomavirus (HPV) infection is essential for the development of cervical cancer and its precursor lesions. However, only certain persistently infected individuals develop cervical cancer. Cyclin-dependent kinase 6 (CDK6) is a critical regulatory cancer-associated gene in the cell cycle and in tumorigenesis. Single nucleotide polymorphisms (SNPs) in microRNA sites in the 3′-untranslated region (UTR) of target genes may result in target gene expression level changes and susceptibility to diseases, including cancer. Therefore, the aim of the present study was to determine whether SNPs in the 3′UTR of the CDK6 gene may affect susceptibility to cervical precancerous lesions in a Chinese population. Five polymorphisms in the 3′UTR of the CDK6 gene were evaluated in 164 cervical precancerous lesion cases and 296 control subjects. Differences in environmental factors between cases and controls were evaluated using the χ2 test or unpaired t-test. Logistic regression was used to examine the association between the five polymorphisms and cervical precancerous lesions. The model-free multifactor dimensionality reduction (MDR) method was performed to evaluate the interaction effect of environment variables and gene polymorphisms. Interactions on the additive scale are calculated by using the relative excess risk due to interaction (RERI). After controlling for potential confounders, a significantly decreased risk of cervical precancerous lesions for the GA genotype, rs8179, and the AT genotype, rs42033 [GA vs. GA: odds ratio (OR)adjusted=0.17, 95% confidence interval (CI), 0.05–0.57; AT vs. AA: ORadjusted=0.18, 95% CI, 0.05–0.59, respectively] was identified. Furthermore, following MDR analysis, a significant three-locus interaction model was identified, which involved the HPV infection, the number of pregnancies and rs8179. Additionally, a significant antagonistic interaction between the HPV infection and rs8179 was identified on an additive scale. Haplotype AGTA was associated with a decreased risk of developing cervical precancerous lesions (ORadjusted=0.21; 95% CI, 0.06–0.75). Thus, the present results indicated that the rs8179 and rs42033 polymorphisms confer genetic susceptibility to cervical precancerous lesions. Furthermore, the interaction between the rs8179 polymorphism in CDK6 and the HPV infection and haplotype AGTA may be associated with cervical precancerous lesions.