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Abstract Background The hippocampus, with its complex subfields, is linked to numerous neuropsychiatric traits. While most research has focused on its global structure or a few specific subfields, a comprehensive analysis of hippocampal substructures and their genetic correlations across a wide range of neuropsychiatric traits remains underexplored. Given the hippocampus’s high heritability, considering hippocampal and subfield volumes (HASV) as endophenotypes for neuropsychiatric conditions is essential. Methods We analyzed MRI-derived volumetric data of hippocampal and subfield structures from 41,525 UK Biobank participants. Genome-wide association studies (GWAS) on 24 HASV traits were conducted, followed by genetic correlation, overlap, and Mendelian randomization (MR) analyses with 10 common neuropsychiatric traits. Polygenic risk scores (PRS) based on HASV traits were also evaluated for predicting these traits. Results Our analysis identified 352 independent genetic variants surpassing a significance threshold of 2.1 × 10−9 within the 24 HASV traits, located across 93 chromosomal regions. Notably, the regions 12q14.3, 17q21.31, 12q24.22, 6q21, 9q33.1, 6q25.1, and 2q24.2 were found to influence multiple HASVs. Gene set analysis revealed enrichment of neural differentiation and signaling pathways, as well as protein binding and degradation. Of 240 HASV-neuropsychiatric trait pairs, 75 demonstrated significant genetic correlations (P

Abstract Background Early detection of colorectal neoplasms can reduce the colorectal cancer (CRC) burden by timely intervention for high-risk individuals. However, effective risk prediction models are lacking for personalized CRC early screening in East Asian (EAS) population. We aimed to develop, validate, and optimize a comprehensive risk prediction model across all stages of the dynamic adenoma-carcinoma sequence in EAS population. Methods To develop precision risk-stratification and intervention strategies, we developed three trans-ancestry PRSs targeting colorectal neoplasms: (1) using 148 previously identified CRC risk loci (PRS148); (2) SNPs selection from large-scale meta-analysis data by clumping and thresholding (PRS183); (3) PRS-CSx, a Bayesian approach for genome-wide risk prediction (PRSGenomewide). Then, the performance of each PRS was assessed and validated in two independent cross-sectional screening sets, including 4600 patients with advanced colorectal neoplasm, 4495 patients with non-advanced adenoma, and 21,199 normal individuals from the ZJCRC (Zhejiang colorectal cancer set; EAS) and PLCO (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; European, EUR) studies. The optimal PRS was further incorporated with lifestyle factors to stratify individual risk and ultimately tested in the PLCO and UK Biobank prospective cohorts, totaling 350,013 participants. Results Three trans-ancestry PRSs achieved moderately improved predictive performance in EAS compared to EUR populations. Remarkably, the PRSs effectively facilitated a thorough risk assessment across all stages of the dynamic adenoma-carcinoma sequence. Among these models, PRS183 demonstrated the optimal discriminatory ability in both EAS and EUR validation datasets, particularly for individuals at risk of colorectal neoplasms. Using two large-scale and independent prospective cohorts, we further confirmed a significant dose–response effect of PRS183 on incident colorectal neoplasms. Incorporating PRS183 with lifestyle factors into a comprehensive strategy improves risk stratification and discriminatory accuracy compared to using PRS or lifestyle factors separately. This comprehensive risk-stratified model shows potential in addressing missed diagnoses in screening tests (best NPV = 0.93), while moderately reducing unnecessary screening (best PPV = 0.32). Conclusions Our comprehensive risk-stratified model in population-based CRC screening trials represents a promising advancement in personalized risk assessment, facilitating tailored CRC screening in the EAS population. This approach enhances the transferability of PRSs across ancestries and thereby helps address health disparity. Graphical Abstract

The β-catenin-dependent canonical Wnt signaling is pivotal in organ development, tissue homeostasis, and cancer. Here, we identified an upstream enhancer of Ctnnb1 – the coding gene for β-catenin, named ieCtnnb1 (intestinal enhancer of Ctnnb1), which is crucial for intestinal homeostasis. ieCtnnb1 is predominantly active in the base of small intestinal crypts and throughout the epithelia of large intestine. Knockout of ieCtnnb1 led to a reduction in Ctnnb1 transcription, compromising the canonical Wnt signaling in intestinal crypts. Single-cell sequencing revealed that ieCtnnb1 knockout altered epithelial compositions and potentially compromised functions of small intestinal crypts. While deletion of ieCtnnb1 hampered epithelial turnovers in physiologic conditions, it prevented occurrence and progression of Wnt/β-catenin-driven colorectal cancers. Human ieCTNNB1 drove reporter gene expression in a pattern highly similar to mouse ieCtnnb1. ieCTNNB1 contains a single-nucleotide polymorphism associated with CTNNB1 expression levels in human gastrointestinal epithelia. The enhancer activity of ieCTNNB1 in colorectal cancer tissues was stronger than that in adjacent normal tissues. HNF4α and phosphorylated CREB1 were identified as key trans-factors binding to ieCTNNB1 and regulating CTNNB1 transcription. Together, these findings unveil an enhancer-dependent mechanism controlling the dosage of Wnt signaling and homeostasis in intestinal epithelia.

Abstract. Background:. Findings on the association of genetic factors and colorectal cancer (CRC) survival are limited and inconsistent, and revealing the mechanism underlying their prognostic roles is of great importance. This study aimed to explore the relationship between functional genetic variations and the prognosis of CRC and further reveal the possible mechanism. Methods:. We first systematically performed expression quantitative trait locus (eQTL) analysis using The Cancer Genome Atlas (TCGA) dataset. Then, the Kaplan-Meier analysis was used to filter out the survival-related eQTL target genes of CRC patients in two public datasets (TCGA and GSE39582 dataset from the Gene Expression Omnibus database). The seven most potentially functional eQTL single nucleotide polymorphisms (SNPs) associated with six survival-related eQTL target genes were genotyped in 907 Chinese CRC patients with clinical prognosis data. The regulatory mechanism of the survival-related SNP was further confirmed by functional experiments. Results:. The rs71630754 regulating the expression of endoplasmic reticulum aminopeptidase 1 (ERAP1) was significantly associated with the prognosis of CRC (additive model, hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.08-1.88, P = 0.012). The results of dual-luciferase reporter assay and electrophoretic mobility shift assay showed that the A allele of the rs71630754 could increase the binding of transcription factor 3 (TCF3) and subsequently reduce the expression of ERAP1. The results of bioinformatic analysis showed that lower expression of ERAP1 could affect the tumor immune microenvironment and was significantly associated with severe survival outcomes. Conclusion:. The rs71630754 could influence the prognosis of CRC patients by regulating the expression of the immune-related gene ERAP1. Trial Registration:. No. NCT00454519 (https://clinicaltrials.gov/)

AbstractBackground The epidemiologic studies investigating the association of birthweight and genetic factors with gastrointestinal cancer remain scarce. The study aimed to prospectively assess the interactions and joint effects of birthweight and genetic risk levels on gastrointestinal cancer incidence in adulthood.Methods A total of 254,997 participants were included in the UK Biobank study. We used multivariate restricted cubic splines and Cox regression models to estimate the hazard ratios (HRs) and 95% confidential intervals (CI) for the association between birthweight and gastrointestinal cancer risk, then constructed a polygenic risk score (PRS) to assess its interaction and joint effect with birthweight on the development of gastrointestinal cancer.Results We documented 2512 incident cases during a median follow-up of 8.88 years. Compare with participants reporting a normal birthweight (2.5–4.5 kg), multivariable-adjusted HR of gastrointestinal cancer incidence for participants with high birthweight (≥4.5 kg) was 1.17 (95%CI: 1.01–1.36). Such association was remarkably observed in pancreatic cancer, with an HR of 1.82 (95%CI: 1.26–2.64). No statistically significant association was observed between low birth weight and gastrointestinal cancers. Participants with high birthweight and high PRS had the highest risk of gastrointestinal cancer (HR: 2.95, 95%CI: 2.19–3.96).Conclusion Our findings highlight that high birthweight is associated with a higher incidence of gastrointestinal cancer, especially for pancreatic cancer. Benefits would be obtained from birthweight control, particularly for individuals with a high genetic risk.KEY MESSAGESThe epidemiologic studies investigating the association of birthweight and genetic factors with gastrointestinal cancer remain scarce.This cohort study of 254,997 adults in the United Kingdom found an association of high birthweight with the incidence of gastrointestinal cancer, especially for pancreatic cancer, and also found that participants with high birthweight and high polygenic risk score had the highest risk of gastrointestinal cancer.Our data suggests a possible effect of in utero or early life exposures on adulthood gastrointestinal cancer, especially for those with a high genetic risk.

Abstract Left ventricular regional wall thickness (LVRWT) is an independent predictor of morbidity and mortality in cardiovascular diseases (CVDs). To identify specific genetic influences on individual LVRWT, we established a novel deep learning algorithm to calculate 12 LVRWTs accurately in 42,194 individuals from the UK Biobank with cardiac magnetic resonance (CMR) imaging. Genome-wide association studies of CMR-derived 12 LVRWTs identified 72 significant genetic loci associated with at least one LVRWT phenotype (P

Abstract Genome-wide association studies have identified numerous variants associated with human complex traits, most of which reside in the non-coding regions, but biological mechanisms remain unclear. However, assigning function to the non-coding elements is still challenging. Here we apply Activity-by-Contact (ABC) model to evaluate enhancer-gene regulation effect by integrating multi-omics data and identified 544,849 connections across 20 cancer types. ABC model outperforms previous approaches in linking regulatory variants to target genes. Furthermore, we identify over 30,000 enhancer-gene connections in colorectal cancer (CRC) tissues. By integrating large-scale population cohorts (23,813 cases and 29,973 controls) and multipronged functional assays, we demonstrate an ABC regulatory variant rs4810856 associated with CRC risk (Odds Ratio = 1.11, 95%CI = 1.05–1.16, P = 4.02 × 10−5) by acting as an allele-specific enhancer to distally facilitate PREX1, CSE1L and STAU1 expression, which synergistically activate p-AKT signaling. Our study provides comprehensive regulation maps and illuminates a single variant regulating multiple genes, providing insights into cancer etiology.

Abstract Background The incidence of early-onset colorectal cancer (EOCRC; patients < 50 years old) has been rising rapidly, whereas the EOCRC genetic susceptibility remains incompletely investigated. Here, we aimed to systematically identify specific susceptible genetic variants for EOCRC. Methods Two parallel GWASs were conducted in 17,789 CRC cases (including 1490 EOCRC cases) and 19,951 healthy controls. A polygenic risk score (PRS) model was built based on identified EOCRC-specific susceptibility variants by using the UK Biobank cohort. We also interpreted the potential biological mechanisms of the prioritized risk variant. Results We identified 49 independent susceptibility loci that were significantly associated with the susceptibility to EOCRC and the diagnosed age of CRC (both P < 5.0×10−4), replicating 3 previous CRC GWAS loci. There are 88 assigned susceptibility genes involved in chromatin assembly and DNA replication pathways, mainly associating with precancerous polyps. Additionally, we assessed the genetic effect of the identified variants by developing a PRS model. Compared to the individuals in the low genetic risk group, the individuals in the high genetic risk group have increased EOCRC risk, and these results were replicated in the UKB cohort with a 1.63-fold risk (95% CI: 1.32–2.02, P = 7.67×10−6). The addition of the identified EOCRC risk loci significantly increased the prediction accuracy of the PRS model, compared to the PRS model derived from the previous GWAS-identified loci. Mechanistically, we also elucidated that rs12794623 may contribute to the early stage of CRC carcinogenesis via allele-specific regulating the expression of POLA2. Conclusions These findings will broaden the understanding of the etiology of EOCRC and may facilitate the early screening and individualized prevention. Graphical Abstract

IntroductionTriclosan (TCS), a widely prescribed broad-spectrum antibacterial agent, is an endocrine-disrupting chemical. The relationship and biological mechanisms between TCS exposure and breast cancer (BC) are disputed. We aimed to examine the correlation between urinary TCS exposure and BC risk and estimated the mediating effects of oxidative stress and relative telomere length (RTL) in the above association.MethodsThis case-control study included 302 BC patients and 302 healthy individuals in Wuhan, China. We detected urinary TCS, three common oxidative stress biomarkers [8-hydroxy-2-deoxyguanosine (8-OHdG), 8-iso-prostaglandin F2α (8-isoPGF2α), 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA)], and RTL in peripheral blood mononuclear cells.ResultsSignificant associations were observed between log-transformed urinary concentrations of TCS, 8-OHdG, HNE-MA, 8-isoPGF2α, RTL, and BC risk, with the odds ratios (95% confidence intervals) being 1.58 (1.32–1.91), 3.08 (1.55–6.23), 3.39 (2.45–4.77), 3.99 (2.48–6.54), and 1.67 (1.35–2.09), respectively. Continuous TCS exposure was significantly positively correlated with RTL, HNE-MA, and 8-isoPGF2α (all p

PM2.5 pollution over Hangzhou Bay area, China has received continuous attention. In this study, PM2.5 samples were collected simultaneously in six typical cities in Zhejiang Province from 15 October 2019 to 15 January 2020 (autumn and winter) and from 1 June to 31 August 2020 (summer), and major water-soluble ions were analyzed. Average concentrations of NO3− and SO42− in the six cities were 3.93–15.64 μg/m3 and 4.61–7.58 μg/m3 in autumn and winter, with mass fractions of NO3− and SO42− in PM2.5 up to 19.6–34.2% and 13.6–26.3%, respectively, while in summer, they were 1.23–2.64 μg/m3 and 2.22–4.14 μg/m3, with mass fractions of 7.0–15.0% and 14.7~25.1%. Both NO3− and SO42− were mostly from gas-to-particle transformation of precursors. High relative humidity in the six cities was suggested to significantly promote the formation of NO3− and SO42−, particularly in autumn and winter, while enhanced atmospheric oxidation favored the formation of SO42− in summer. However, the formation of NO3− was inhibited under a high temperature of >15 °C. The concentrations of SO42− and NO3 were mostly correlated with each other among the six cities. Potential source contribution function analysis indicated that both SO42− and NO3− were mostly from local pollution of Hangzhou Bay area in Zhejiang Province and also transported from Shanghai and the southern region of Jiangsu Province. This study contributed to the understanding of regional characteristics of SO42− and NO3− in Hangzhou Bay area and suggested that joint prevention and control efforts should be strengthened to reduce regional PM2.5 pollution.

Abstract. Background:. Pancreatic adenocarcinoma (PAAD) is an extremely lethal malignancy. Identification of the functional genes and genetic variants related to PAAD prognosis is important and challenging. Previously identified prognostic genes from several expression profile analyses were inconsistent. The regulatory genetic variants that affect PAAD prognosis were largely unknown. Methods:. Firstly, a meta-analysis was performed with seven published datasets to systematically explore the candidate prognostic genes for PAAD. Next, to identify the regulatory variants for those candidate genes, expression quantitative trait loci analysis was implemented with PAAD data resources from The Cancer Genome Atlas. Then, a two-stage association study in a total of 893 PAAD patients was conducted to interrogate the regulatory variants and find the prognostic locus. Finally, a series of biochemical experiments and phenotype assays were carried out to demonstrate the biological function of variation and genes in PAAD progression process. Results:. A total of 128 genes were identified associated with the PAAD prognosis in the meta-analysis. Fourteen regulatory loci in 12 of the 128 genes were discovered, among which, only rs4887783, the functional variant in the promoter of Ring Finger and WD Repeat Domain 3 (RFWD3), presented significant association with PAAD prognosis in both stages of the population study. Dual-luciferase reporter and electrophoretic mobility shift assays demonstrated that rs4887783-G allele, which predicts the worse prognosis, enhanced the binding of transcript factor REST, thus elevating RFWD3 expression. Further phenotypic assays revealed that excess expression of RFWD3 promoted tumor cell migration without affecting their proliferation rate. RFWD3 was highly expressed in PAAD and might orchestrate the genes in the DNA repair process. Conclusions:. RFWD3 and its regulatory variant are novel genetic factors for PAAD prognosis.

Abstract Whether the definition of hypertension according to 2017 AHA/ACC guidelines and blood pressure (BP) changes was related to the increased risk of chronic kidney disease (CKD) remained debated. This prospective cohort study aimed to investigate the association of BP and long‐term BP change with CKD risk with different glucose metabolism according to the new hypertension guidelines. This study examined 12 951 participants and 11 183 participants derived from the older people cohort study, respectively. Participants were divided into three groups based on blood glucose and the risks were assessmented by the logistic regression model. During a 10 years of follow‐up period, 2727 individuals developed CKD (21.1%). Compared with those with BP

The longitudinal immunologic status of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients and its association with the clinical outcome are barely known. Thus, we sought to analyze the temporal profiles of specific antibodies, as well as the associations between the antibodies, proinflammatory cytokines, and survival of patients with coronavirus disease 2019 (COVID-19). A total of 1830 laboratory-confirmed COVID-19 cases were recruited. The temporal profiles of the virus, antibodies, and cytokines of the patients until 12 weeks since illness onset were fitted by the locally weighted scatter plot smoothing method. The mediation effect of cytokines on the associations between antibody responses and survival were explored by mediation analysis. Of the 1830 patients, 1435 were detectable for SARS-CoV-2, while 395 were positive in specific antibodies only. Of the 1435 patients, 2.4% presented seroconversion for neither immunoglobulin G (IgG) nor immunoglobulin M (IgM) during hospitalization. The seropositive rates of IgG and IgM were 29.6% and 48.1%, respectively, in the first week, and plateaued within five weeks. For the patients discharged from the hospital, the IgM decreased slowly, while high levels of IgG were maintained at around 188 AU·mL−1 for the 12 weeks since illness onset. In contrast, in the patients who subsequently died, IgM declined rapidly and IgG dropped to 87 AU·mL−1 at the twelfth week. Elevated interleukin-6, interleukin-8, interleukin-10, interleukin-1β, interleukin-2R, and tumor necrosis factor-α levels were observed in the deceased patients in comparison with the discharged patients, and 12.5% of the association between IgG level and mortality risk was mediated by these cytokines. Our study deciphers the temporal profiles of SARS-CoV-2-specific antibodies within the 12 weeks since illness onset and indicates the protective effect of antibody response on survival, which may help to guide prognosis estimation.

Background: Estimation of absolute risk of developing colorectal neoplasm is essential for personalized colorectal cancer (CRC) screening. We developed models to determine relative and absolute risks of colorectal neoplasm based on lifestyle and genetic variants and to validate their application in risk-adapted screening.Methods: We prospectively collected data from 203 advanced neoplasms, 464 non-advanced adenomas, and 1,213 healthy controls from a CRC screening trial in China in 2018–2019. The risk prediction model based on four lifestyle factors and a polygenic risk score (PRS) consisted of 19 CRC-associated single-nucleotide polymorphisms. We assessed the relative and 10-year absolute risks of developing colorectal neoplasm and the yield of a risk-adapted screening approach incorporating risk models, fecal immunochemical test, and colonoscopy.Results: Compared to the participants with favorable lifestyle and lower PRS, those with unfavorable lifestyle and higher PRS had 2.87- and 3.79-fold higher risk of colorectal neoplasm in males and females, respectively. For a 50-year-old man or a 50-year-old woman with the highest risk profile, the estimated 10-year absolute risk of developing colorectal neoplasm was 6.59% (95% CI: 6.53–6.65%) and 4.19% (95% CI: 4.11–4.28%), respectively, compared to 2.80% (95% CI: 2.78–2.81%) for men and 2.24% (95% CI: 2.21–2.27%) for women with the lowest risk profile. The positive predictive value for advanced neoplasm was 31.7%, and the number of colonoscopies needed to detect one advanced neoplasm was 3.2.Conclusion: The risk models, absolute risk estimates, and risk-adapted screening presented in our study would contribute to developing effective personalized CRC prevention and screening strategies.

Abstract Background Esophageal squamous cell carcinoma (ESCC) is one of the common gastrointestinal malignancy with an inferior prognosis outcome. DNA replication licensing aberration induced by dysregulation of minichromosome maintenance proteins (MCMs) causes genomic instability and cancer metastasis. SUMOylation modification plays a pivotal role in regulation of genomic integrity, while its dysregulation fueled by preexisting germline variants in cancers remains poorly understood. Methods Firstly, we conducted two‐stage survival analysis consisting of an exome‐wide association study in 904 ESCC samples and another independent 503 ESCC samples. Then, multipronged functional experiments were performed to illuminate the potential biological mechanisms underlying the promising variants, and MCM10 influences the ESCC progression. Finally, we tested the effects of MCM10 inhibitors on ESCC cells. Results A germline variant rs2274110 located at the exon 15 of MCM10 was identified to be significantly associated with the prognosis of ESCC patients. Individuals carrying rs2274110‐AA genotypes confer a poor survival (hazard ratio = 1.61, 95% confidence interval = 1.35–1.93, p = 1.35 × 10−7), compared with subjects carrying rs2274110‐AG/GG genotypes. Furthermore, we interestingly found that the variant can increase SUMOylation levels at K669 site (Lys[K]699Arg[R]) of MCM10 protein mediated by SUMO2/3 enzymes, which resulted in an aberrant overexpression of MCM10. Mechanistically, aberrant overexpression of MCM10 facilitated the proliferation and metastasis abilities of ESCC cells in vitro and in vivo by inducing DNA over‐replication and genomic instability, providing functional evidence to support our population finding that high expression of MCM10 is extensively presented in tumor tissues of ESCC and correlated with inferior survival outcomes of multiple cancer types, including ESCC. Finally, MCM10 inhibitors Suramin and its analogues were revealed to effectively block the metastasis of ESCC cells. Conclusions These findings not only demonstrate a potential biological mechanism between aberrant SUMOylation, genomic instability and cancer metastasis, but also provide a promising biomarker aiding in stratifying ESCC individuals with different prognosis, as well as a potential therapeutic target MCM10.

Abstract Pancreatic cancer is one of the deadliest malignancies with few early detection tests or effective therapies. PI3K‐AKT signaling is recognized to modulate cancer progression. We previously identified that a genetic variant in PKN1 increased pancreatic cancer risk through the PKN1/FAK/PI3K/AKT pathway. In order to investigate the associations between genetic variations in that pathway and pancreatic cancer prognosis, we conducted a two‐stage survival analysis in a total of 547 Chinese pancreatic cancer patients. Consequently, a variant, rs13167294 A>C in PIK3R1, was significantly associated with poor survival in both stages and with hazard ratio being 1.32 (95% CI = 1.13‐1.56, P = 0.0007) in the combined analysis. Function annotation and prediction suggested that genetic variants in this locus might affect overall survival of pancreatic cancer patients by regulating PIK3R1 expression.

Objective: Essential metals play important roles in the carcinogenic process. However, seldom longitudinal investigations have evaluated their roles in lung cancer development. We aimed to investigate the associations between multiple essential metals and lung cancer incidence and to explore the potential mechanisms. Methods: A nested case-control study of 440 incident lung cancer cases and 1:3 frequency matched 1320 healthy controls from the Dongfeng-Tongji Cohort was conducted. The baseline plasma concentrations of 11 essential metals (cobalt, copper, iron, manganese, molybdenum, rubidium, selenium, strontium, stannum, vanadium, and zinc) were measured, and their associations with lung cancer incidence were estimated. Effect of positive metal (zinc) on 4-year telomere attrition was then evaluated among an occupational cohort of 724 workers. We also assessed the transcriptional regulation effects of plasma zinc on mRNA expression profiles, and the expressions of zinc-related genes were further compared in pair-wised lung tumor and normal tissues. Results: Elevated plasma level of zinc was associated with lower incident risk of lung cancer [OR (95% CI) = 0.89 (0.79, 0.99)] and decreased 4-year telomere attrition [β (95% CI) = −0.73 (−1.27, −0.19)]. These effects were pronounced among males. In particularly, zinc could regulate the expressions of 8 cancer-related genes, including SOD1, APE, TP53BP1, WDR33, LAPTM4B, TRIT1, HUWE1, and ZNF813, which were over-expressed in lung tumor tissues. Conclusions: We propose that high plasma zinc could prevent incident lung cancer, probably by slowing down telomere attrition and regulating the expressions of cancer-related genes. These results provided a new insight into lung cancer prevention. Keywords: Essential metals, Zinc, Lung cancer, Cohort study, Telomere attrition, Gene expression

Introduction and aim: It is indicated that high levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are associated with increased incident type 2 diabetes risk. However, whether serum ALT levels could improve the discrimination of type 2 diabetes remains unclear. Methods: The data was derived from the Dongfeng-Tongji cohort study, which was established in 2008 and followed until October 2013. A total of 17,173 participants free of type 2 diabetes at baseline were included and 1159 participants developed diabetes after 4.51 (0.61) years of follow-up. Cox proportional hazard regression model was used to calculate the hazard ratios (HRs) for the association between ALT and AST levels with incident diabetes risk. Receiver-operating characteristic (ROC) curves analysis was used to evaluate the predictive accuracy of models incorporating traditional risk factors with and without ALT. Results: Compared with the lowest quartile of ALT and AST levels, the highest quartile had a significantly higher risk of developing type 2 diabetes (HR: 2.17 [95% CI: 1.78–2.65] and 1.29 [1.08–1.54], respectively) after adjustment for potential confounders. The addition of ALT levels into the traditional risk factors did not improve the predictive ability of type 2 diabetes, with AUC increase from 0.772 to 0.774; P = 0.86. Conclusions: Although elevated ALT or AST levels increased incident type 2diabetes risk, addition of ALT levels into the prediction model did not improve the discrimination of type 2 diabetes.

Objective: This study was intended to investigate the relationship between COVID-19 disease and ovarian function in reproductive-aged women.Methods: Female COVID-19 patients of reproductive age were recruited between January 28 and March 8, 2020 from Tongji Hospital in Wuhan. Their baseline and clinical characteristics, as well as menstrual conditions, were recorded. Differentials in ovarian reserve markers and sex hormones (including anti-Müllerian hormone [AMH], follicle-stimulating hormone [FSH], the ratio of FSH to luteinizing hormone [LH], estradiol [E2], progesterone [P], testosterone [T], and prolactin [PRL] were compared to those of healthy women who were randomly selected and individually matched for age, region, and menstrual status. Uni- and multi-variable hierarchical linear regression analyses were performed to identify risk factors associated with ovarian function in COVID-19 women.Results: Seventy eight patients agreed to be tested for serum hormone, of whom 17 (21.79%) were diagnosed as the severe group and 39 (50%) were in the basal level group. Menstrual status (P = 0.55), menstrual volumes (P = 0.066), phase of menstrual cycle (P = 0.58), and dysmenorrhea history (P = 0.12) were similar without significant differences between non-severe and severe COVID-19 women. Significant lower serum AMH level/proportion (0.19/0.28 vs. 1.12 ng/ml, P = 0.003/0.027; AMH ≤ 1.1 ng/ml: 75/70.4 vs. 49.7%, P = 0.009/0.004), higher serum T (0.38/0.39 vs. 0.22 ng/ml, P < 0.001/0.001) and PRL (25.43/24.10 vs. 12.12 ng/ml, P < 0.001/0.001) levels were observed in basal level and the all-COVID-19 group compared with healthy age-matched control. When adjusted for age, menstrual status and parity variations in multivariate hierarchical linear regression analysis, COVID-19 disease was significantly associated with serum AMH (β = −0.191; 95% CI: −1.177–0.327; P = 0.001), T (β = 0.411; 95% CI: 11.154–22.709; P < 0.001), and PRL (β = 0.497; 95% CI: 10.787–20.266; P < 0.001), suggesting an independent risk factor for ovarian function, which accounted for 3.2% of the decline in AMH, 14.3% of the increase in T, and 20.7% of the increase in PRL.Conclusion: Ovarian injury, including declined ovarian reserve and reproductive endocrine disorder, can be observed in women with COVID-19. More attention should be paid to their ovarian function under this pandemic, especially regarding reproductive-aged women.Clinical Trial Number: ChiCTR2000030015.

Abstract Hirschsprung's disease (HSCR) is a rare and complex congenital disorder characterized by the absence of the enteric neurons in lower digestive tract with an incidence of 1/5 000. Affected infant usually suffer from severe constipation with megacolon and distended abdomen, and face long‐term complications even after surgery. In the last 2 decades, great efforts and progresses have been made in understanding the genetics and molecular biological mechanisms that underlie HSCR. However, only a small fraction of the genetic risk can be explained by the identified mutations in the previously established genes. To search novel genetic alterations, new study designs with advanced technologies such as genome/exome‐wide association studies (GWASs/EWASs) and next generation sequencing (NGS) on target genes or whole genome/exome, were applied to HSCR. In this review, we summaries the current development of the genetics researches on HSCR based on GWASs/EWASs and NGS, focusing on the newly discovered variants and genes, and their potential roles in HSCR pathogenesis.

Pancreatic ductal adenocarcinoma is a lethal human cancer with a poor 5-year overall survival rate. Here the authors perform an exome-wide analysis in a cohort of PDAC patients to identify three novel missense variants in PKN1, DOK2, and APOB genes, that are associated with PDAC risk.

Abstract Background Emerging studies have investigated the association between different anthropometric indices with diabetes risk but the results were inconsistent. The aims of the study were to examine the associations of different anthropometric indices with incident diabetes risk and whether novel anthropometric indices improve diabetes prediction beyond traditional indices among elderly Chinese. Methods Nine thousand nine hundred sixty-two elderly individuals (age ≥ 60 years old) derived from the prospective Dongfeng-Tongji cohort were included. Hazard ratio (HR) and corresponding 95% confidence interval (CI) were evaluated by Cox proportional hazard model to examine the associations between traditional anthropometric indices (body mass index [BMI], waist circumference [WC], waist-to-height ratio [WHtR]), novel anthropometric indices (visceral adiposity index [VAI], a body shape index [ABSI], body roundness index [BRI]) and diabetes risk. Receiver operating characteristic (ROC) curve and area under curve (AUC) were applied to compare the novel anthropometric indices with the traditional indices in diabetes prediction. Results During mean 4.6 years of follow-up, 614 incident cases of type 2 diabetes (T2D) were identified. Significant positive associations were detected between BMI, WC, WHtR, VAI and BRI and incident T2D risk. For ABSI, no significant association was observed in either men or women. BMI was the strongest predictor in diabetes in men (AUC = 0.655) comparable with the other anthropometric indices (P

Abstract Background Breast cancer is the leading cause of cancer morbidity among Shanghai and Hong Kong women, which contributes to 20–25% of new female cancer incidents. This study aimed to describe the temporal trend of breast cancer and interpret the potential effects on the observed secular trends. Methods Cancer incident data were obtained from the cancer registries. Age-standardized incidence rate was computed by the direct method using the World population of 2000. Average annual percentage change (AAPC) in incidence rate was estimated by the Joinpoint regression. Age, period and cohort effects were assessed by using a log-linear model with Poisson regression. Results During 1976–2009, an increasing trend of breast cancer incidence was observed, with an AAPC of 1.73 [95% confidence interval (CI): 1.54–1.92)] for women in Hong Kong and 2.83 (95% CI, 2.26–3.40) in Shanghai. Greater upward trends were revealed in Shanghai women aged 50 years old or above (AAPC = 3.09; 95% CI, 1.48–4.73). Using age at 50 years old as cut-point, strong birth cohort effects were shown in both pre- and post-menopausal women, though a more remarkable effect was suggested in Shanghai post-menopausal women. No evidence for a period effect was indicated. Conclusions Incidence rate of breast cancer has been more speedy in Shanghai post-menopausal women than that of the Hong Kong women over the past 30 years. Decreased birth rate and increasing environmental exposures (e.g., light-at-night) over successive generations may have constituted major impacts on the birth cohort effects, especially for the post-menopausal breast cancer; further analytic studies are warranted.

Genome-wide association studies have been performed to identify genetic variants that are associated with susceptibility to colorectal cancer. Here, the authors expand on these studies and identify a variant that regulates the expression of ETV6 and find that over-expression of ETV6 blocks cell proliferation in vitro.

IntroductionMethadone maintenance treatment (MMT) programs have been rapidly scaled up nationwide in China in recent years, and psychosocial intervention measures, including counseling, were recommended for improving the outcomes of MMT. However, the effectiveness of counseling in MMT programs remains controversial. This study investigated the efficacy of educational and behavioral counseling (EBC) mode in an MMT program in China.MethodsA total of 125 eligible participants were randomized to EBC or a control group. Patients in the EBC group received weekly, manual-guided, group educational counseling for 8 weeks and individual behavioral counseling for the next 8 weeks. Patients in the control group received standard methadone maintenance treatment as usual (TAU).ResultsDuring the 16-week trial, the EBC group showed better treatment attendance (P = 0.022) and a greater increase in knowledge regarding heroin addiction (P = 0.001) and MMT (P = 0.005) than did the TAU group. Between the two groups, there were no significant differences regarding drug abstinence and reduction of risky behaviors.ConclusionEBC affiliated with MMT improved patients’ cognition and adherence to treatment, facilitating their successful recovery.Clinical Trial RegistrationChiCTR-IOR-15006673: http://www.chictr.org.cn.

Whether cigarette smoking and moderate drinking are associated with non-alcoholic fatty liver disease (NAFLD)has not been fully described. This study investigated the separate and joint effects of smoking and moderate drinking on Chinese men with NAFLD.Across-sectional assay from DFTJ Cohort study was performed with a size of 9432 elderly Chinese men excluding excessive alcohol consumption (

OBJECTIVES:The aim of this study is to examine the bidirectional association between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). METHODS:The data was derived from the Dongfeng-Tongji cohort study, which was established in 2008 and followed until October 2013. NAFLD was classified as none, mild, moderate/severe based on ultrasound examination. The analysis to examine the association between NAFLD and incident T2DM risk included 18,111 participants free of diabetes at baseline and the duration of follow-up was 4.60 ± 0.60 years. Cox proportional regression model was used to calculate the hazard ratio (HR) for the association. The analysis to investigate the association between T2DM and incident NAFLD risk included 12,435 participants free of NAFLD at baseline. Logistic regression model was used to calculate the odd ratio (OR) of NAFLD. RESULTS:Compared with those without NAFLD, individuals with mild or moderate/severe NAFLD had a monotonic elevated risk of developing T2DM (HR: 1.88 [95% CI: 1.63-2.18] and 2.34 [1.85-2.96], respectively) after adjustment for potential confounders. In a parallel analysis, compared to participants with fasting plasma glucose < 6.1 mmol/L, the ORs of developing NAFLD in subjects with impaired fasting glucose and T2DM were 1.35 (95% CI: 1.16-1.57) and 1.40 (95% CI: 1.22-1.62), respectively. CONCLUSIONS:Our results provide compelling evidence that the NAFLD-T2DM association is bidirectional in Chinese population.

The present paper proposes a new unconditionally stable method to solve telegraph equation by using associated Hermite (AH) orthogonal functions. Unlike other numerical approaches, the time variables in the given equation can be handled analytically by AH basis functions. By using the Galerkin’s method, one can eliminate the time variables from calculations, which results in a series of implicit equations. And the coefficients of results for all orders can then be obtained by the expanded equations and the numerical results can be reconstructed during the computing process. The precision and stability of the proposed method are proved by some examples, which show the numerical solution acquired is acceptable when compared with some existing methods.

It is well-established that abnormal protein phosphorylation could play an essential role in tumorgenesis by disrupting a variety of physiological processes such as cell growth, signal transduction and cell motility. Moreover, increasing numbers of phosphorylation-related variants have been identified in association with cancers. ADD1 (α-adducin), a versatile protein expressed ubiquitously in eukaryotes, exerts an important influence on membrane cytoskeleton, cell proliferation and cell-cell communication. Recently, a missense variant at the codon of ADD1's phosphorylation site, rs4963 (Ser586Cys), was reported to modify the risk of non-cardia gastric cancer. To explore the role of ADD1-rs4963 in colorectal cancer (CRC), we conducted a case-control study with a total of 1054 CRC cases and 1128 matched controls in a Chinese population. After adjustment for variables including age, gender, smoking and drinking, it was demonstrated that this variant significantly conferred susceptibility to CRC (G versus C: OR = 1.16, 95% CI = 1.03-1.31, P = 0.016; CG versus CC: OR = 1.25, 95% CI = 1.02-1.55, P = 0.036; GG versus CC: OR = 1.35, 95% CI = 1.06-1.72, P = 0.015). We further investigated the interaction of ADD1-rs4963 with smoking or drinking exposure, but found no significant result. This study is the first report of an association between ADD1 and CRC risk, promoting our knowledge of the genetics of CRC.

Hypoxia is a prominent characteristic of inflammatory tissue lesions. It can affect platelet function. While mean platelet volume (MPV) and platelet distribution width (PDW) are sample platelet indices, they may reflect subcinical platelet activation. To investigated associations between adiposity indices and platelet indices, 17327 eligible individuals (7677 males and 9650 females) from the Dongfeng-Tongji Cohort Study (DFTJ-Cohort Study, n=27009) were included in this study, except for 9682 individuals with missing data on demographical, lifestyle, physical indicators and diseases relative to PDW and MPV. Associations between adiposity indices including waist circumstance (WC), waist-to-height ratio (WHtR), body mass index (BMI), and MPV or PDW in the participants were analyzed using multiple logistic regressions. There were significantly negative associations between abnormal PDW and WC or WHtR for both sexes (ptrend

Rationale: The individual effects of early-life tobacco smoke exposure and its interactions with genetic factors on lung cancer in adulthood remain unclear. Objectives: To investigate the associations of early-life tobacco exposures as well as their interactions with polygenic risk scores (PRSs) with lung cancer incidence and mortality. Methods: A total of 432,831 participants from the UK Biobank study were included. We estimated the associations of in utero exposure to tobacco smoke, the age of smoking initiation and their interactions with PRSs with lung cancer incidence and mortality in adulthood using Cox proportional hazard models. Measurements and Main Results: Lung cancer incidence (hazard ratio [HR]: 1.59, 95% confidence interval [CI], 1.44-1.76) increased among participants with in utero tobacco exposure. Multivariable-adjusted HRs (with 95% CIs) of lung cancer incidence for smoking initiation in adulthood, adolescence, and childhood (versus never-smokers) were 6.10 (5.25-7.09), 9.56 (8.31-11.00), and 15.15 (12.90-17.79) (Ptrend<0.001). Similar findings were observed in lung cancer mortality. Participants with high PRSs and in utero tobacco exposure (versus low PRSs participants without in utero exposure) had an HR of 2.35 for lung cancer incidence (95% CI, 1.97-2.80, Pinteraction = 0.089) and 2.43 for mortality (95% CI, 2.05-2.88, Pinteraction= 0.032). High PRSs with smoking initiation in childhood (versus never-smokers with low PRSs) had HRs of 18.71 for incidence (95% CI, 14.21-24.63, Pinteraction = 0.004) and 19.74 for mortality (95% CI, 14.98-26.01, Pinteraction = 0.033). Conclusions: In utero and childhood/adolescence exposure to tobacco smoke and its interaction with genetic factors may substantially increase the risks of lung cancer incidence and mortality in adulthood. [ABSTRACT FROM AUTHOR]

ObjectivesRecent genome-wide association study found rs1801274, a functional single nucleotide polymorphism (SNP) in IgG receptor gene FCGR2A, was associated with increased risk of Kawasaki disease (KD). However, subsequent studies on the role of this SNP were limited and controversial.MethodsA case-control study was conducted in a Chinese Han population including 428 KD patients and 493 controls to examine the association between rs1801274 and KD susceptibility. A meta-analysis was performed in combination with the relevant published studies to further clarify such an association.ResultsOur case-control study found that rs1801274 was significantly associated with increased risk of KD in the Chinese Han population, with an odds ratio (OR) of 1.58 (95% CI = 0.96-2.62) for the GA genotype and 1.93 (95% CI = 1.16-3.19) for the AA genotype compared with the GG genotype. The result of meta-analysis further demonstrated that the A allele of rs1801274 was significantly correlated with KD risk under the allelic model (OR = 1.35, 95% CI = 1.27-1.44) without heterogeneity by fixed-effects model analysis (Q = 17.30, p = 0.139). Moreover, sensitivity analysis supported the robustness of this meta-analysis.ConclusionThese results further confirm that rs1801274 in the FCGR2A gene is significantly associated with increased risk of KD.

Epidemiological studies have investigated the potential anticancer effects of mushroom intake. This review aims to clarify the evidence on the association of dietary mushroom intake with breast cancer risk and to quantify its dose-response relationship. Relevant studies were identified by a search of PubMed, Web of Science and Google Scholar up to December 31, 2013. Observational studies with relative risks (RRs) or hazard ratios (HRs) or odd ratios (ORs) and 95% confidence intervals (CIs) of breast cancer for three or more categories of mushroom intake were eligible. The quality of included studies was assessed by using Newcastle-Ottawa Scale. A dose-response meta-analysis was performed by utilizing generalized least squares trend estimation. Eight case-control studies and two cohort studies with a total of 6890 cases were ultimately included. For dose-response analysis, there was no evidence of non-linear association between mushroom consumption and breast cancer risk (P = 0.337) and a 1 g/d increment in mushroom intake conferred an RR of 0.97 (95% CI: 0.96-0.98) for breast cancer risk, with moderate heterogeneity (I(2) = 56.3%, P = 0.015). Besides, available menopause data extracted from included studies were used to evaluate the influence of menopausal statues. The summary RRs of mushroom consumption on breast cancer were 0.96 (95% CI: 0.91-1.00) for premenopausal women and 0.94 (95% CI: 0.91-0.97) for postmenopausal women, respectively. Our findings demonstrated that mushroom intake may be inversely associated with risk of breast cancer, which need to be confirmed with large-scale prospective studies further.

The human forkhead box A1 (FOXA1) and A2 (FOXA2) transcription factors have been found to control estrogen and androgen signaling through co-regulating target genes with sex hormone receptors. Here we used an integrative strategy to examine the hypothesis that genetic variants at FOXA1/2 binding elements may be associated with sexual dimorphism of hepatocellular carcinoma (HCC) risk. Firstly we extracted chromatin immunoprecipitation-sequencing (ChIP-seq) data of FOXA1, FOXA2 and estrogen receptor 1(ERα) from ENCODE database to obtain dual target regions of FOXA/ERα, and further intersected these regions with genes' promoters. Then we used MATCH program to predict FOXA binding elements, in which genetic variants were retrieved by dbSNP database (NCBI, build 134). A total of 15 candidate variants were identified in this stage. Secondly we performed a case-control study with 1,081 HCC patients and 2,008 matched controls and found a significant association of SERPINA6-rs1998056 with female HCC risk under common genetic models (e.g. GG versus CC: OR = 2.03, 95% CI = 1.26-3.27, P = 0.004). Moreover, results from our real-time quantitative polymerase chain reaction (qPCR) using 72 normal liver tissues adjacent to the tumors showed that SERPINA6 expression was significantly different among different genotypes of this variant (GG versus CC: P = 0.032; Group test: P = 0.060). In summary, our study suggested that SERPINA6-rs1998056 regulated by FOXA/ERα might be associated with female HCC risk.

The study probed the association between bilirubin and hepatitis B virus (HBV) infection and progression. A cross-sectional analysis of 28,500 middle aged and elderly Chinese participants was performed to analyze the differences of bilirubin in terms of hepatitis B surface antigen (HBsAg) positive or negative and the correlation between bilirubin and severity of hepatic fibrosis estimated by non-invasive indices. Bilirubin was significantly higher in the HBsAg (+) group than the HBsAg (−) group. Higher bilirubin levels were consistently associated with elevated liver fibrosis indices among HBsAg carriers. Compared with quartile 1 of total bilirubin (TBil), the multivariable-adjusted ORs (95% CIs) for elevated fibrosis indices of quartile 4 were 2.24 (95% CIs, 1.57–3.21) estimated by fibrosis 4 score (FIB-4) and 2.22 (95% CIs, 1.60–3.08) estimated by aspartate transaminase to platelet ratio index (APRI). In addition, direct bilirubin (DBil) had a stronger association with elevated liver fibrosis indices than did indirect bilirubin (IBil). Furthermore, the relationship between DBil and elevated fibrosis indices was more robust among participants who were female, overweight or had central fat distribution. These findings suggested that bilirubin levels, especially DBil, were independently associated with an increased risk of increased fibrosis indices.

BackgroundThe prevalence of metabolic syndrome (MetS) is growing rapidly in China. Tai chi and dancing are common types of exercise among middle-aged and elderly Chinese. It remains unclear whether these activities are associated with a lower risk of MetS.Methodology/principal findingsA total of 15,514 individuals (6,952 men, 8,562 women) aged 50 to 70 years from the Dongfeng-Tongji Cohort in Shiyan, China participated in a cross-sectional study. Physical activity and other lifestyle factors were assessed with semi-structured questionnaires during face-to-face interviews. MetS was defined by the current National Cholesterol Education Program/Adult treatment Panel III criteria for Asian Americans. The prevalence of MetS was 33.2% in the study population. In the multivariable-adjusted logistic regression analyses, total physical activity levels were monotonically associated with a lower odds of MetS [OR 0.75 comparing extreme quintiles, 95% confidence interval (CI) 0.66-0.86, PConclusions/significanceJogging, tai chi and dancing are associated with a significantly lower risk of having MetS in middle-aged and older Chinese. Future intervention studies should consider the role of jogging, tai chi and dancing in preventing MetS.

Plasma lipid levels are important risk factors for cardiovascular disease and are influenced by genetic and environmental factors. Recent genome wide association studies (GWAS) have identified several lipid-associated loci, but these loci have been identified primarily in European populations. In order to identify genetic markers for lipid levels in a Chinese population and analyze the heterogeneity between Europeans and Asians, especially Chinese, we performed a meta-analysis of two genome wide association studies on four common lipid traits including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) in a Han Chinese population totaling 3,451 healthy subjects. Replication was performed in an additional 8,830 subjects of Han Chinese ethnicity. We replicated eight loci associated with lipid levels previously reported in a European population. The loci genome wide significantly associated with TC were near DOCK7, HMGCR and ABO; those genome wide significantly associated with TG were near APOA1/C3/A4/A5 and LPL; those genome wide significantly associated with LDL were near HMGCR, ABO and TOMM40; and those genome wide significantly associated with HDL were near LPL, LIPC and CETP. In addition, an additive genotype score of eight SNPs representing the eight loci that were found to be associated with lipid levels was associated with higher TC, TG and LDL levels (P = 5.52 × 10(-16), 1.38 × 10(-6) and 5.59 × 10(-9), respectively). These findings suggest the cumulative effects of multiple genetic loci on plasma lipid levels. Comparisons with previous GWAS of lipids highlight heterogeneity in allele frequency and in effect size for some loci between Chinese and European populations. The results from our GWAS provided comprehensive and convincing evidence of the genetic determinants of plasma lipid levels in a Chinese population.

BackgroundA prediction model for tuberculosis incidence is needed in China which may be used as a decision-supportive tool for planning health interventions and allocating health resources.MethodsThe autoregressive integrated moving average (ARIMA) model was first constructed with the data of tuberculosis report rate in Hubei Province from Jan 2004 to Dec 2011.The data from Jan 2012 to Jun 2012 were used to validate the model. Then the generalized regression neural network (GRNN)-ARIMA combination model was established based on the constructed ARIMA model. Finally, the fitting and prediction accuracy of the two models was evaluated.ResultsA total of 465,960 cases were reported between Jan 2004 and Dec 2011 in Hubei Province. The report rate of tuberculosis was highest in 2005 (119.932 per 100,000 population) and lowest in 2010 (84.724 per 100,000 population). The time series of tuberculosis report rate show a gradual secular decline and a striking seasonal variation. The ARIMA (2, 1, 0) × (0, 1, 1)12 model was selected from several plausible ARIMA models. The residual mean square error of the GRNN-ARIMA model and ARIMA model were 0.4467 and 0.6521 in training part, and 0.0958 and 0.1133 in validation part, respectively. The mean absolute error and mean absolute percentage error of the hybrid model were also less than the ARIMA model.Discussion and conclusionsThe gradual decline in tuberculosis report rate may be attributed to the effect of intensive measures on tuberculosis. The striking seasonal variation may have resulted from several factors. We suppose that a delay in the surveillance system may also have contributed to the variation. According to the fitting and prediction accuracy, the hybrid model outperforms the traditional ARIMA model, which may facilitate the allocation of health resources in China.

BACKGROUND: Neural Tube Defects (NTDs) are among the most prevalent and most severe congenital malformations worldwide. Polymorphisms in key genes involving the folate pathway have been reported to be associated with the risk of NTDs. However, the results from these published studies are conflicting. We surveyed the literature (1996-2011) and performed a comprehensive meta-analysis to provide empirical evidence on the association. METHODS AND FINDINGS: We investigated the effects of 5 genetic variants from 47 study populations, for a total of 85 case-control comparisons MTHFR C677T (42 studies; 4374 cases, 7232 controls), MTHFR A1298C (22 studies; 2602 cases, 4070 controls), MTR A2756G (9 studies; 843 cases, 1006 controls), MTRR A66G (8 studies; 703 cases, 1572 controls), and RFC-1 A80G (4 studies; 1107 cases, 1585 controls). We found a convincing evidence of dominant effects of MTHFR C677T (OR 1.23; 95%CI 1.07-1.42) and suggestive evidence of RFC-1 A80G (OR 1.55; 95%CI 1.24-1.92). However, we found no significant effects of MTHFR A1298C, MTR A2756G, MTRR A66G in risk of NTDs in dominant, recessive or in allelic models. CONCLUSIONS: Our meta-analysis strongly suggested a significant association of the variant MTHFR C677T and a suggestive association of RFC-1 A80G with increased risk of NTDs. However, other variants involved in folate pathway do not demonstrate any evidence for a significant marginal association on susceptibility to NTDs.

BACKGROUND: There are many discussions about dyslexia based on studies conducted in western countries, and some risk factors to dyslexia, such as gender and home literacy environment, have been widely accepted based on these studies. However, to our knowledge, there are few studies focusing on the risk factors of dyslexia in China. Therefore, the aim of our study was to investigate the prevalence of dyslexia and its potential risk factors. METHODS: A cross-sectional study was conducted in Qianjiang, a city in Hubei province, China. Two stages sampling strategy was applied to randomly selected 5 districts and 9 primary schools in Qianjiang. In total, 6,350 students participated in this study and there were 5,063 valid student questionnaires obtained for the final analyses. Additional questionnaires (such as Dyslexia Checklist for Chinese Children and Pupil Rating Scale) were used to identify dyslexic children. The chi-square test and multivariate logistic regression were employed to reveal the potential risk factors to dyslexia. RESULTS: Our study revealed that the prevalence of dyslexia was 3.9% in Qianjiang city, which is a middle-sized city in China. Among dyslexic children, the gender ratio (boys to girls) was nearly 3∶1. According to the P-value in the multivariate logistic regression, the gender (P

BACKGROUND: Researchers have provided evidence that telomere dysfunction play an important role in cancer development. MNS16A is a polymorphic tandem repeats minisatellite of human telomerase (hTERT) gene that influences promoter activity of hTERT and thus implicates to relate with risk of several malignancies. However, results on association between MNS16A and cancer risk remain controversial. We therefore conduct a meta-analysis to derive a more precise estimation of association between MNS16A and cancer risk. METHODS: A systematic literature search was conducted by searching PubMed, ISI Web of Knowledge, Human Genome and Epidemiology Network Navigator and Google Scholar digital database for publications on associations between MNS16A and cancer risk. Variants with statistically significant associations by meta-analysis were assessed using Venice criteria. RESULTS: 10 case-control articles enrolling 6101 cases and 10521 controls were brought into our meta-analysis. The relationships were strong epidemiological credibility in cerebral cancer and breast cancer population (P for heterogeneity > 0.1). The cumulative analysis in chronologic order suggested a clear tendency towards a significant association with additional study samples. CONCLUSIONS: The results provided a more accurate depiction of the role of MNS16A in cerebral cancer and breast cancer susceptibility. Additional larger studies were warranted to validate our findings.

BACKGROUND: A common single nucleotide polymorphism (SNP), rs10795668, located at 10p14, was first identified to be significantly associated with risk of colorectal cancer (CRC) by a genome-wide association study (GWAS) in 2008; however, another GWAS and following replication studies yielded conflicting results. METHODS: We conducted a case-control study of 470 cases and 475 controls in a Chinese population and then performed a meta-analysis, integrating the current study and 9 publications to evaluate the association between rs10795668 and CRC risk. Heterogeneity among studies and publication bias were assessed by the χ²-based Q statistic test and Egger's test, respectively. RESULTS: In the case-control study, significant association between the SNP and CRC risk was observed, with per-A-allele OR of 0.71 (95%CI: 0.54-0.94, P = 0.017). The following meta-analysis further confirmed the significant association, with per-A-allele OR of 0.91 (95%CI: 0.89-0.93, P(heterogeneity) >0.05) in European population and 0.86 (95%CI: 0.78-0.96, P(heterogeneity)