Xuzai Lu

Genetic Variants in the Folate Pathway and the Risk of Neural Tube Defects: A Meta-Analysis of the Published Literature

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.

Non-linear dose–response relationship between cigarette smoking and pancreatic cancer risk: Evidence from a meta-analysis of 42 observational studies

BACKGROUND Question remains about the shape of the dose-response relationship between cigarette smoking and pancreatic cancer risk. METHODS Relevant studies were identified by searching PubMed, ISI Web of Science and China National Knowledge Infrastructure (CNKI) databases and by reviewing the reference lists of retrieved articles. Random-effects models were applied to estimate summary relative risks (RRs). RESULTS Forty-two publications were finally included. The overall meta-analysis showed evidence of non-linear association between smoking intensity and pancreatic cancer risk (P for non-linearity=0.000). Compared with non-smokers, the summary RRs were 1.5 (95% confidence interval (CI): 1.4, 1.6) for 10 cigarettes/day, 1.9 (95% CI: 1.8, 2.0) for 20 cigarettes/day, 2.0 (95% CI: 1.9, 2.1) for 30 cigarettes/day and 2.1 (95% CI: 1.9, 2.3) for 40 cigarettes/day with marginal between-study heterogeneity (I(2)=29%). Similar results were also found for smoking duration and cumulative amount of cigarettes smoked. Besides, the summary RR for former smokers reduced with increasing time since quitting smoking compared with current smokers without heterogeneity (P for non-linearity=0.008, I(2)=0%). The results of stratified analysis by study design were comparable to those of overall meta-analysis. When stratified by sex, non-linear dose-response associations were detected for all metrics of cigarette smoking in women, while linear relationships were observed for smoking duration and cumulative amount of cigarettes smoked in men except for smoking intensity. CONCLUSION This meta-analysis reveals a non-linear dose-response association between cigarette smoking and pancreatic cancer risk, but it might differ between sexes.

Genetic variations in TERT-CLPTM1L locus are associated with risk of lung cancer in Chinese population.

Recent genome‐wide association studies (GWAS) have reported multiple genetic variations at 5p15.33 (TERT‐CLPTM1L) associated with risk of lung cancer. However, most of the associated variations identified by GWAS thus far are unlikely to be the actual causal variants, but may be mostly marker‐single nucleotide polymorphisms tagging functional variations that influence gene expression. This study aimed to explore the function‐validated and potentially functional variations in TERT‐CLPTM1L locus conferring susceptibility to lung cancer. A case–control study including 502 cases and 502 controls in Chinese Han population was firstly conducted. Bioinformatic approaches are applied to prioritize genetic variations based on their potential functionality. In the logistic regression analysis, TERT‐rs2853669, rs2736108, and CLPTM1L‐rs31490 were significant associated with increased risk of lung cancer (OR = 1.46, 95% CI = 1.22–1.75; OR = 1.22, 95% CI = 1.00–1.49 and OR = 1.74, 95% CI = 1.35–2.23 under additive model, respectively). The significant associations were observed in non‐small‐cell lung cancer but not‐in‐small‐cell lung cancer, and more prominent in adenocarcinoma. Haplotype analysis presented a significant allele‐dose effect of haplotypes in increasing risk of lung cancer (P for trend = 1.894 × 10−6). Moreover, significant multiplicative interactions were observed between smoking and these three polymorphisms of TERT‐rs2853669, rs2736108, and CLPTM1L‐rs31490, even after bonferroni correction for multiple comparisons (Pinteraction = 1.316 × 10−9, 3.912 × 10−4, and 2.483 × 10−5, respectively). These findings indicated that the function‐validated and potentially functional variations in TERT‐CLPTM1L locus, modified by smoking, may play a substantial role in the susceptibility to lung cancer.

Excess Body Mass Index and Risk of Liver Cancer: A Nonlinear Dose-Response Meta-Analysis of Prospective Studies

Background Excess body weight measured as body mass index (BMI) has a positive association with risk of common cancers. However, previous meta-analyses related to BMI and liver cancer had inconsistent results. The purpose of the current study is to establish a nonlinear dose-response relationship between BMI and incidence risk of liver cancer. Methods A systematic literature search for relevant articles published from 1966 to November 2011 was conducted in PUBMED and EMBASE digital databases. Additional articles were manually searched by using the reference lists of identified papers. Restricted cubic splines and generalized least-squares regression methods were used to model a potential curvilinear relationship and to make a dose-response meta-analysis. Stratified analysis, sensitivity analysis and assessment of bias were performed in our meta-analysis. Results 8 articles including 1,779,471 cohort individuals were brought into meta-analysis. A non-linear dose-response association between BMI and risk of liver cancer was visually significant (P for nonlinearity<0.001), besides, the point value of BMI also enhanced the results quantitatively, where relative risks were 1.02 (95%CI = 1.02–1.03), 1.35 (95%CI = 1.24–1.47) and 2.22-fold (95%CI = 1.74–2.83) when BMI was at the point of 25, 30 and 35 kg/m2 compared with reference (the median value of the lowest category), respectively. The ethnicity of the population was found as the main source of heterogeneity. In subsequent stratified analysis, no evidence of heterogeneity was showed in Asian and White populations (P for heterogeneity>0.1), and all value of BMI still presented significantly increased risk of cancer. Conclusions The findings from meta-analysis provided that excess BMI had significant increased association with risk of liver cancer, although the biological mechanisms underlying the obesity-cancer link still need to be clarified.

Prevalence and Associated Risk Factors of Dyslexic Children in a Middle-Sized City of China: A Cross-Sectional Study

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<0.01), mothers education level (P<0.01), and learning habits (P<0.01) (active learning, scheduled reading time) were associated with dyslexia. Conclusion The prevalence rate of dyslexic children in middle-sized cities is 3.9%. The potential risk factors of dyslexic children revealed in this study will have a great impact on detecting and treating dyslexic children in China as early as possible, although more studies are still needed to further investigate the risk factors of dyslexic children in China.

Exome sequencing identified NRG3 as a novel susceptible gene of Hirschsprung's disease in a Chinese population.

Hirschsprung’s disease (HSCR) is a complex developmental defect characterized by the absence of enteric ganglia in the gastrointestinal tract. Although the genetic defect of enteric nervous system (ENS) was identified to play a critical role in the progress of HSCR, the systemic genetic dissection of HSCR still needs to be clarified. In this study, we firstly performed exome sequencing of two HSCR patients from a Han Chinese family, including the affected mother and son. After the initial quality filtering (coverage ≥ 5X and SNP quality score ≥ 40) of the raw data, we identified 13,948 and 13,856 single nucleotide variants (SNVs), respectively. We subsequently compared the SNVs against public databases (dbSNP130, HapMap, and 1000 Genome Project) and obtained a total of 15 novel nonsynonymous SNVs in 15 genes, which were shared between these two patients. Follow-up Sanger sequencing and bioinformatics analysis highlighted variant c.853G>A (p.E285K) in NRG3, a gene involved in the development of ENS. In the validation phase, we sequenced all nine exons of NRG3 in 96 additional sporadic HSCR cases and 110 healthy individuals and identified another nonsynonymous variant c.1329G>A (p.M443I) and two synonymous variants c.828G>A (p.T276T) and c.1365T>A (p.P455P) only in the cases. Our results indicated that NRG3 may be a susceptibility gene for HSCR in a Chinese population.

Functional Polymorphisms in FAS/FASL System Increase the Risk of Neuroblastoma in Chinese Population

The FAS and FASL system plays a substantial role in apoptosis and immune escape of cells. Three polymorphisms located in the promoter regions of FAS (-1377G/A and -670A/G) and FASL (-844T/C) have been shown to alter the transcriptional activity of the genes, respectively. This study was conducted to evaluate the effects of these polymorphisms on the susceptibility of neuroblastoma in the Chinese population. A total of 203 patients with neuroblastoma and 411 controls were recruited in this case-control study. Polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) was applied for genotyping. Unconditional logistic regression was used to estimate cancer risk by calculating odds ratios (ORs) and their 95% confidence intervals (95% CIs). It was observed that significantly increased risks of neuroblastoma associated with FAS -1377G/A and FASL -844T/C polymorphisms, with ORs equal to 1.55 (95% CI, 1.10–2.20) for FAS -1377 A allele and 2.90 (95% CI, 2.04–4.12) for FASL -844CC genotype carriers compared with non-carriers, respectively. However, no association was found between the polymorphisms of FAS -670A/G and risk of neuroblastoma. In addition, the cumulative effect of FAS and FASL polymorphisms on risk of neuroblastoma was observed (P for trend = 2.502×10−10), with OR for the carriers of both FAS -1377A allele and FASL -844CC genotypes equaled to 3.95 (95% CI, 2.40–6.51). This work reveals that polymorphisms of FAS -1377G/A and FASL -844T/C but not FAS -670A/G are associated with risk of neuroblastoma in Chinese. These findings support the hypothesis that genetic polymorphism in FAS/FASL death system may influence individual susceptibility to neuroblastoma.

Systematic Confirmation Study of GWAS-Identified Genetic Variants for Kawasaki Disease in A Chinese Population

Genome-wide association studies (GWASs) have identified multiple single nucleotide polymorphisms (SNPs) associated with Kawasaki disease (KD). In this study, we replicated the associations of 10 GWAS-identified SNPs with KD in a Han Chinese population. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression, and cumulative effect of non-risk genotypes were also performed. Although none of the SNPs reached the corrected significance level, 4 SNPs showed nominal associations with KD risk. Compared with their respective wild type counterparts, rs1801274 AG+GG genotypes and rs3818298 TC+CC genotypes were nominally associated with the reduced risk of KD (OR = 0.77, 95% CI = 0.59–0.99, P = 0.045; OR = 0.74, 95% CI = 0.56–0.98, P = 0.038). Meanwhile, rs1801274 GG genotype, rs2736340 CC genotype or rs4813003 TT genotype showed a reduced risk trend (OR = 0.57, 95% CI = 0.35–0.93, P = 0.024; OR = 0.46, 95% CI = 0.26–0.83, P = 0.010; OR = 0.64, 95% CI = 0.43–0.94, P = 0.022), compared with rs1801274 AG+AA genotypes, rs2736340 CT+TT genotypes or rs4813003 TC+CC genotypes, respectively. Furthermore, a cumulative effect was observed with the ORs being gradually decreased with the increasing accumulative number of non-risk genotypes (Ptrend<0.001). In conclusion, our study suggests that 4 GWAS-identified SNPs, rs2736340, rs4813003, rs3818298 and rs1801274, were nominally associated with KD risk in a Han Chinese population individually and jointly.

The SNP rs402710 in 5p15.33 Is Associated with Lung Cancer Risk: A Replication Study in Chinese Population and a Meta-Analysis

Background Lung cancer is the most commonly diagnosed cancer and leading cause of cancer mortality in the world. A single nucleotide polymorphism (SNP), rs402710, located in 5p15.33, was firstly identified to be associated with the lung cancer risk in a genome-wide association study. However, some following replication studies yielded inconsistent results. Methodology and Findings A case-control study of 611 cases and 1062 controls in a Chinese population was conducted, and then a meta-analysis integrating the current and previously published studies with a total 31811 cases and 36333 controls was performed to explore the real effect of rs402710 on lung cancer susceptibility. Significant associations between the SNP rs402710 and lung cancer risk were observed in both case-control study and meta-analysis, with ORs equal to 0.77 (95%CI = 0.63–0.95) and 0.83 (95%CI = 0.81–0.86) in dominant model, respectively. By stratified analysis of our case-control study, the associations were also observed in never smoker group and non-small cell lung cancer(NSCLC) group with ORs equal to 0.71 (95%CI = 0.53–0.95) and 0.69 (95%CI = 0.55–0.87), which was remarkable that larger effect of the minor allele T was seen in the two groups than that in overall lung cancer. Besides, the sensitive and cumulative analysis indicated the robust stability of the current results of meta-analysis. Conclusion The results from our replication study and the meta-analysis provided firm evidence that rs402710 T allele significantly contributed to decreased lung cancer risk, and the case-control study implied that the variant may yield stronger effect on NSCLC and never smokers. However, the mechanism underlying the polymorphism conferring susceptibility to lung cancer is warranted to clarify in the follow-up studies.

The Genetic Variant on Chromosome 10p14 Is Associated with Risk of Colorectal Cancer: Results from a Case-Control Study and a Meta-Analysis

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 Eggers 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, Pheterogeneity>0.05) in European population and 0.86 (95%CI: 0.78–0.96, P heterogeneity <0.05) in Asian population. Besides, sensitivity analyses and publication bias assessment indicated the robust stability and reliability of the results. Conclusions Results from our case-control study and the followed meta-analysis confirmed the significant association of rs10795668 with CRC risk.