Huimin Xia

Association of potentially functional variants in the XPG gene with neuroblastoma risk in a Chinese population

XPG gene plays a critical role in the nucleotide excision repair pathway. However, the association between XPG gene polymorphisms and neuroblastoma risk has not been investigated. In this study with 256 neuroblastoma cases and 531 cancer‐free controls, we investigated the effects of five potentially functional polymorphisms (rs2094258 C>T, rs751402 C>T, rs2296147 T>C, rs1047768 T>C and rs873601G>A) on neuroblastoma risk. We calculated odds ratio (OR) and 95% confidence interval (CI) to evaluate the association between the five selected polymorphisms and neuroblastoma risk. False‐positive report probability (FPRP) was utilized to determine whether significant findings were noteworthy or because of a chance. We also performed genotype–phenotype association analysis to explore the biological plausibility of our findings. We found that the rs2094258 T allele was significantly associated with decreased neuroblastoma risk (CT versus CC: adjusted OR = 0.65, 95% CI = 0.47–0.90, P = 0.010; and CT/TT versus CC: adjusted OR = 0.71, 95% CI = 0.53–0.97, P = 0.030) after adjusting for age and gender. The association was more prominent for subjects with retroperitoneal tumour or early‐stage tumour. We also found that carriers of the 2–3 risk genotypes had a significantly increased neuroblastoma risk when compared to carriers of the 0–1 risk genotypes. The association with risk genotypes was more predominant in older children, females and subjects with retroperitoneal tumour or early stage. Our results were further supported by FPRP analysis and genotype–phenotype association analysis. In conclusion, our study verified that the XPG gene rs2094258 C>T polymorphism may contribute to neuroblastoma susceptibility. Our findings require further validation by studies with larger sample size and concerning different ethnicities.

Association of Common Genetic Variants in Pre-microRNAs and Neuroblastoma Susceptibility: A Two-Center Study in Chinese Children

Neuroblastoma is a commonly occurring extracranial pediatric solid tumor without defined etiology. Polymorphisms in pre-miRNAs have been demonstrated to associate with the risk of several cancers. So far, no such polymorphism has been investigated in neuroblastoma. With this in mind, we performed a two-center case-control study to assess the association of genetic variants in pre-miRNAs and neuroblastoma susceptibility in Chinese children, including 393 cases and 812 controls. We found that miR-34b/c rs4938723 T > C polymorphism was significantly associated with decreased neuroblastoma risk (TC versus TT: adjusted odds ratio [OR] = 0.51, 95% confidence interval [CI] = 0.39–0.67; TC/CC versus TT: adjusted OR = 0.62, 95% CI = 0.48–0.79). We also observed the significant association between the miR-218 rs11134527 A > G polymorphism and decreased neuroblastoma risk (AG versus AA: adjusted OR = 0.73, 95% CI = 0.56–0.96). Stratified analysis further demonstrated that the protective effect of the rs4938723 T > C polymorphism remained prominent in the subgroups, regardless of age, gender, and clinical stages. In term of sites of origin, this polymorphism significantly reduced the risk of tumors originating from the adrenal gland. We further validated the significant results using false-positive report probability analyses. Overall, the miR-34b/c rs4938723 T > C and miR-218 rs11134527 A > G polymorphisms displayed a protective role from neuroblastoma. These findings need further validation.

Genetic Variations of GWAS-Identified Genes and Neuroblastoma Susceptibility: a Replication Study in Southern Chinese Children

Neuroblastoma is one of the most commonly diagnosed solid cancers for children, and genetic factors may play a critical role in neuroblastoma development. Previous genome-wide association studies (GWASs) have identified nine genes associated with neuroblastoma susceptibility in Caucasians. To determine whether genetic variations in these genes are also associated with neuroblastoma susceptibility in Southern Chinese children, we genotyped 25 polymorphisms within these genes by the TaqMan method in 256 cases and 531 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the associations. We performed a meta-analysis to further evaluate the associations. Furthermore, we calculated the area under the receiver-operating characteristic curves (AUC) to assess which gene/genes may better predict neuroblastoma risk. We confirmed that CASC15 rs6939340 A > G, rs4712653 T > C, rs9295536 C > A, LIN28B rs221634 A > T, and LMO1 rs110419 A > G were associated with significantly altered neuroblastoma susceptibility. We also confirmed that rs6939340 A > G (G versus A: OR = 1.30, 95% CI = 1.13-1.50) and rs110419 G > A (A versus G: OR = 1.37, 95% CI = 1.19-1.58) were associated with increased neuroblastoma risk for all subjects. We also found that the combination of polymorphisms in CASC15, LIN28B, and LMO1 may be used to predict neuroblastoma risk (AUC = 0.63, 95% CI = 0.59-0.67). Overall, we verified five GWAS-identified polymorphisms that were associated with neuroblastoma susceptibility alteration for Southern Chinese population; however, these results need further validation in studies with larger sample sizes.

LMO1 gene polymorphisms contribute to decreased neuroblastoma susceptibility in a Southern Chinese population

Neuroblastoma is one of the most commonly diagnosed extracranial solid tumors in infancy; however, the etiology of neuroblastoma remains largely unknown. Previous genome-wide association study (GWAS) indicated that several common genetic variations (rs110419 A > G, rs4758051 G > A, rs10840002 A > G and rs204938 A > G) in the LIM domain only 1 (LMO1) gene were associated with neuroblastoma susceptibility. The aim of this study was to evaluate the correlation between the four GWAS-identified LMO1 gene polymorphisms and neuroblastoma risk in a Southern Chinese population. We genotyped the four polymorphisms in 256 neuroblastoma cases and 531 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the associations. False-positive report probability was calculated for all significant findings. We found that the rs110419 A > G polymorphism was associated with a significantly decreased neuroblastoma risk (AG vs. AA: adjusted OR = 0.65, 95% CI = 0.47–0.91; GG vs. AA: adjusted OR = 0.58, 95% CI = 0.36–0.91; AG/GG vs. AA: adjusted OR = 0.63, 95% CI = 0.46–0.86), and the protective effect was more predominant in children of age > 18 months, males, subgroups with tumor in adrenal gland and mediastinum, and patients in clinical stages III/IV. These results suggested that LMO1 gene rs110419 A > G polymorphism may contribute to protection against neuroblastoma. Our findings call for further validation studies with larger sample size.

The TP53 gene rs1042522 C>G polymorphism and neuroblastoma risk in Chinese children

TP53, a tumor suppressor gene, plays a critical role in cell cycle control, apoptosis, and DNA damage repair. Previous studies have indicated that the TP53 gene Arg72Pro (rs1042522 C>G) polymorphism is associated with susceptibility to various types of cancer. We evaluated the association of the TP53 gene rs1042522 C>G polymorphism with neuroblastoma susceptibility in a hospital-based study among the Chinese Han population. Enrolled were 256 patients and 531 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) generated using logistic regression models were used to determine the strength of the association of interest. No association was detected between rs1042522 C>G polymorphism and neuroblastoma risk. In our stratification analysis of age, gender, sites of origin, and clinical stages, we observed that subjects with rs1042522 CG/GG genotypes had a lower risk of developing neuroblastoma in the mediastinum (Adjusted OR=0.52, 95% CI=0.33-0.82, P=0.005) than those carrying the CC genotype. These results indicate that TP53 gene rs1042522 C>G polymorphism may exert a weak and site-specific effect on neuroblastoma risk in Southern Chinese children and warrant further confirmation.

Composition of gut microbiota in infants in China and global comparison.

Symbiotic gut microbiota is essential for human health, and its compositional changes have been associated with various complex disorders. However, systematic investigation of the acquisition and development of gut microbial communities during early infancy are relatively rare, particularly for infants from non-Western countries. In this study, we characterize the colonization and development of infant microbiota in healthy Chinese infants and compare the pattern with those from other countries. The fecal microbiota of 2-month-old infants was considerably more diverse than that of neonates, as indicated by higher relative abundances of Veillonella, Clostridium, Bacteroides, Lactobacillus, Collinsella and Prevotella, and reduction of Escherichia and Enterococcus. The fecal microbiota of vaginally delivered infants (both neonates and 2-month-old) had significant enrichment of Bacteroides, Parabacteroides and Megamonas, whereas cesarean delivered infants had enrichment of Prevotella, Streptococcus and Trabulsiella. By global comparison, we identify three different enterotypes, referred as “P-type”, “A-type ”and “F-type” which were highly abundant in Proteobacteria, Actinobacteria and Firmicutes, respectively. The three enterotypes’ compositons vary geographically. All Chinese infants in our study belong to the P-type. These findings may provide novel insights into our understanding of the establishment of infant fecal bacterial communities.

The Association between GWAS-identified BARD1 Gene SNPs and Neuroblastoma Susceptibility in a Southern Chinese Population

A previous genome-wide association study (GWAS) has found that some common variations in the BARD1 gene were associated with neuroblastoma susceptibility especially for high-risk subjects, and the associations have been validated in Caucasians and African-Americans. However, the associations between BARD1 gene polymorphisms and neuroblastoma susceptibility have not been studied among Asians, not to mention Chinese subjects. In the present study, we investigated the association of three BARD1 polymorphisms (rs7585356 G>A, rs6435862 T>G and rs3768716 A>G) with neuroblastoma susceptibility in 201 neuroblastoma patients and 531 controls using TaqMan methodology. Overall, none of these polymorphisms was significantly associated with neuroblastoma susceptibility. However, stratified analysis showed a more profound association between neuroblastoma risk and rs6435862 TG/GG variant genotypes among older children (adjusted OR=1.55, 95% CI=1.04-2.31), and children with adrenal gland-originated disease (adjusted OR=2.94, 95% CI=1.40-6.18), or with ISSN clinical stages III+IV disease (adjusted OR=1.75, 95% CI=1.09-2.84). Similar results were observed for the variant genotypes of rs3768716 A>G polymorphism among these three subgroups. Our results suggest that the BARD1 rs6435862 T>G and rs3768716 A>G polymorphisms may contribute to increased susceptibility to neuroblastoma, especially for the subjects at age ≥12 months, with adrenal gland-originated or with late clinical stage neuroblastoma. These findings need further validation by prospective studies with larger sample size with subjects enrolled from multicenter, involving different ethnicities.

Connections between the human gut microbiome and gestational diabetes mellitus

Abstract The human gut microbiome can modulate metabolic health and affect insulin resistance, and it may play an important role in the etiology of gestational diabetes mellitus (GDM). Here, we compared the gut microbial composition of 43 GDM patients and 81 healthy pregnant women via whole-metagenome shotgun sequencing of their fecal samples, collected at 21–29 weeks, to explore associations between GDM and the composition of microbial taxonomic units and functional genes. A metagenome-wide association study identified 154 837 genes, which clustered into 129 metagenome linkage groups (MLGs) for species description, with significant relative abundance differences between the 2 cohorts. Parabacteroides distasonis, Klebsiella variicola, etc., were enriched in GDM patients, whereas Methanobrevibacter smithii, Alistipes spp., Bifidobacterium spp., and Eubacterium spp. were enriched in controls. The ratios of the gross abundances of GDM-enriched MLGs to control-enriched MLGs were positively correlated with blood glucose levels. A random forest model shows that fecal MLGs have excellent discriminatory power to predict GDM status. Our study discovered novel relationships between the gut microbiome and GDM status and suggests that changes in microbial composition may potentially be used to identify individuals at risk for GDM.

BARD1 Gene Polymorphisms Confer Nephroblastoma Susceptibility

BRCA1-associated RING domain protein 1 (BARD1) is a tumor suppressor, which forms a heterodimer with BRCA1. Three BARD1 gene polymorphisms (rs7585356 G > A, rs6435862 T > G and rs3768716 A > G) were initially identified as high-risk neuroblastoma susceptibility loci by a previous GWAS. Because of the general tumor-suppressing function of BARD1, we hypothesized that these BARD1 gene polymorphisms might modify the susceptibility to nephroblastoma. We genotyped these polymorphisms in 145 cases and 531 controls using Taqman methods. Out of three polymorphisms, only the rs7585356 G > A polymorphism was significantly associated with increased susceptibility to nephroblastoma [AA vs. GG: adjusted odds ratio (OR) = 1.78, 95% confidence interval (CI) = 1.01–3.12]. Combined analysis of three polymorphisms indicated that subjects with 3 risk genotypes exhibited significantly elevated nephroblastoma risk, when compared with subjects with 0–2 risk genotypes (adjusted OR = 1.72, 95% CI = 1.02–2.89). Stratified analysis revealed that in term of clinical stage, rs7585356 AA carriers were associated with increased risk of developing clinical stage I + II nephroblastoma. The presence of three risk genotypes was significantly associated with nephroblastoma risk in females and clinical stage I + II nephroblastoma. Our results suggested that BARD1 rs7585356 G > A may be associated with nephroblastoma risk.

Effect of short-term room temperature storage on the microbial community in infant fecal samples

Sample storage conditions are important for unbiased analysis of microbial communities in metagenomic studies. Specifically, for infant gut microbiota studies, stool specimens are often exposed to room temperature (RT) conditions prior to analysis. This could lead to variations in structural and quantitative assessment of bacterial communities. To estimate such effects of RT storage, we collected feces from 29 healthy infants (0–3 months) and partitioned each sample into 5 portions to be stored for different lengths of time at RT before freezing at −80 °C. Alpha diversity did not differ between samples with storage time from 0 to 2 hours. The UniFrac distances and microbial composition analysis showed significant differences by testing among individuals, but not by testing between different time points at RT. Changes in the relative abundance of some specific (less common, minor) taxa were still found during storage at room temperature. Our results support previous studies in children and adults, and provided useful information for accurate characterization of infant gut microbiomes. In particular, our study furnished a solid foundation and justification for using fecal samples exposed to RT for less than 2 hours for comparative analyses between various medical conditions.