Liping Sun

Comparative study of serology and histology based detection of Helicobacter pylori infections: a large population-based study of 7,241 subjects from China

Two detection methods for H. pylori infections, i.e. serological antibody titer measurements by Hp-ELISA and histological scoring by HE staining, have been compared to investigate the relationship between the diagnosis methods, to clarify the application scope of each diagnosis method and to determine its influencing factors. In the 7,241 subjects who participated in gastric cancer screening, H. pylori infection rate was 70.14% by the Hp-HE method and 41.87% by the Hp-ELISA method when 34EIU was recognized as the cut-off value. The IgG titers increased with the elevation of HE scores; however, the two methods were not closely correlated among those in different gastric disease status. Age, gender and drinking status did not have significant impact on the relationship between the two methods; however, smoking status seemed to significantly influence the correlation of the two diagnosis methods. In conclusion, it was necessary to reevaluate the cut-off value when using ELISA test kits in different population groups. In most cases, the results of two H. pylori infection diagnosis methods show high correlation. However, this relationship can be affected by smoking and gastric diseases status. Additionally, the dynamic change of H. pylori antibody titers is an indicator of gastric disease development.

Promoter polymorphisms in DNA repair gene ERCC5 and susceptibility to gastric cancer in Chinese.

Genetic variations in excision repair cross-complementing group 5 (ERCC5) might influence individual vulnerability to gastric cancer (GC). We investigated effects of two putatively functional polymorphisms in ERCC5 promoter region, rs751402 (+25A>G) and rs2296147 (+202C>T), and their potential interaction with environment factors on the risk of developing GC. We performed a sex- and age-matched case-control design with 400 GC cases and 400 healthy controls for rs751402 and 403 GC cases and 403 healthy controls for rs2296147. Our results showed that rs751402 were associated with increased GC risk (AA vs. GG: OR=1.99, 95%CI: 1.20-3.31, P=0.008; AG+AA vs. GG: OR=1.41, 95%CI: 1.07-1.86, P=0.016), and rs2296147 was also associated with increased cancer risk (CC vs. TT: OR=2.17, 95%CI: 1.04-4.54, P=0.039; CC vs. CT+TT: OR=2.26, 95%CI: 1.09-4.69, P=0.028). In a stratified analysis, rs751402 (AG+AA vs. GG: OR=1.44, 95%CI: 1.02-2.02, P=0.037) and rs2296147 (CC vs. CT+TT: OR=2.33, 95%CI: 1.00-5.44, P=0.050) were also found to be associated with diffuse-type GC risk. The most common GT haplotype (rs751402-rs2296147) showed protective effect for GC development (OR=0.73, 95%CI: 0.58-0.91, P=0.005), and especially for diffuse-type GC (OR=0.68, 95%CI: 0.52-0.90, P=0.006). Genetic effects on increased GC risk seemed to be enhanced by Helicobacter pylori infection, smoking and alcohol drinking, with corresponding adjusted ORs of 4.57, 2.42 and 2.50 for the rs751402 AG/AA variants, and of 5.32, 3.20 and 6.87 for the rs2296147 CC variant, but their interaction effects on GC risk didnt reach statistically significance. ERCC5 rs751402 and rs2296147 polymorphisms might alter the risk of developing GC and especially the diffuse subtype. Further validation of our results in larger populations and additional studies evaluating their function impact are required.

Temporal changes in serum biomarkers and risk for progression of gastric precancerous lesions: A longitudinal study

Effectively managing precancerous lesions is crucial to reducing the gastric cancer (GC) burden. We evaluated associations of temporal changes in multiple serological markers (pepsinogen I [PGI], PGII, PGI/II ratio, gastrin‐17 and anti‐Helicobacter pylori IgG) with risk for progression of gastric precancerous lesions. From 1997 to 2011, repeated esophagogastroduodenoscopies with gastric mucosal biopsies and blood sample collections were conducted on 2,039 participants (5,070 person‐visits) in the Zhuanghe Gastric Diseases Screening Program, Liaoning, China. Serum biomarkers were measured using ELISA, and gastric biopsies were evaluated using standardized histologic criteria. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using generalized estimating equations for correlated binary outcomes. The ORs for progression of gastric conditions comparing those whose serum PGI, PGII, and anti‐H. pylori IgG levels increased ≥50% relative to those whose decreased ≥50% were, respectively 1.67 (CI, 1.22‐2.28), 1.80 (CI, 1.40‐2.33) and 1.93 (CI, 1.48‐2.52). The OR for those whose PGI/II ratio decreased ≥50% relative to those whose increased ≥50% was 1.40 (CI, 1.08‐1.81), and for those whose PGII and anti‐H. pylori IgG levels both increased ≥50% relative to those whose levels both decreased ≥50% the OR was 3.18 (CI, 2.05‐4.93). Changes in gastrin‐17 were not statistically significantly associated with progression. These findings suggest that temporal changes in serum PGI, PGII, PGI/II ratio, and anti‐H. pylori IgG levels (especially PGII and anti‐H. pylori IgG combined) may be useful for assessing and managing risk for progression of gastric precancerous lesions.

A Serological Biopsy Using Five Stomach-Specific Circulating Biomarkers for Gastric Cancer Risk Assessment: A Multi-Phase Study

Objectives:We aimed to assess a serological biopsy using five stomach-specific circulating biomarkers—pepsinogen I (PGI), PGII, PGI/II ratio, anti-Helicobacter pylori (H. pylori) antibody, and gastrin-17 (G-17)—for identifying high-risk individuals and predicting risk of developing gastric cancer (GC).Methods:Among 12,112 participants with prospective follow-up from an ongoing population-based screening program using both serology and gastroscopy in China, we conducted a multi-phase study involving a cross-sectional analysis, a follow-up analysis, and an integrative risk prediction modeling analysis.Results:In the cross-sectional analysis, the five biomarkers (especially PGII, the PGI/II ratio, and H. pylori sero-positivity) were associated with the presence of precancerous gastric lesions or GC at enrollment. In the follow-up analysis, low PGI levels and PGI/II ratios were associated with higher risk of developing GC, and both low (<0.5u2009pmol/l) and high (>4.7u2009pmol/l) G-17 levels were associated with higher risk of developing GC, suggesting a J-shaped association. In the risk prediction modeling analysis, the five biomarkers combined yielded a C statistic of 0.803 (95% confidence interval (CI)=0.789–0.816) and improved prediction beyond traditional risk factors (C statistic from 0.580 to 0.811, P<0.001) for identifying precancerous lesions at enrollment, and higher serological biopsy scores based on the five biomarkers at enrollment were associated with higher risk of developing GC during follow-up (P for trend <0.001).Conclusions:A serological biopsy composed of the five stomach-specific circulating biomarkers could be used to identify high-risk individuals for further diagnostic gastroscopy, and to stratify individuals’ risk of developing GC and thus to guide targeted screening and precision prevention.

Follow-up study on a high risk population of gastric cancer in north China by serum pepsinogen assay*

OBJECTIVE:u2003 To explore the features and clinical significance of serum pepsinogen (PG) assay in a follow‐up study on a high‐risk gastric cancer (GC) population.

Factors affecting the serum gastrin 17 level: an evidence-based analysis of 3906 serum samples among Chinese.

OBJECTIVE:u2003 To investigate the influence of gender, age, site of lesion, disease type and Helicobacter pylori (H. pylori) infection on the human serum gastrin‐17 level and to study the diagnostic value of serum gastrin‐17 in gastric precancerous lesions and gastric cancer.

Polymorphisms of multiple genes involved in NER pathway predict prognosis of gastric cancer

Nucleotide excision repair (NER) is a versatile system that repairs various DNA damage. Polymorphisms of core NER genes could change NER ability and affect gastric cancer (GC) prognosis. We systematically analyzed the association between 43 SNPs of ten key NER pathway genes (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, ERCC8, XPA, XPC, and DDB2) and overall survival (OS) of 373 GC patients in Chinese. Genotyping was performed by Sequenom MassARRAY platform. We found for the first time that carriers of ERCC2 rs50871 GG genotype demonstrated significantly increased hazards of death than GT/TT individuals (HR=2.55, P=0.002); ERCC6 rs1917799 heterozygote GT were associated with significantly shorter OS than wild-type TT (adjusted HR=1.68, P=0.048); patients with DDB2 rs3781619 GG genotype suffered higher hazards of death compared with AG/AA carriers (adjusted HR=2.30, P=0.003). Patients with ERCC1 rs3212961 AA/AC genotype exhibited longer OS than CC genotype (adjusted HR=0.63, P=0.028); ERCC5 rs2094258 AA/AG genotype revealed significantly favorable OS compared with GG genotype (adjusted HR=0.65, P=0.033); DDB2 rs830083 CG genotype could increase OS compared with GG genotype (adjusted HR=0.61, P=0.042). Furthermore, patients simultaneously carrying two “hazard” genotypes exhibited even significantly worse survival with HR of 3.75, 3.76 and 6.30, respectively. Similarly, combination of “favorable” genotypes predicted better prognosis with HR of 0.56, 0.49 and 0.33, respectively. In conclusion, ERCC2 rs50871 G/T, ERCC6 rs1917799 G/T, DDB2 rs3781619 A/G polymorphisms could predict shorter OS while ERCC1 rs3212961 A/C, ERCC5 rs2094258 A/G, DDB2 rs830083 C/G polymorphisms could predict longer OS of GC, which might serve as promising biomarkers for GC prognosis.

The Differential Expression of Core Genes in Nucleotide Excision Repair Pathway Indicates Colorectal Carcinogenesis and Prognosis

Background Nucleotide excision repair (NER) plays a critical role in maintaining genome integrity. This study aimed to investigate the expression of NER genes and their associations with colorectal cancer (CRC) development. Method Expressions of NER genes in CRC and normal tissues were analysed by ONCOMINE. The Cancer Genome Atlas (TCGA) data were downloaded to explore relationship of NER expression with clinicopathological parameters and survival of CRC. Results ERCC1, ERCC2, ERCC5, and DDB2 were upregulated while ERCC4 was downregulated in CRC. For colon cancer, high ERCC3 expression was related to better T stage; ERCC5 expression indicated deeper T stage and distant metastasis; DDB2 expression suggested earlier TNM stage. For rectal cancer, ERCC2 expression correlated with favourable T stage; XPA expression predicted worse TNM stage. ERCC2 expression was associated with worse overall survival (OS) in colon cancer (HR = 1.53, P = 0.043). Colon cancer patients with high ERCC4 expression showed favorable OS in males (HR = 0.54, P = 0.035). High XPC expression demonstrated decreased death hazards in rectal cancer (HR = 0.40, P = 0.026). Conclusion ERCC1, ERCC2, ERCC4, ERCC5, and DDB2 were differently expressed in CRC and normal tissues; ERCC2, ERCC3, ERCC5, XPA, and DDB2 correlated with clinicopathological parameters of CRC, while ERCC2, ERCC4, and XPC might predict CRC prognosis.

SNP-SNP Interaction between TLR4 and MyD88 in Susceptibility to Coronary Artery Disease in the Chinese Han Population

The toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-dependent signaling pathway plays a role in the initiation and progression of coronary artery disease (CAD). We investigated SNP–SNP interactions between the TLR4 and MyD88 genes in CAD susceptibility and assessed whether the effects of such interactions were modified by confounding risk factors (hyperglycemia, hyperlipidemia and Helicobacter pylori (H. pylori) infection). Participants with CAD (n = 424) and controls (n = 424) without CAD were enrolled. Polymerase chain restriction-restriction fragment length polymorphism was performed on genomic DNA to detect polymorphisms in TLR4 (rs10116253, rs10983755, and rs11536889) and MyD88 (rs7744). H. pylori infections were evaluated by enzyme-linked immunosorbent assays, and the cardiovascular risk factors for each subject were evaluated clinically. The significant interaction between TLR4 rs11536889 and MyD88 rs7744 was associated with an increased CAD risk (p value for interaction = 0.024). In conditions of hyperglycemia, the interaction effect was strengthened between TLR4 rs11536889 and MyD88 rs7744 (p value for interaction = 0.004). In hyperlipidemic participants, the interaction strength was also enhanced for TLR4 rs11536889 and MyD88 rs7744 (p value for interaction = 0.006). Thus, the novel interaction between TLR4 rs11536889 and MyD88 rs7744 was related with an increased risk of CAD, that could be strengthened by the presence of hyperglycemia or hyperlipidemia.

Promoter Polymorphism of Toll-Like Receptor 4 is Associated with a Decreased Risk of Coronary Artery Disease: A Case-Control Study in the Chinese Han Population

Background Coronary artery disease (CAD) is considered a chronic inflammatory disease of the blood vessels. Toll-like receptor 4 (TLR4) is a transmembrane receptor involved in inflammatory reactions. The aim of this study was to determine the association between polymorphisms in the promoter region and 3′-untranslated region (3′-UTR) of TLR4, and the associated CAD risk. Material/Methods This study enrolled 424 participants with CAD and 424 controls without CAD. The polymorphisms in the promoter region and 3′-UTR of TLR4 were identified from the HapMap database, including rs10116253, rs10983755, and rs11536889. Genomic DNA was extracted from peripheral blood. Polymerase chain reaction-restriction fragment length polymorphism was performed to identify genotype polymorphisms. Relative luciferase activity was measured using the dual-luciferase reporter assay system. Results TLR4 rs10116253 in the promoter region was associated with CAD risk. The variant (CC+TC) genotypes of rs10116253 were associated with a decreased CAD risk (OR 95% CI 0.73 (0.54–0.98), p=0.034). In the stratification analyses, the variant (CC+TC) genotypes of rs10116253 were observed to have a relationship with decreased CAD risk in the male subgroup (OR: 95% CI 0.68 (0.48–0.98), p=0.041). Moreover, the variant CC and (CC+TC) genotypes of rs10116253 were correlated with a decreased CAD risk in participants younger than 60-year-old (TC: OR (95% CI 0.62 (0.39–0.98), p=0.042; TC+CC: OR 95% CI 0.63 (0.41–0.98), p=0.039). Regarding rs10116253, the luciferase activity of the mutant C allele construct was lower than that of the wild T allele construct (5.215±0.009 vs. 5.304±0.041; p=0.087). Conclusions The results provided evidence of an association between the TLR4 rs10116253 in the promoter region and a reduced risk of CAD.