Huakang Tu

Helicobacter pylori-related host gene polymorphisms associated with susceptibility of gastric carcinogenesis: a two-stage case-control study in Chinese

Stomach carcinogenesis progresses stepwise from normal mucosa/superficial gastritis, atrophic gastritis (GA) to gastric cancer (GC). Host factors independent of or combined with Helicobacter pylori infection may modulate the carcinogenesis process. In this two-stage study, we selected 24 putative functional tag single-nucleotide polymorphisms (tagSNPs) for six H.pylori-related host genes, MUC1, toll-like receptor 4 (TLR4), protein tyrosine phosphatase, non-receptor type 11 (PTPN11), IL-1B, PGC and PGA3-5, and analyzed their influence and interaction with H.pylori on the GA and GC risks. Using high-throughput genotyping, the 24 tagSNPs were preliminarily assessed in a screening population of 552 controls, 254 GA and 236 GC subjects; subsequently, five candidate tagSNPs for gastric diseases risk in the TLR4, PGC and PTPN11 genes were re-evaluated in a larger population of 1276 controls, 907GA and 714 GC subjects. We observed that PGC rs6458238, PGC rs4711690 and PTPN11 rs12229892 were associated with susceptibilities to GA and/or GC. Moreover, rs4711690 and rs12229892 and H.pylori demonstrated significant interaction effects on GA risk. In gastric cancerous specimens, we observed significantly higher messenger RNA level in the subjects carrying the PGC rs6458238 GA genotype than that in subjects with the common GG genotype. These findings indicated that genetic variations of two crucial H.pylori-related host genes, H.pyloris mucosal effecter PGC gene and H.pyloris cellular messenger PTPN11 gene, either dependent or independent of interaction with H.pylori, were associated with the risks of GC and/or GA that precede carcinoma. Functional studies and further independent large-scale studies especially in other ethnic populations are still needed to confirm our results.

Health Related Quality of Life for Stone Formers

PURPOSE Urolithiasis is a common urological condition that causes significant pain and suffering. Until recently few studies had been done to examine how quality of life is affected in stone formers. We hypothesized that patients with multiple recurrent episodes of urolithiasis have worse health related quality of life. Thus, we identified specific factors that impact health related quality of life in patients with urolithiasis. MATERIALS AND METHODS In an institutional review board approved study we recruited 386 patients through mailings and through the outpatient clinic who were evaluated at our institution for urolithiasis in the last 5 years. Each patient was asked to answer questionnaires on stone disease, including SF-36®, a validated 36-item health care quality of life survey. RESULTS Of the 386 patients recruited for study 115 responded to our inquiry. Variables such as surgical complications, time from last stone episode, number of emergency room visits and number of surgeries correlated with the SF-36 domains. CONCLUSIONS Urolithiasis is associated with severe physical and psychological effects that lead to clinically significant impairment in quality of life. Our findings confirm and expand the findings of previous groups showing the many ways in which stone formation can affect patient quality of life. Appreciation of these effects in the acute and chronic treatment settings may change the way that the disease is approached.

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.

Serum anti-Helicobacter pylori immunoglobulin G titer correlates with grade of histological gastritis, mucosal bacterial density, and levels of serum biomarkers

Abstract Objective. Clinical implications of serum anti-Helicobacter pylori immunoglobulin G (IgG) titer were unclear. This study investigated the associations of serum anti-H. pylori IgG titer with grade of histological gastritis, mucosal bacterial density and levels of serum biomarkers, including pepsinogen (PG) I, PGII, PGI/II ratio and gastrin-17. Material and methods. Study participants were from a screening program in northern China. Serum anti-H. pylori IgG measurements were available for 5922 patients with superficial gastritis. Serum anti-H. pylori IgG titer and serum biomarkers were measured using ELISA, and gastric biopsies were evaluated using standardized criteria. Results. In patients with mild, moderate or severe superficial gastritis, the mean serum anti-H. pylori IgG titers were 17.3, 33.4 and 54.4 EIU (p for trend < 0.0001), respectively. As mucosal H. pylori density score increased from 0 to 3, the mean serum anti-H. pylori IgG titers also increased from 24.7 to 44.8 EIU (p for trend < 0.0001). Serum anti-H. pylori IgG titer was associated positively with serum PGI, PGII and gastrin-17 concentrations and negatively with PGI/II ratio, and the association was the strongest for PGII. The mean PGII concentration of the patients in the highest quartile of IgG titer was twice the mean concentration of the patients in the lowest quartile (17.2 vs. 8.6 EIU, p < 0.0001). Conclusions. Our results suggest that serum anti-H. pylori IgG titer was associated positively with grade of histological gastritis, mucosal bacterial density and concentrations of serum PGI, PGII and gastrin-17, and negatively with PGI/II ratio.

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 (<0.5 pmol/l) and high (>4.7 pmol/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.

Association of nucleotide excision repair pathway gene polymorphisms with gastric cancer and atrophic gastritis risks.

Polymorphisms of NER genes could change NER ability, thereby altering individual susceptibility to GC. We systematically analyzed 39 SNPs of 8 key genes of NER pathway in 2686 subjects including 898 gastric cancer (GC), 851 atrophic gastritis (AG) and 937 controls (CON) in northern Chinese. SNP genotyping were performed using Sequenom MassARRAY platform. The results demonstrated that DDB2 rs830083 GG genotype was significantly associated with increased GC risk compared with wildtype CC (OR=2.32, P = 6.62 × 10−9); XPC rs2607775 CG genotype conferred a 1.73 increased odds of GC risk than non-cancer subjects compared with wild-type CC (OR=1.73, P= 3.04 × 10−4). The combined detection of these two polymorphisms demonstrated even higher GC risk (OR=3.05). Haplotype analysis suggested that DDB2 rs2029298-rs326222-rs3781619-rs830083 GTAG haplotype was significantly associated with disease risk in each step of CON→AG→GC development (AG vs. CON: OR=2.88, P= 7.51 × 10−7; GC vs. AG: OR=2.90, P=5.68 × 10−15; GC vs. CON: OR=8.42, P=2.22 × 10−15); DDB2 GTAC haplotype was associated with reduced risk of GC compared with CON (OR=0.63, P= 8.31 × 10−12). XPC rs1870134-rs2228000- rs2228001-rs2470352-rs2607775 GCAAG haplotype conferred increased risk of GC compared with AG (OR=1.88, P= 6.98 × 10−4). XPA rs2808668 and drinking, DDB2 rs326222, rs3781619, rs830083 and smoking demonstrated significant interactions in AG; XPC rs2607775 had significant interaction with smoking in GC. In conclusion, NER pathway polymorphisms especially in “damage incision” step were significantly associated with GC risk and had interactions with environment factors. The detection of NER pathway polymorphisms such as DDB2 and XPC might be applied in the prediction of GC risk and personalized prevention in the future. NOVELTY & IMPACT STATEMENTS NER pathway polymorphisms especially in “damage incision” step were significantly associated with GC risk and had interactions with environment factors, which might be applied in the prediction of GC risk and personalized prevention in the future.

Polymorphic rs9471643 and rs6458238 upregulate PGC transcription and protein expression in overdominant or dominant models

The pepsinogen C (PGC) gene encodes a major differentiation biomarker for gastric mucosa and has two single nucleotide polymorphisms, rs9471643 G>C and rs6458238 G>A, within its 5′ upstream region that are involved in gastric carcinogenesis. However, in what genetic models the two polymorphisms modulate disease risk and how they relate to gastric carcinogenesis needs further study. We fitted the most appropriate genetic models to the PGC polymorphisms and validated their robustness; then with knowledge of the genetic model, we investigated the influence of functional variant alleles or genotypes on gene expression in vitro and in vivo. We confirmed that rs9471643 CG genotype was stably associated with reduced gastric cancer risk in complete overdominant model. This favorable CG genotype was also associated with reduced atrophic gastritis risk in subjects carrying rs6458238 AG/AA genotype. The G>C transition at rs9471643 enhanced promoter activity and transcription factor binding ability, and the CG genotype was consistently associated with elevated levels of PGC mRNA, in situ protein and serum protein in complete overdominant model based‐analyses. Additionally, rs6458238 AG/AA genotype was associated with reduced atrophic gastritis risk in dominant model. Its favorable A allele was related to higher promoter activity and lower transcription factor binding ability, and the AG/AA genotype showed association with elevated levels of serum PGC protein in dominant model based‐analyses. Our results suggest that rs9471643 CG and rs6458238 AG/AA genotypes have important roles in up‐regulating PGC expression, which may partially explain why individuals with these favorable genotypes have decreased risks of getting gastric cancer.

No association between mitochondrial DNA copy number and colorectal adenomas

Despite previously reported associations between peripheral blood mtDNA copy number and colorectal cancer, it remains unclear whether altered mtDNA copy number in peripheral blood is a risk factor for colorectal cancer or a biomarker for undiagnosed colorectal cancer. Though colorectal adenomas are well‐recognized precursor lesions to colorectal cancer, no study has evaluated an association between mtDNA copy number and colorectal adenoma risk. Hence, we investigated an association between peripheral blood mtDNA copy number and incident, sporadic colorectal adenoma in 412 colorectal adenoma cases and 526 cancer‐free controls pooled from three colonoscopy‐based case–control studies that used identical methods for case ascertainment, risk factor determination, and biospecimen collection. We also evaluated associations between relative mtDNA copy number and markers of oxidative stress, including circulating F2‐isoprostanes, carotenoids, and fluorescent oxidation products. We measured mtDNA copy number using a quantitative real time polymerase chain reaction (PCR). We used unconditional logistic regression to analyze the association between mtDNA copy number and colorectal adenoma risk after multivariable adjustment. We found no association between logarithmically transformed relative mtDNA copy number, analyzed as a continuous variable, and colorectal adenoma risk (odds ratio = 1.02, 95%CI: 0.82–1.27; P = 0.86). There were no statistically significant associations between relative mtDNA copy number and other markers of oxidative stress. Our findings, taken together with those from previous studies, suggest that relative mtDNA copy number in peripheral blood may more likely be a marker of early colorectal cancer than of risk for the disease or of in vivo oxidative stress.

Effects of calcium and vitamin D3 on transforming growth factors in rectal mucosa of sporadic colorectal adenoma patients: a randomized controlled trial.

Transforming growth factor alpha (TGFα) and TGFβ1 are growth‐promoting and ‐inhibiting autocrine/paracrine growth factors, respectively, that may (1) affect risk for colorectal cancer and (2) be modifiable by anti‐proliferative exposures. The effects of supplemental calcium and vitamin D3 on these two markers in the normal‐appearing colorectal mucosa in humans are unknown. We conducted a pilot, randomized, double‐blind, placebo‐controlled, 2 × 2 factorial clinical trial (n = 92; 23/treatment group) of calcium 2 g and/or vitamin D3 800 IU/d versus placebo over 6 mo. TGFα and TGFβ1 expression was measured in biopsies of normal‐appearing rectal mucosa using automated immunohistochemistry and quantitative image analysis at baseline and 6‐mo follow‐up. In the calcium, vitamin D3, and calcium plus vitamin D3 groups relative to the placebo group (1) the mean overall expression of TGFβ1 increased by 14% (P = 0.25), 19% (P = 0.17), and 22% (P = 0.09); (2) the ratio of TGFα expression in the upper 40% (differentiation zone) to that in the lower 60% (proliferation zone) of the crypts decreased by 34% (P = 0.11), 31% (P = 0.22), and 26% (P = 0.33); and (3) the TGFα/TGFβ1 ratio in the upper 40% of the crypts decreased by 28% (P = 0.09), 14% (P = 0.41), and 22% (P = 0.24), respectively. These preliminary results, although not statistically significant, suggest that supplemental calcium and vitamin D3 may increase TGFβ1 expression and shift TGFα expression downward from the differentiation to the proliferation zone in the crypts in the normal‐appearing colorectal mucosa of sporadic colorectal adenoma patients, and support further investigation in a larger clinical trial.

A comprehensive evaluation of fasting serum gastrin-17 as a predictor of diseased stomach in Chinese population

Abstract Background and aim. Fasting serum gastrin-17 (FsG17) is considered as a noninvasive biomarker reflecting the structure and functional status of gastric mucosa, but its clinical utility remains unclear. This study aimed to evaluate FsG17 comprehensively: establish the ranges and cut-off points of FsG17 levels in different gastric diseases, identify their influencing factors, and investigate the accuracy of FsG17 for identifying diseased stomach. Methods. The study included 4064 participants from Northern China between 2008 and 2013. FsG17 and serum Helicobacter pylori IgG antibody levels were measured by enzyme-linked immunosorbent assay. Diagnostic accuracy was assessed by receiver operator characteristic curves. Multivariate logistic regression analysis was performed to determine the best predictors of gastric histopathological conditions. Results. Median FsG17 levels in healthy, non-atrophic, atrophic, and cancerous stomachs were 1.8, 4.0, 3.8, and 6.1 pmol/l, respectively. Age, smoking status, alcohol consumption, H. pylori infection, and predominant lesion site were factors that affected FsG17 levels. The optimal cut-off values for FsG17 were 3.0 pmol/l (sensitivity of 59.3% and specificity of 67.3%) for discriminating between healthy stomach and diseased stomach and 10.7 pmol/l (sensitivity of 37% and specificity of 83.7%) for discriminating between cancerous stomach and cancer-free stomach; the screening accuracy was higher (sensitivity of 50.0% and specificity of 83.0%) for gastric cancer in the corpus. Multivariate analysis showed that FsG17, gender, age, and H. pylori infection were independent predictors of cancerous stomach. Conclusion. With the progression from health stomach to malignancy, FsG17 levels significantly increased and were influenced by other factors. FsG17 combined with age, gender, and H. pylori infection could distinguish between cancerous stomach and cancer-free stomach. The results will enhance our understanding of the potential clinical utility of FsG17.