ITGA1 polymorphisms and haplotypes are associated with gastric cancer risk in a Korean population

AIM:To evaluate the association between the geneticpolymorphisms and haplotypes of the ITGA1 gene and the risk of gastric cancer.METHODS:The study subjects were 477 age-and sex-matched case-control pairs.Genotyping was performed for 15 single nucleotide polymorphisms(SNPs)in ITGA1.The associations between gastric cancer and these SNPs and haplotypes were analyzed with multivariate conditional logistic regression models.Multiple testing corrections were carried out following methodology for controlling the false discovery rate.Gene-based association tests were performed using the versatile gene-based association study(VEGAS)method.RESULTS:In the codominant model,the ORs for SNPs rs2432143(1.517;95%CI:1.144-2.011)and rs2447867(1.258;95%CI:1.051-1.505)were statistically significant.In the dominant model,polymorphisms of rs1862610 and rs2447867 were found to be significant risk factors,with ORs of 1.337(95%CI:1.029-1.737)and 1.412(95%CI:1.061-1.881),respectively.In the recessive model,only the rs2432143 polymorphism was significant(OR=1.559,95%CI:1.150-2.114).The C-C type of ITGA1 haplotype block 2 was a significant protective factor against gastric cancer in the both codominant model(OR=0.602,95%CI:0.212-0.709,P=0.021)and the dominant model(OR=0.653,95%CI:0.483-0.884).The ITGA1 gene showed a significant gene-based association with gastric cancer in the VEGAS test.In the dominant model,the A-T type of ITGA1 haplotype block 2 was a significant risk factor(OR=1.341,95%CI:1.034-1.741).SNP rs2447867 might be related to the severity of gastric epithelial injury due to inflammation and,thus,to the risk of developing gastric cancer.CONCLUSION:ITGA1 gene SNPs rs1862610,rs2432143,and rs2447867 and the ITGA1 haplotype block that includes SNPs rs1862610 and rs2432143 were significantly associated with gastric cancer.     

Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms

BACKGROUND & AIMS: Genetic variations in proinflammatory and anti-inflammatory cytokine genes influence individual response to carcinogenic exposures. Polymorphisms in interleukin (IL)-1 beta and its endogenous receptor antagonist are associated with risk of Helicobacter pylori-related gastric cancer. The aim of this study was to evaluate the role of proinflammatory cytokine gene polymorphisms in gastric and esophageal cancers defined by anatomic subsite. METHODS: We assessed polymorphisms of the IL-1 gene cluster and 4 other cytokine genes in a population-based case-control study of upper gastrointestinal cancers, including gastric cardia (n = 126) and noncardia adenocarcinoma (n = 188), esophageal squamous cell carcinoma (n = 53), and adenocarcinoma (n = 108), and frequency-matched controls (n = 212). ORs for the different cancers were computed from logistic regression models adjusted for potential confounding factors. RESULTS: Proinflammatory genotypes of tumor necrosis factor alpha and IL-10 were each associated with more than doubling of the risk of noncardia gastric cancer. Carriage of multiple proinflammatory polymorphisms of IL-1B(o) IL-1 receptor antagonist, tumor necrosis factor A, and IL-10 conferred greater risk, with ORs (and 95% confidence intervals) of 2.8 (1.6-5.1) for one, 5.4 (2.7-10.6) for 2, and 27.3 (7.4-99.8) for 3 or 4 high-risk genotypes. In contrast, these polymorphisms were not consistently related to the risks of esophageal or gastric cardia cancers. Polymorphisms in IL-4 and IL-6 were not associated with any of the cancers studied. CONCLUSIONS: A proinflammatory cytokine genetic profile increases the risk of noncardia gastric adenocarcinoma but not other upper gastrointestinal cancers, possibly by inducing a hypochlorhydric and atrophic response to gastric H. pylori infection.     

XRCC1 polymorphisms and risk of colorectal cancer: a meta-analysis

Purpose  

Previous studies investigating the association between X-ray repair cross-complementation group 1 (XRCC1) polymorphisms and colorectal cancer (CRC) risk has provided inconsistent results. The aim of our study was to clarify the effects of XRCC1variants on CRC risk.     

The association between Helicobacter pylori infection and early gastric cancer: a meta-analysis

OBJECTIVE: Helicobacter pylori (H. pylori) is recognized as a definite carcinogen for gastric cancer. The prevalence of H. pylori infection in patients with gastric cancer varies widely among studies and no meta-analysis on the prevalence of H. pylori infection in early gastric cancer (EGC) has been performed. We aimed to review systematically the relationship between H. pylori infection and EGC, and different types of EGC. METHODS: Observational studies reporting raw data on the prevalence of H. pylori infection in EGC and controls, or comparing different types of EGC, conducted in adult populations, and published in the English language were identified through MEDLINE and EMBASE up to June 2006. RESULTS: Of 87 relevant studies, 19 case-control studies met inclusion criteria. Of these, 15 studies compared EGC (N = 2,722) and non-neoplasm controls (N = 13,976) or advanced gastric cancer (AGC) (N = 1,130), 9 studies compared the intestinal-type (I-EGC) and diffuse-type (D-EGC) of EGC, and 2 studies compared the differentiated-type (DF-EGC) and undifferentiated-type (UDF-EGC) of EGC and were included in the meta-analysis. The prevalence of H. pylori infection was significantly higher in patients with EGC (87.3%) than in non-neoplasm controls (61.4%) (OR 3.38, 95% CI 2.15-5.33, P < 0.00001). However, significant heterogeneity was seen (P < 0.00001). Four large sample (N > or = 100) studies (N = 2,060) may result in the heterogeneity, but the conclusion remained unchanged when sensitivity analysis was made with the other 11 homogeneous small sample studies alone, in which the prevalence of H. pylori infection was significantly higher in EGC (N = 662) than that in controls (N = 5,898) (87.8%vs 68.6%, P < 0.00001), and the odds ratio (OR 3.28, 95% CI 2.34-4.61) was similar to the large sample studies alone (OR 3.40, 95% CI 1.14-10.12). The prevalence of H. pylori infection in EGC was significantly higher than in AGC (6 studies) (OR 2.13, 95% CI 1.75-2.59) and 16-fold higher in patients with DF-EGC than in those with UDF-EGC (OR 16.53, 95% CI 2.64-103.43). No significant difference in the prevalence of H. pylori infection was seen between the patients with I-EGC and D-EGC types (OR 0.75, 95% CI 0.26-2.18). CONCLUSIONS: This study indicates that H. pylori infection is strongly associated with early gastric cancer when compared with non-neoplasm controls or advanced gastric cancer. To determine more accurately the effect size of H. pylori in EGC, age-matched normal controls or adjusting for age in the analysis should be considered in H. pylori-related gastric cancer case-control studies.     

The association of OPG polymorphisms with risk of osteoporotic fractures: A systematic review and meta-analysis

Background:Subjects with low bone mineral density and osteoporosis are more likely to suffer osteoporotic fractures during their lifetime. Polymorphisms in osteoprotegerin (OPG) gene are found to be associated with low bone mineral density and osteoporosis risk but their association with fracture risk is inconclusive. Here, we performed a meta-analysis to investigate the relationship between OPG polymorphisms with susceptibility to osteoporotic fractures.Methods:Eligible studies investigating the association between common OPG polymorphisms (A164G, T245G, T950C, and G1181C) and risk of osteoporotic fracture were retrieved from PubMed, EMBASE, Web of Science, and the Cochrane Library. Odds ratio (OR) and the 95% confidence interval (CI) were calculated in the allelic, dominant, recessive, and homozygous model. Subgroup analyses of vertebral fractures, Caucasians, and postmenopausal women were also performed.Results:A total of 14 studies comprising 5459 fracture cases and 9860 non-fracture controls were included. A163G was associated with fracture risk in dominant (OR = 1.29, 95%CI 1.11–1.50), recessive (OR = 1.64, 95%CI 1.10–2.44), and homozygous model (OR = 1.73, 95%CI 1.16–2.59). T245G was significantly correlated with susceptibility to fractures in all genetic models. Subjects with CC genotype of T950C had a reduced risk of fracture compared to those with CT or TT genotypes (OR = 0.81, 95%CI 0.70–0.94, P = .004). Subgroup analysis showed that A163G and T245G but not T950C and G1181C were associated with vertebral fracture risk.Conclusion:OPG A163G and T245G polymorphisms were risk factors of osteoporotic fractures while T950C had a protective role. These polymorphisms can be used as predictive markers of fractures.     

Lethal-7-related polymorphisms are associated with susceptibility to and prognosis of gastric cancer

BACKGROUND The lethal-7(let-7)family members and their targets are involved in the development and progression of tumors.Let-7-related polymorphisms have been reported to be associated with tumorigenesis and prognosis.In gastric cancer,however,the related studies are limited.AIM To investigate the role of let-7-related microRNA polymorphisms in the tumorigenesis and prognosis of gastric cancer in a Chinese population.METHODS A total of 898 gastric cancer patients and 992 tumor-free controls were recruited into this study from 2008 to 2013.Gastric cancer patients were followed periodically.Ten single nucleotide polymorphisms(SNPs)in the let-7 gene region or their target mRNAs were genotyped using the MassARRAY system and their associations with the risk for or overall survival of gastric cancer were analyzed.RESULTS All the ten SNPs were in Hardy-Weinberg equilibrium.The C allele of the rs3811463 polymorphism in the 3’-untranslated region(UTR)of LIN28A was associated with a lower risk of gastric cancer[odds ratio(OR)=0.74,95%confidence interval(CI):0.61-0.88,P=0.001]after adjustment for age and Helicobacter pylori status.Seven hundred and thirty-five gastric cancer patients who had undergone radical tumorectomy were included in the survival analysis and their 5-year survival rate was 53.9%(95%CI:50.1%-57.6%).The rs10889677 in the 3’-UTR of IL23R was corresponded to the prognosis of gastric cancer in a dose-response manner,in which the death risk increased by 25%[hazard ratio(HR)=1.25,95%CI:1.04-1.45,P=0.011]with each increase in the number of C alleles after controlling for other potential clinicopathological parameters.CONCLUSION The let-7-related polymorphism rs3811463 in LIN28A is associated with the susceptibility to gastric cancer and the let-7-related polymorphism rs10889677 in IL23R is associated with the prognosis of gastric cancer.     

Interleukin 1B and interleukin 1RN polymorphisms are associated with increased risk of gastric carcinoma

BACKGROUND & AIMS: Interleukin (IL)-1 gene cluster proinflammatory polymorphisms have been associated with development of gastric atrophy and with increased risk of gastric carcinoma. We aimed to determine the association between IL-1 loci polymorphisms and increased risk of gastric carcinoma in samples from a Portuguese population, and to find whether there was any relationship with the histologic types of gastric carcinoma. METHODS: In a case-control study including 220 controls and 152 patients with gastric carcinoma (intestinal, 76; diffuse, 37; and atypical, 39), both the IL-1B-511 biallelic polymorphism and the IL-1RN penta-allelic variable number of tandem repeats were genotyped. RESULTS: We found a significant association between the IL-1 polymorphisms and increased risk for tumor development in patients with intestinal-type gastric carcinoma. A trend towards an increased risk of tumor development was also observed in patients with diffuse-type gastric carcinoma. No significant relationship was observed in patients with atypical carcinoma. Carriers of IL-1B-511T and IL-1RN*2 homozygotes had increased risk for developing intestinal-type gastric carcinoma with odds ratios of 2.7 (95% confidence interval [CI], 1.5-4.9) and 3.1 (95% CI, 1.5-6.5), respectively. Statistical analysis showed an interaction between the 2 loci with the risk conferred by the IL-1B-511T allele substantially increased (odds ratio, 9.0; 95% CI, 3.5-23.0) in individuals homozygous for the IL-1RN*2 allele. CONCLUSIONS: Our results provide further support to the association between IL-1 gene cluster proinflammatory polymorphisms and increased risk of gastric carcinoma. Furthermore, we found evidence pointing to the existence of a synergistic interaction between the IL-1B and IL-1RN polymorphisms.     

The association between the interleukin-1 polymorphisms and gastric cancer risk depends on the family history of gastric carcinoma in the study population

OBJECTIVES: The association between interleukin-1 polymorphisms, H. pylori and increased gastric cancer risk remains controversial. AIMS: To compare the prevalence of these polymorphisms in individuals with two mutually exclusive diseases connected with infection, gastric cancer, and duodenal ulcer. METHODS: 121 gastric cancer and 119 duodenal ulcer patients. Genomic DNA was typed for polymorphisms at position -511, -31 in the interleukin-1beta gene (IL-1 beta) using primer extension and mass-spectrometry. Analysis of the variable number of tandem repeats in intron 2, in its receptor antagonist gene (IL-1RN) was performed by PCR and agarose gel electrophoresis. RESULTS: All subjects were successfully genotyped for the three gene loci. IL-1 beta-511 was found to be in reverse linkage disequilibrium with IL-1 beta-31. The differences between gastric cancer and duodenal ulcer patients concerned only heterozygous variant of IL-1beta and were related to family history of gastric cancer, tumor stage, histology, site. Thus, CT carriers were found to have a higher risk of sporadic [OR 2.21 (95% CI, 1.22-3.99)], early [OR 2.81 (95% CI, 1.14-6.93)], diffuse [OR 2.48, (95% CI 1.21-5.09)] or non-cardia gastric cancer [OR 1.88 (95% CI 1.06-3.33)]. Furthermore, CT genotype was significantly more prevalent in gastric cancer patients with negative than in those with a positive family history (p = 0.039). CONCLUSIONS: The association between the interleukin-1 polymorphisms and gastric cancer risk depends on the family history of gastric carcinoma in the study population. This phenomenon may be in part responsible for differences in results of interleukin-1 studies performed on populations with low and high gastric cancer prevalence.     

Folate intake, MTHFR polymorphisms, and risk of esophageal, gastric, and pancreatic cancer: a meta-analysis

BACKGROUND & AIMS: Increasing evidence suggests that a low folate intake and impaired folate metabolism may be implicated in the development of gastrointestinal cancers. We conducted a systematic review with meta-analysis of epidemiologic studies evaluating the association of folate intake or genetic polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR), a central enzyme in folate metabolism, with risk of esophageal, gastric, or pancreatic cancer. METHODS: A literature search was performed using MEDLINE for studies published through March 2006. Study-specific relative risks were weighted by the inverse of their variance to obtain random-effects summary estimates. RESULTS: The summary relative risks for the highest versus the lowest category of dietary folate intake were 0.66 (95% confidence interval [CI], 0.53-0.83) for esophageal squamous cell carcinoma (4 case-control), 0.50 (95% CI, 0.39-0.65) for esophageal adenocarcinoma (3 case-control), and 0.49 (95% CI, 0.35-0.67) for pancreatic cancer (1 case-control, 4 cohort); there was no heterogeneity among studies. Results on dietary folate intake and risk of gastric cancer (9 case-control, 2 cohort) were inconsistent. In most studies, the MTHFR 677TT (variant) genotype, which is associated with reduced enzyme activity, was associated with an increased risk of esophageal squamous cell carcinoma, gastric cardia adenocarcinoma, noncardia gastric cancer, gastric cancer (all subsites), and pancreatic cancer; all but one of 22 odds ratios were >1, of which 13 estimates were statistically significant. Studies of the MTHFR A1298C polymorphism were limited and inconsistent. CONCLUSIONS: These findings support the hypothesis that folate may play a role in carcinogenesis of the esophagus, stomach, and pancreas.     

Fracture risk associated with smoking: a meta-analysis

OBJECTIVES: To assess fracture risk associated with smoking. DESIGN: Systematic review. DATA SOURCES: Cohort, case-control, and cross-sectional studies identified by searching PubMed and EMBASE, and by recursive screening of reference lists. SUBJECTS: Fifty studies including 512 399 subjects were included. MAIN OUTCOME MEASURE: Fracture occurrence in current, previous, and never smokers. RESULTS: Fracture risk was significantly increased in current smokers for all fracture types combined (pooled relative risk 1.26, 95% CI 1.12-1.42) and for hip (1.39, 95% CI 1.23-1.58) and spine fractures (1.76, 95% CI 1.10-2.82), but not for wrist fractures (0.86, 95% CI 0.46-1.60). In previous smokers the estimate was significantly lower for as well all types of fractures (1.02, 95% CI 0.85-1.22, P = 0.03 compared with current smokers), as for hip fractures (1.19, 95% CI 1.06-1.34, P = 0.04). There was a trend towards higher risk estimates in previous smokers for hip fractures in case-control studies than in cohort studies. A similar difference between case-control and cohort studies was not present for current smokers. There was a geographical heterogeneity: the risk of hip fractures associated with current smoking increased with latitude, i.e. the risk was higher in Northern Europe and the USA than in Southern Europe and countries close to the equator. CONCLUSIONS: Smoking is associated with an increased overall fracture risk, an increased risk of hip and spine but not wrist fractures. Cessation of smoking seems associated with a decrease in fracture risk. The impact of smoking varied geographically with an increase with latitude.     

Differential effects of NOD2 polymorphisms on colorectal cancer risk: a meta-analysis

Introduction

Since Kurzawski et al. described an association between the 3020insC NOD2 single nucleotide polymorphism and the risk of colorectal cancer(CRC) in 2004, reports published in the past several years have controversial results regarding the relationship between the development of CRC and NOD2 gene polymorphisms. To clarify the potential role of NOD2 P286S, R702W, G908R, and 3020insC polymorphisms in CRC patients, we have undertaken a systematic review and meta-analysis of published articles.

Materials and methods

Studies reporting on NOD2 polymorphisms and CRC were searched in the PubMed, EMBASE, and the Science Citation Index from the inception of each database to May, 2009. The search strategy included the keywords “CRC”, “colon cancer”, “rectal cancer”, “polymorphism”, and “NOD2/CARD15”.

Result

Eight eligible case-control studies about Caucasians from four countries contributed data on 5,888 subjects (cases: 3,524; controls: 2,364). Compared to the wild genotype, the R702W, G908R, and 3020insC polymorphisms were associated with an increased risk of CRC (odds ratio (OR): 1.59, 1.98, 1.44; 95% confidence interval (CI): 1.09–2.32, 1.14–3.44, 1.13–1.84; P?=?0.02, 0.01, 0.003). However, P268S polymorphism did not influence CRC risk (OR: 1.27; CI: 0.32–5.00; P?=?0.73).

Conclusions

These findings indicate that NOD2 R702W, G908R, and 3020insC polymorphisms contribute to CRC susceptibility in Caucasians. Meta-analysis of these polymorphisms in NOD2 gene will help determine their role in CRC carcinogenesis.