Polymorphisms of matrix metalloproteinase-7 and chymase are associated with susceptibility to and progression of gastric cancer in Japan

Background  Matrix metalloproteinases (MMPs) are a family of enzymes that degrade most macromolecules making up the extracellular matrix. MMPs are involved in not only the gastric mucosal inflammatory response but also the pathogenesis of Helicobacter pylori-associated diseases. In the renin-angiotensin system, chymase (CMA) is related to gastric carcinogenesis and angiogenesis in H. pylori-infected patients. We aimed to clarify the association of MMP-7-181 and CMA/B polymorphisms with susceptibility to gastric cancer and cancer progression in H. pylori-infected patients. Methods  We assessed the MMP-7-181 and CMA/B polymorphisms in H. pylori-positive patients with gastric cancer (n = 160), gastric ulcer (n = 157), duodenal ulcer (n = 121), and H. pylori-positive gastritis alone as controls (n = 156). Results  For gastric cancer risk, the age-and sex-adjusted odds ratio (OR) of the MMP-7-181 G allele carrier relative to the A/A genotype was significantly increased [OR, 2.32; 95% confidence interval (CI), 1.24–4.35], especially in patients with noncardia cancer (OR, 2.31; 95% CI, 1.22–4.36) and those with clinical stage III or IV cancer (OR, 3.66; 95% CI, 1.54–8.73). Carriage of the CMA/B A allele was significantly associated with gastric cancer development (OR, 1.73; 95% CI, 1.10–2.71). Simultaneous carriage of both the MMP-7-181 G allele and the CMA/B A allele dramatically increased the gastric cancer risk (OR, 8.18; 95% CI, 2.79–23.93). Conclusions  In Japan, carriage of the MMP-7-181 G allele and of the CMA/B A allele were each associated with an increased risk for H. pylori-related noncardia gastric cancer development. MMP-7-181 and CMA/B genotyping tests might be useful tools for screening for individuals with higher gastric cancer risk.     

Association and Interaction of −58C>T and ±9 bp Polymorphisms of BDKRB2 Gene Causing Susceptibility to Essential Hypertension

Introduction. Bradykinin, a vasodilator by nature has been documented to have a protective role against hypertension and cardiovascular complications. Polymorphisms of bradykinin B2 receptor (BDKRB2) gene are reported to be predisposing factors for hypertension. Evaluation of the association between ?58C>T and ±9 bp polymorphisms of BDKRB2 with essential hypertension (EHT) was attempted. Methods. Two hundred and fourteen primary hypertensives and 249 controls were genotyped for the selected markers by polymerase chain reaction, gel electrophoresis (±9 bp), and SSCP (?58C>T). Results. While ?58C>T polymorphism did not reveal any association with EHT, ±9 bp polymorphism showed a significant association with high risk for heterozygotes (+9/?9) when tested against the pooled frequencies of homozygotes (OR [odds ratio] = 1.63, 95% confidence interval [CI] = 1.12–2.38, P = .02), and this risk was 1.7 folds high in males (OR = 1.74, 95% CI = 1.05–2.86, P = .06) and 1.9 folds high in familial cases (OR = 1.96, 95% CI = 1.09–3.53, P = .04). In contrast, significant protective effect was observed for ?9/–9 genotype against EHT when tested under dominant model in general (OR = 0.59, 95% CI = 0.41–0.86, P = .01), in males (OR = 0.49, 95% CI = 0.30–0.82, P = .01), and in familial cases (OR = 0.50, 95% CI = 0.28–0.89, P = .04). Significant risk for +9 bp allele was observed in general (OR = 1.39, 95% CI = 1.05–1.86, P = .04) and in males (OR = 1.65, 95% CI = 1.13–2.41, P = .02). The interaction information analysis revealed a synergistic effect between the two polymorphisms contributing to EHT. +9/+9 genotype of ±9 bp polymorphism when present in combination with CC genotype of ?58C>T polymorphism showed 2.2-fold higher risk for developing EHT. Conclusions. The results suggest that allele +9 bp might be a risk factor for EHT in general and specially in males. Markers ?58C>T and ±9 bp may act synergistically causing susceptibility to EHT.     

Elevated risk of colorectal cancer associated with the AA genotype of the cyclin D1 A870G polymorphism in an Indian population

Purpose: To investigate whether the common cyclin D1 (CCND1) A870G polymorphism is a risk factor for colorectal cancer (CRC) in an Indian population. Methods: In this study, 301 newly diagnosed CRC patients and 291 healthy control subjects were genotyped by the PCR-RFLP method. Genotype frequencies were compared between cases and controls, and the association of genotypes with CRC was studied. Results: The CCND1 870 A allele was more frequently observed in CRC patients than controls (0.63 vs. 0.56, P=0.01), and after adjustment for age, sex, smoking habits, family history, family income and the consumption of meat, fish, vegetables and fruit, an increased risk was observed for the AA genotype compared to the GG+AG genotype (OR=1.56; 95% CI: 1.10–2.21). The increased risk were also found for colon (OR=1.96; 95% CI: 1.08–3.57) and rectal cancer (OR=1.51; 95% CI: 1.04–2.19). No correlation was observed between genotypes and age of diagnosis of CRC (49.9, 48.7 and 49.4 years for the GG, AG and AA genotypes, respectively; P=0.84). Multivariate analysis also revealed a stronger positive association with the AA genotype among patients with high meat intake (OR=2.67; 95% CI: 1.29–5.51), and particularly significant inverse associations with the GG+AG genotypes were also found for those with high vegetable consumption (OR=0.46; 95% CI: 0.27–0.79 of 2–3 servings/day, and OR=0.31; 95% CI: 0.18–0.53 for >3 servings/day) and fish intake (OR=0.48; 95% CI: 0.28–0.82). Conclusion: These data support the hypothesis that the CCND1 A870G polymorphism may increase the risk of CRC in our Indian population.     

Novel interleukin 1β polymorphism increased the risk of gastric cancer in a Korean population

Background Polymorphisms in the gene for interleukin 1 (IL-1B) have been found to increase the risks of gastric cancer and its precursors in response to Helicobacter pylori infection in white populations. However, there has been no independent confirmation of the role of IL-1B markers in gastric cancer patients from Asian populations. Moreover, there have been conflicting data regarding the effect of IL-1B-511/-31 on the risk of gastric cancer or its precursors in Asian populations. Therefore, we assessed an additional polymorphism in the promoter region of IL-1B at position-1473 with the IL-1B-511/-31 polymorphisms in a Korean population.Methods In a case-control study, including 331 gastric cancer cases and 433 controls, we assessed the association between the three polymorphisms and the risk of gastric cancer. All genotyping was performed in duplicate. To assess the DNA-binding activity of IL-1B-1473 in vitro, we performed an electrophoretic mobility shift assay (EMSA).Results When cases were divided according to the histologic type of the tumor, a significant difference in genotype frequencies for IL-1B-1473 was observed only between intestinal-type cases and controls (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.0–3.5 and OR 2.1 and 95% CI, 1.1–4.2 in the CG and GG genotypes, respectively). In the cases, there was a deviation from Hardy-Weinberg equilibrium in the IL-1B-511/-31 loci confined to the intestinal type, due to the excess of heterozygotes. The IL-1B-1473G allele showed decreased binding to nuclear extract, indicating a wearker promoter activity on EMSA.Conclusions We identified a novel single-nucleotide polymorphism, 1473CG, in the IL-1B promoter that was significantly associated with gastric cancer among Koreans. Our results also suggest that the association between IL-1B polymorphism and an increased risk of gastric cancer may depend on the histologic type of gastric cancer.     

CYP2C19 polymorphisms in patients with gastric and colorectal carcinoma

Background It has been reported that up to 80% of human cancer arise as a consequence of environmental exposure and host susceptibility factors. Environmental carcinogens are predominantly metabolized by the cytochrome P450 (CYP) superfamily of drug-or xenobiotic-metabolizing enzymes. Genetic variations in these enzymes affect individuals' susceptibility to carcinogens. Aim of the study The aim of this study was to evaluate the relationship between CYP2C19 polymorphism and susceptibility to these cancers by means of CYP2C19 genotyping among Turkish subjects. Methods DNA of subjects were isolated from leukocytes by high pure template preparation kit (Roche Diagnostics, GmbH, Mannheim, Germany) and genotypes were detected by LightCycler CYP2C19 Mutation Detection Kit by real-time PCR with LightCycler instrument (Roche Diagnostics, cat. no. 3113914). Results Being male was associated with a 3.5-fold (OR: 4.27, CI: 2.27–8.05) and 4.27-fold (OR: 3.50, CI: 1.948–6.301) risk for colorectal and gastric carcinoma, respectively. The CYP2C19 ^* 3 heterozygote genotype was not found in either gastric or colorectal carcinoma patients. Although the frequency of CYP2C19^*2 heterozygote genotype is high in patients with gastric and colorectal carcinoma, it is not significantly associated with cancer (OR: 1.79, CI: 0.829–3.865 and OR: 1.998, CI: 0.961–4.154, respectively). Conclusion Although the frequency of CYP2C19 ^* 2 heterozygote genotype is high in our patients with gastric and colorectal carcinoma, there is no the relationship between CYP2C19 polymorphism and susceptibility to these cancer.     

Helicobacter pylori infection in combination with the serum pepsinogen I/II ratio and interleukin-1β-511 polymorphisms are independent risk factors for gastric cancer in Thais

Background Thailand has the lowest incidence of gastric cancer in the world. Helicobacter pylori infection, a low serum pepsinogen I/II ratio, and interleukin (IL)-1β-511 polymorphisms are suspected to be risk factors for gastric cancer. Methods A total of 167 Thais, comprising 56 cancer patients and 111 volunteers without cancer, underwent an esophagogastroduodenoscopic examination and three fixed-point biopsies; a cancer tissue biopsy was also done, and blood samples were collected. The subjects without cancer were divided into normal subjects and chronic gastritis patients. IL-1β-511 polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism, and the serum levels of pepsinogen I and II were determined by a radioimmunoassay. Helicobacter pylori IgG antibody and tissue pathology were tested in all groups. Results The pepsinogen I/II ratio was significantly lower in the gastric cancer group than in the normal and chronic gastritis groups [odds ratio (OR), 2.3; 95% confidence interval (CI), 1.10–4.80; P = 0.025]. Gastric cancer patients were positive for the H. pylori IgG antibody more frequently than negative (OR, 2.946; 95% CI, 1.4–6.39; P = 0.005). However, only 15 (27%) cancer patients were both positive for H. pylori IgG antibody and had low serum pepsinogen I/II. The C/C genotype was found more frequently in the gastric cancer group than in the group with a normal gastric mucosa (OR, 0.64; 95% CI, 0.50–0.81; P = 0.014). Conclusions A low serum pepsinogen I/II ratio combined with positivity for H. pylori IgG, and a IL-1β-511 C/C genotype may be independent risk factors for gastric cancer in Thais. Presented at the 19th World Congress of the International Society of Digestive Surgery, Pacifico Yokohama, Japan, December 8–11, 2004 (Helicobacter pylori Symposium)     

Impact of pepsinogen C polymorphism on individual susceptibility to gastric cancer and its precancerous conditions in a Northeast Chinese population

Purpose  Human pepsinogen C (PGC) is an aspartic protease produced specifically by the gastric mucosa, and is considered as a mature marker of gastric epithelium. This study examined the contributions of PGC polymorphisms and the Helicobacter pylori (H. pylori) infection to the risk of gastric cancer (GC), and its precancerous conditions in a Northeast Chinese population. Methods  The PGC insertion/deletion polymorphism was evaluated by polymerase chain reaction analysis, followed by direct DNA sequencing in 564 cases of GC, atrophic gastritis (AG), gastric ulcer (GU) and superficial gastritis (as control). All cases were frequency-matched 1:1 by gender and age (±5). H. pylori infection was identified by serum anti-H. pylori IgG measurement through enzyme-linked immunosorbent assay. Results  Patients with a homozygous PGC allele 1 genotype had a significant risk of AG [adjusted odds ratio (OR) 3.11; 95% confidence interval (CI) 1.44–6.71] or of GC (OR 3.00; 95% CI 1.38–6.51), and a significantly elevated risk of intestinal metaplasia (OR 1.90, 95% CI 1.11–3.27). PGC polymorphism with H. pylori infection increased risk of GU (OR 8.69; 95% CI 1.01–74.69), and AG (OR 11.12; 95% CI 1.37–90.84) or GC (OR 10.61; 95% CI 1.28–87.79) in a super-multiplicative manner. The S value was 5.40, 6.48 and 4.34; and the AP value was 72.09, 7.00 and 69.69%, respectively. Conclusions  The PGC gene polymorphism increases an individual’s susceptibility to GC and its precancerous conditions. Moreover, the PGC gene polymorphism shows a positive link to H. pylori infection in the development of GC.     

Influence of Peroxisome Proliferator-activated Receptor (PPAR)γ Plo12Ala Polymorphism as a Shared Risk Marker for Both Gastric Cancer and Impaired Fasting Glucose (IFG) in Japanese

Activation of peroxisome proliferator-activated receptor γ (PPARγ) has been shown to inhibit the proliferation of gastric cancer cells. A common polymorphism at codon 12 of this gene (Pro12Ala) has been shown to confer protection against diabetes and colorectal cancer. We investigated the influence of PPARγ gene Plo12Ala polymorphism on the risk of gastric cancer and on the severity of Helicobacter pylori-induced gastritis as well as impaired fasting glucose (IFG) in Japanese. About 215 patients with gastric cancer (GC) and 201 patients without GC enrolled in this study. Plo12Ala polymorphism of PPARγ was investigated by PCR-RFLP in all of the subjects. The gastritis score of noncancerous antral mucosa was calculated by the updated Sydney system. The diagnosis of IFG was based on repeated evidence of serum fasting glucose (SFG) concentration of greater than or equal to 110 mg/dl. The Plo12Ala genotype of PPARγ showed a significantly higher frequency in GC patients than in controls (OR = 2.43; 95%CI = 1.04–5.67). In contrast, the Plo12Ala genotype held a lower risk of IFG (OR = 0.33; 95%CI = 0.13–0.83). The same genotype was associated with an increased risk of non-cardiac gastric cancer (OR = 2.39; 95%CI = 1.02–5.65), lower third gastric cancer (OR = 3.56; 95%CI = 1.31–9.71), advanced cancer (OR = 2.93; 95%CI = 1.13–7.58), and Lauren’s intestinal cancer (OR = 2.94; 95%CI = 1.13–7.66). Among 151 gastric cancer subjects, the atrophy and metaplasia scores of the antral mucosa adjacent to cancer showed a tendency to be higher in those with the12Ala allele. Our study suggests that the PPARγ Pro12Ala polymorphism may be a shared risk marker of both IFG and gastric cancer in Japanese.     

Association between gastric cancer and -1993 polymorphism of TBX21 gene

AIM: To investigate the association between the polymorphism of TBX21 gene and the risk of gastric cancer in a Chinese population.METHODS: The -1993 polymorphism located in TBX21 gene promoter region was identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The risk between TBX21 gene genotype and gastric cancer was determined by multivariate logistic regression analysis in 220 gastric cancer patients and 262 cancer-free controls matched by age, sex and ethnicity.RESULTS: Compared with the TBX21 -1993TT genotype, the -1993CC genotype exhibited a significantly elevated risk for gastric cancer [Odds ratio (OR) = 3.42, 95% confidence interval (CI): 1.41-8.31]. The relationship between the -1993 polymorphic genotype and the invasive status such as lymph node and distant metastasis was found among the gastric cancer patients (OR = 4.02, 95% CI: 1.87-8.66; OR = 7.02, 95% CI: 3.44-14.34, respectively).CONCLUSION: TBX21 -1993 polymorphism might contribute to the risk of gastric cancer, especially to the distant metastasis.     

Studies of the association of the GNB3 825C>T polymorphism with components of the metabolic syndrome in white Danes

Aims/hypothesis The 825C>T polymorphism in the gene encoding the G protein β3 subunit (GNB3) causes enhanced G protein activation and increased in vitro cell proliferation. This polymorphism is also repeatedly associated with an increased risk of hypertension and has been studied in relation to obesity with divergent results. Only a few association studies have investigated whether this polymorphism is related to type 2 diabetes or the metabolic syndrome. We estimated the impact of the GNB3 825C>T polymorphism in relatively large-scale association studies of common phenotypes of the metabolic syndrome. Materials and methods The GNB3 825C>T polymorphism was genotyped in 7,518 white Danish subjects using mass spectrometry analysis of PCR products. Case–control studies were undertaken for obesity, hypertension, type 2 diabetes and the metabolic syndrome, and a meta-analysis including data from the present study and previous studies of hypertension was performed. Quantitative trait studies of metabolic variables were carried out in 4,387 glucose-tolerant subjects. Results We observed minor differences in 825C>T genotype distributions for type 2 diabetes (CC/CT/TT 49/41/10% (control) vs 46/46/9% (cases), respectively, p=0.007); however, after correction for multiple testing, these were not statistically significant. No association was found with hypertension, obesity or the metabolic syndrome. Curiously, the T allele was associated with nominally lower systolic and diastolic blood pressure levels—a finding in contrast with most previous studies–but not with other metabolic variables. Meta-analysis demonstrated a high degree of heterogeneity between study populations of different ethnic origin. Although there was a tendency towards an increased risk of hypertension among 825T allele carriers, this was not statistically significant. Conclusions/interpretation The present study suggests no major involvement of the GNB3 825C>T polymorphism in components of the metabolic syndrome.     

Significant association between toll‐like receptor gene polymorphisms and gallbladder cancer

Background: Toll‐like receptors (TLRs) are evolutionarily conserved cell surface receptors of innate immune system. Various polymorphisms in TLR genes have been identified and associated with susceptibility toward various malignancies such as prostate cancer, gastric cancer and colorectal cancer. The present study was undertaken to examine the potential association of two polymorphisms in TLR2 and TLR4 genes with gallbladder cancer (GBC) susceptibility. Methods: Genotypes and allelic frequencies of TLR2 and TLR4 gene polymorphisms were determined for 233 GBC patients and 257 cancer‐free controls randomly selected from the population, using polymerase chain reaction–restriction fragment length polymorphism. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated in a multivariate logistic regression analysis for the association of TLR polymorphisms with GBC. Results: ‘del’ allele carriers of TLR2 (Δ22) polymorphism were associated with a 1.54‐fold increased risk for GBC (95% CI=1.02–2.24; P_trend=0.091). The TLR4 Ex4+936C >T polymorphism (g.14143C>T; rs4986791) was also found to be significantly associated with the overall higher risk of GBC under a dominant mode of inheritance (OR=1.96; 95% CI=1.11–2.26; P_trend=0.021). The false‐positive report probability (FPRP) approach advocated that these results were noteworthy (FPRP<0.5). Subgroup analysis showed that TLR4 Ex4+936C>T polymorphism was associated with an increased risk of GBC in females and GBC cases with gallstones (OR=2.85 and 2.22 respectively). Conclusion: In summary, low‐penetrance variants in TLR genes may alter the susceptibility towards gallbladder cancer.     

Polymorphisms of interleukin-1 and interleukin-2 genes in patients with gastric cancer in Korea

Background and Aim: Interleukin (IL)‐1 gene polymorphism has been reported to be associated with the increment of gastric cancer (GC) and the decrement of duodenal ulcers (DU). In addition, IL‐2 is known to induce Helicobacter pylori (H. pylori)‐associated gastric atrophy, but it is not known whether IL‐2 gene polymorphism increases the risk of GC (GC) or peptic ulcer diseases. Therefore, we compared the genotypes of IL‐1B, IL‐1RN, and IL‐2 gene polymorphisms with risk of gastric ulcers (GU), GC, and DU in Korean patients. Methods: In total, 116 GU, 122 GC, and 104 DU patients were included consecutively and compared with 100 healthy controls. Polymorphisms of the IL‐1B‐511/‐31 gene, the penta‐allelic variable number of tandem repeats of the IL‐1RN gene, and the IL‐2‐330 gene were analyzed by polymerase chain reaction with restriction fragment length polymorphism or confronting two‐pair primers methods. Results: The age–sex‐adjusted odds ratios (OR) for the IL‐1B‐511 T genotype relative to the C/C genotype (OR = 0.82, 95% confidence interval [CI] 0.41–1.65), IL‐1RN*2 genotype relative to the L/L genotype (OR = 0.85, 95% CI 0.41–1.78), and IL‐2‐330 T genotype relative to the G/G genotype (OR = 1.94, 95% CI 0.76–4.96) were not increased in GC. There was also no significant difference in the genotypes of these cytokine polymorphisms between the study group (GU or DU) and control group. In addition, genotypic frequency was not associated with H. pylori positivity and histological type of GC. Conclusion: IL‐1B‐511, IL‐1RN, and IL‐2 genetic polymorphisms were not important contributors to the pathogenesis of GU, GC, and DU in Korean patients.     

Human NAD(P)H:quinone oxidoreductase 1 (NQO1) and sulfotransferase 1A1 (SULT1A1) polymorphisms and urothelial cancer risk in Taiwan

Purpose To investigate whether the NAD(P)H:quinone oxidoreductase 1 (NQO1) and sulfotransferase 1A1 (SULT1A1) polymorphisms are associated with urothelial cancer (UC) risk in Taiwan. Methods In this study, 600 study subjects (including 300 UC patients and 300 cancer-free controls) were recruited from September 1998 to December 2005. We analyzed the NQO1 and SULT1A1 polymorphisms by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. A comprehensive interview was conducted to collect information, including baseline characteristics and cigarette smoking status. We used an unconditional multivariate logistic regression to calculate the odds ratio (OR) and 95% confidence interval (CI). Results We found a significantly increased UC risk in study subjects with the NQO1 C/T and T/T genotypes (OR = 1.5; 95% CI: 1.03–2.1). A significantly increased UC risk was found in those with the SULT1A1 G/G genotype (OR = 2.0; 95% CI: 1.3–3.2). Subjects who had ever smoked with either the NQO1 C/T and T/T genotypes or the SULT1A1 G/G genotype had significantly increased UC risks, showing ORs of 3.0 and 5.3, respectively. Subjects carrying both the NQO1 C/T and T/T genotypes and the SULT1A1 G/G genotype had a significantly increased UC risk (OR = 3.7; 95% CI, 1.4–9.7). Moreover, those who had ever smoked with both the NQO1 C/T and T/T genotypes and the SULT1A1 G/G genotype had the highest UC risk (OR = 8.6; 95% CI: 2.5–29.7). Conclusions These findings suggest that NQO1 and SULT1A1 polymorphisms are associated with the risk of UC, particularly among those who have ever smoked.     

Integrin alpha-2 and beta-3 gene polymorphisms and colorectal cancer risk

Background and aims  Integrins such as α₂β₁, α_IIbβ₃, and α_vβ₃ have been suggested as key players for cancer development and progression. Several polymorphisms affecting these molecules, two in integrin α₂ (ITGA2 807C>T and 1648G>A) and one in β₃ (ITGB3 176T>C), influence their levels, structure, and possibly their function. To analyze the role of ITGA2 and ITGB3 polymorphisms for colorectal cancer risk and clinical presentation, we performed a case–control study. Materials and methods  Four hundred thirty-three colorectal cancer patients and 433 healthy sex- and age-matched control subjects were investigated. ITGA2 and ITGB3 polymorphisms were determined by 5′-nuclease assays. Results/findings  The ITGA2 807C>T polymorphism was associated with reduced colorectal cancer risk. In a codominant model, the odds ratio for each additional 807-T allele for colorectal cancer was 0.77 (95% confidence interval 0.64–0.94; p = 0.011). The ITGA2 1648G> and the ITGB3 176T>C polymorphism were not associated with colorectal cancer. None of the three polymorphisms investigated was associated with tumor size, histological grade, presence of primary lymph node metastases, tumor stage, or age at diagnosis. Interpretation/conclusion  We conclude that the ITGA2 807C>T polymorphism may be associated with reduced colorectal cancer risk. Armin Gerger and Günter Hofmann contributed equally to this work.     

A multigenic study on breast cancer risk associated with genetic polymorphisms of ER Alpha, COMT and CYP19 gene in BRCA1/BRCA2 negative Shanghai women with early onset breast cancer or affected relatives

High penetrance genes such as BRCA1 or BRCA2 account for only a small proportion of familial breast cancer in Chinese population. Estrogen has been proposed to participate in the proliferation and carcinogenesis of breast cancer. To investigate the association between genetic polymorphisms in genes encoding estrogen metabolizing, estrogen biosynthesizing enzyme and estrogen receptor and the breast cancer risk in BRCA1/BRCA2 negative Shanghai women, we conducted a case-control study including 114 cases with early-onset breast cancer or affected relatives and 121 healthy controls. The genotypes of estrogen receptor alpha (ERα), aromatase (CYP19), and catechol-O-methyltransferase (COMT) genes were analyzed by direct DNA-sequencing. Compared with H/H genotype of COMT Val158Met, COMT Val158Met L/L genotype was associated with a nonsignificantly elevated risk of breast cancer (OR: 3.72; 95% CI: 0.99–13.96, P = 0.051). There was no statistically significant difference in genotype frequency of the ERα PvuII, ERα XbaI and CYP19 Arg264Cys polymorphism between controls and cases. When stratified by menopausal status, COMT Val158Met L/L (OR: 11.94; 95% CI: 1.48–96.03, P = 0.02) and ERα PvuII P/p genotypes (OR: 2.67; 95% CI: 1.01–7.05, P = 0.048) were associated with a significantly elevated risk of breast cancer in premenopausal women, and there was a association between ERα XbaI x/x genotype and the nonsignificantly increased risk of breast cancer in premenopausal women (OR: 6.88; 95% CI: 0.80–59.15, P = 0.079). The multigenic analysis showed maybe these high risk genotypes had combined effect on breast cancer risk. Our findings suggest that polymorphism of genes involving estrogen-metabolizing pathway, estrogen- biosynthesizing pathway and estrogen receptor pathway may play an important role in the etiology of BRCA1/2 negative breast cancer with hereditary predisposing factors. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Zhen Hu and Chuan-Gui Song contributed equally to the work.     

Inducible nitric oxide synthase polymorphism is associated with the increased risk of differentiated gastric cancer in a Japanese population

INTRODUCTION Gastric cancer is the second most frequent cancer in the world, accounting for a large proportion of cancer cases in Asia, Latin America, and some countries in Europe[1]. H pylori strains carrying the cytotoxin-associated gene A (cagA) are st…     

TREX1 polymorphisms associated with autoantibodies in patients with systemic lupus erythematosus

Three-prime repair exonucleases 1 and 2 (TREX1 and TREX2) play a role in the metabolism and clearance of DNA. The objective of this study was to confirm whether polymorphisms of TREX1 and TREX2 are associated with genetic susceptibility to systemic lupus erythematosus (SLE), and examine associations with autoantibodies (auto-Abs) in SLE. We investigated the genetic variants in 24 Korean individuals by direct sequencing. The genotype distributions of single-nucleotide polymorphisms (SNPs) and haplotypes were analyzed with multiple logistic regression models while controlling for covariates. We identified 12 and 5 SNPs of TREX1 and TREX2, of which −20260G>C, −389T>C, −381C>T, and +531C>T SNPs of TREX1; −23386G>C, −14703G>A, −7279C>T, and +1747C>T SNPs of TREX2; and each of three haplotypes were selected for larger scale genotyping (n = 1,053). No statistically significant association with the risk of SLE was observed in TREX1 and TREX2. TREX1 polymorphism −20260G>C showed protective effect on the production of anti-Ro Ab, and +531C>T in exon 16 and ht2 [G–T–C–T] showed also protective effect on the production of anti-dsDNA Ab, although the effect of +531C>T disappeared after multiple correction. An erratum to this article can be found at     

Multi-drug resistance 1 polymorphism is associated with reduced risk of gastric cancer in the Japanese population

BACKGROUND AND AIMS: Host genetic factors play a key role in gastric carcinogenesis, but the mechanism has not been clarified. The multi-drug resistance 1 (MDR1) gene mediates the expression of P-glycoprotein, which has a role in active transport of various substrates, including xenobiotics, and thus has a protective function in various tissues and organs like gastrointestinal epithelial cells. C3435T polymorphism in exon 26 of the MDR1 gene influences P-glycoprotein expression and activity in the gastrointestinal tract. We investigated the influences of MDR1 gene polymorphism on the risk of gastric cancer. METHOD: The study was performed on 157 patients with gastric cancer (GC) and 104 patients without GC as the control group. C3435T polymorphism of MDR1 was investigated by PCR-RFLP in all of the patients. RESULTS: The MDR1 3435 TT genotype showed a significantly higher frequency in controls than in GC patients (OR = 0.43; 95% CI = 0.23-0.79). There were no significant differences of the CT and CC genotype frequencies between GC patients and controls. We also found that the 3435TT genotype of MDR1 was associated with a lower risk of non-cardiac cancer (OR = 0.42; 95% CI = 0.23-0.79), middle-third cancer (OR = 0.36; 95% CI = 0.17-0.77), advanced cancer (OR = 0.31; 95% CI = 0.13-0.73), venous invasion (OR = 0.30; 95% CI = 0.10-0.91), and lymph node metastasis (OR = 0.28; 95% CI = 0.13-0.65). CONCLUSION: Our data suggest that 3435T/T polymorphism of MDR1 is associated with a reduced risk of gastric cancer in the Japanese population.     

Lack of association between TNF 238 G/A polymorphism and type 2 diabetes: a meta-analysis

The aim of this meta-analysis was to determine the nature of the association between TNF 238 G/A polymorphism and the risk for T2D. We searched databases updated on January 2009 for all publications on the association between this variation and T2D. Data on genotypes and the numbers of cases and controls were assessed using Review Manager 4.2. Meta-analysis of the overall and specific populations was conducted, and odds ratios (OR) and 95% confidence intervals (95% CI) were calculated in the fixed-effect model. I ² statistic was calculated to examine heterogeneity, and publication bias was evaluated by Egger test. The overall OR (95% CI) for AA and GA genotypes versus GG genotype for TNF-α-238 was 1.15 (0.92–1.44), which in European and Asian populations were 1.18 (0.92–1.51) and 1.13 (0.62–2.04), respectively. This first meta-analysis of data from the current and published studies did not detect any association between the polymorphism of TNF 238 G/A and risk for T2D.     

Association of leptin -2548G/A and leptin receptor Q223R polymorphisms with increased risk for oral cancer

Purpose  We investigated the possible association of DNA polymorphisms −2548G/A and Q223R in the leptin (LEP) and leptin receptor (LEPR) genes, respectively, which both affect the amount of circulating cytokine-type hormone leptin, with risk for development of oral cancer. Methods  Polymerase chain reaction-based restriction analysis was performed in DNA samples of 150 patients with oral squamous cell carcinoma (OSCC) and 152 healthy control subjects of equivalent gender, age, and ethnicity (Greeks and Germans). Results  Compared to controls, the homozygous high gene expression genotype A/A of the LEP −2548G/A polymorphism was significantly increased in the subgroups of patients with advanced cancer stages (P = 0.0001; OR 9.0, 95% CI 2.62–30.89), with a positive family history of cancer (P = 0.0346; OR 3.55, 95% CI 1.15–11.01), without tobacco abuse (P = 0.0051; OR 9.69, 95% CI 1.03–91.24), and without alcohol abuse (P = 0.0472; OR 2.16, 95% CI 0.87–5.37). The homozygous low-leptin-binding genotype G/G of the LEPR Q223R polymorphism was strongly associated with an increased risk for OSCC for all patients (P = 0.0028; OR 4.11, 95% CI 1.30–12.97) as well for most of the patient subgroups. Conclusions  The above findings are consistent with the growth-promoting role of leptin in cancer and its induction effect on angiogenesis and metastasis. This is the first study indicating the association of these LEP and LEPR gene polymorphisms with increased risk for OSCC.