Gene polymorphisms in the ornithine decarboxylase-polyamine pathway modify gastric cancer risk by interaction with isoflavone concentrations.

BACKGROUND: The study aimed to examine the association between genes encoding molecules in the ornithine decarboxylase (ODC)-polyamine pathway (ODC1, AMD1, NQO1, NOS2A, and OAZ2) and gastric cancer risk and whether the gene-phytoestrogen interaction modifies gastric cancer risk. METHODS: Among 76 gastric cancer cases and their 1:4 matched controls within the Korean Multi-center Cancer Cohort, a total of 30 SNPs in five genes involved in the ODC pathway were primarily analyzed. The second-stage genotyping in 388 matched case-control sets was conducted to reevaluate the significant SNPs interacting with phytoestrogens during the primary analysis. The summary odds ratios (ORs) [95 % confidence intervals (CIs)] for gastric cancer were estimated. Interaction effects between the SNPs and plasma concentrations of phytoestrogens (genistein, daidzein, equol, and enterolactone) were evaluated. RESULTS: In the pooled analysis, NQO1 rs1800566 showed significant genetic effects on gastric cancer without heterogeneity [OR 0.83 (95 % CI 0.70-0.995)] and a greater decreased risk at high genistein/daidzein levels [OR 0.36 (95 % CI 0.15-0.90) and OR 0.26 (95 % CI 0.10-0.64), respectively; p interaction < 0.05]. Risk alleles of AMD1 rs1279599, AMD1 rs7768897, and OAZ2 rs7403751 had a significant gene-phytoestrogen (genistein and daidzein) interaction effect to modify the development of gastric cancer. They had an increased gastric cancer risk at low isoflavone levels, but a decreased risk at high isoflavone levels (p interaction < 0.01). CONCLUSIONS: Our findings suggest that common variants in the genes involved in the ODC pathway may contribute to the risk of gastric cancer possibly by modulating ODC polyamine biosynthesis or by interaction between isoflavones and NQO1, OAZ2, and AMD1.

Soluble c-Met protein as a susceptible biomarker for gastric cancer risk: A nested case-control study within the Korean Multicenter Cancer Cohort.

This study was conducted to evaluate the relevance of the soluble form of c-Met protein, a truncated form of the c-Met membrane receptor involved in the CagA pathway, as a potential biomarker for gastric cancer. Among 290 gastric cancer case-control sets selected from the Korean Multicenter Cancer Cohort, the plasma concentrations of soluble c-Met protein were measured with enzyme-linked immunosorbent assays. Using analysis of variance and covariance models with age, sex, smoking, Helicobacter pylori infection, and CagA seropositivity, the mean concentrations of soluble c-Met protein between cases and controls were compared. To evaluate the association between gastric cancer and a c-Met protein level, odds ratios and 95% confidence intervals were estimated using conditional logistic regression models. Interactions between CagA-related genes and the soluble c-Met protein concentration were also investigated. The overall median plasma concentration of soluble c-Met among cases was significantly lower than those of controls (1.390 vs. 1.610 ng/mL, p < 0.0001). Closer to the onset of gastric cancer, the soluble c-Met protein level decreased linearly in a time-dependent manner (p for trend = 0.0002). The combined effects between the CagA-related genes and the soluble c-Met protein concentration significantly intensified risks for gastric cancer. Restricted analyses including cases that had been diagnosed within 1 year after entering the cohort had a fair degree of ability (area under the receiver operating characteristic curve of 0.73-0.77) to discriminate gastric cancer cases from normal controls. Our findings demonstrate the potential of the soluble form of c-Met protein as a novel biomarker for gastric cancer. The beneficial effects of a high soluble c-Met concentration in human plasma are strongly supported.

Genetic susceptibility factors on genes involved in the steroid hormone biosynthesis pathway and progesterone receptor for gastric cancer risk.

BACKGROUND: The objective of the study was to investigate the role of genes (HSD3B1, CYP17A1, CYP19A1, HSD17B2, HSD17B1) involved in the steroid hormone biosynthesis pathway and progesterone receptor (PGR) in the etiology of gastric cancer in a population-based two-phase genetic association study. METHODS: In the discovery phase, 108 candidate SNPs in the steroid hormone biosynthesis pathway related genes and PGR were analyzed in 76 gastric cancer cases and 322 controls in the Korean Multi-Center Cancer Cohort. Statistically significant SNPs identified in the discovery phase were re-evaluated in an extended set of 386 cases and 348 controls. Pooled- and meta-analyses were conducted to summarize the results. RESULTS: Of the 108 SNPs in steroid hormone biosynthesis pathway related genes and PGR analyzed in the discovery phase, 23 SNPs in PGR in the recessive model and 10 SNPs in CYP19A1 in the recessive or additive models were significantly associated with increased gastric cancer risk (p<0.05). The minor allele frequencies of the SNPs in both the discovery and extension phases were not statistically different. Pooled- and meta-analyses showed CYP19A1 rs1004982, rs16964228, and rs1902580 had an increased risk for gastric cancer (pooled OR [95% CI] = 1.22 [1.01-1.48], 1.31 [1.03-1.66], 3.03 [1.12-8.18], respectively). In contrast, all PGR SNPs were not statistically significantly associated with gastric cancer risk. CONCLUSIONS: Our findings suggest CYP19A1 that codes aromatase may play an important role in the association of gastric cancer risk and be a genetic marker for gastric cancer susceptibility.

Innate immunity and non-Hodgkin's lymphoma (NHL) related genes in a nested case-control study for gastric cancer risk.

OBJECTIVE: Genetic variants regulating the host immune system may contribute to the susceptibility for the development of gastric cancer. Little is known about the role of the innate immunity- and non-Hodgkin's lymphoma (NHL)-related genes for gastric cancer risk. This nested case-control study was conducted to identify candidate genes for gastric cancer risk for future studies. METHODS: In the Discovery phase, 3,072 SNPs in 203 innate immunity- and 264 NHL-related genes using the Illumine GoldenGateTM OPA Panel were analyzed in 42 matched case-control sets selected from the Korean Multi-center Cancer Cohort (KMCC). Six significant SNPs in four innate immunity (DEFA6, DEFB1, JAK3, and ACAA1) and 11 SNPs in nine NHL-related genes (INSL3, CHMP7, BCL2L11, TNFRSF8, RAD50, CASP7, CHUK, CD79B, and CLDN9) with a permutated p-value <0.01 were re-genotyped in the Replication phase among 386 cases and 348 controls. Odds ratios (ORs) for gastric cancer risk were estimated adjusting for age, smoking status, and H. pylori and CagA sero-positivity. Summarized ORs in the total study population (428 cases and 390 controls) are presented using pooled- and meta-analyses. RESULTS: Four SNPS had no heterogeneity across the phases: in the meta-analysis, DEFA6 rs13275170 and DEFB1 rs2738169 had both a 1.3-fold increased odds ratio (OR) for gastric cancer (95% CIs = 1.1-1.6; and 1.1-1.5, respectively). INSL3 rs10421916 and rs11088680 had both a 0.8-fold decreased OR for gastric cancer (95% CIs = 0.7-0.97; and 0.7-0.9, respectively). CONCLUSIONS: Our findings suggest that certain variants in the innate immunity and NHL-related genes affect the gastric cancer risk, perhaps by modulating infection-inflammation-immunity mechanisms that remain to be defined.

Interaction effects between genes involved in the AKT signaling pathway and phytoestrogens in gastric carcinogenesis: a nested case-control study from the Korean Multi-Center Cancer Cohort.

SCOPE: To investigate whether genes involved in AKT/nuclear factor kappa B signaling and/or gene-environment interactions between the genes and phytoestrogens may be susceptible factors for gastric cancer. METHODS AND RESULTS: The representative single nucleotide polymorphisms (SNPs) identified during the primary analysis (screening a total of 622 SNPs within ± 5 kbp of the 51 target gene locations) were further investigated in 317 matched case-control sets. The summary odds ratios (ORs) and 95% confidence intervals (CIs) for gastric cancer were calculated. Interaction effects between the SNPs and phytoestrogen biomarkers (genistein, daidzein, equol, and enterolactone) were computed. CDK1 rs4145643, FAS rs6586161, and FAS rs1468063 in the AKT signaling pathway presented significant genetic effects on gastric cancer (OR = 0.81 (95% CI: 0.66-0.99) for CDK1 rs4145643; OR = 1.27 (95% CI: 1.03-1.58) for FAS rs6586161; OR = 1.29 (95% CI: 1.03-1.56) for FAS rs1468063; Cochran Q statistics > 0.10). Risk alleles of FAS rs6586161, FAS rs1468063, MAP3K1 rs16886448, and MAP3K1 rs252902 showed significant interaction effects with enterolactone (p(interaction) < 0.05). CONCLUSION: CDK1 and FAS genes involved in AKT signaling and influenced by anti-carcinogenic property of phytoestrogens can play a role as susceptible genetic factors in gastric carcinogenesis. FAS and MAP3K1 genes significantly interact with enterolactone, thereby modifying the individual's risk for gastric cancer.

Genetic susceptibility on CagA-interacting molecules and gene-environment interaction with phytoestrogens: a putative risk factor for gastric cancer.

OBJECTIVES: To evaluate whether genes that encode CagA-interacting molecules (SRC, PTPN11, CRK, CRKL, CSK, c-MET and GRB2) are associated with gastric cancer risk and whether an interaction between these genes and phytoestrogens modify gastric cancer risk. METHODS: In the discovery phase, 137 candidate SNPs in seven genes were analyzed in 76 incident gastric cancer cases and 322 matched controls from the Korean Multi-Center Cancer Cohort. Five significant SNPs in three genes (SRC, c-MET and CRK) were re-evaluated in 386 cases and 348 controls in the extension phase. Odds ratios (ORs) for gastric cancer risk were estimated adjusted for age, smoking, H. pylori seropositivity and CagA strain positivity. Summarized ORs in the total study population (462 cases and 670 controls) were presented using pooled- and meta-analysis. Plasma concentrations of phytoestrogens (genistein, daidzein, equol and enterolactone) were measured using the time-resolved fluoroimmunoassay. RESULTS: SRC rs6122566, rs6124914, c-MET rs41739, and CRK rs7208768 showed significant genetic effects for gastric cancer in both the pooled and meta-analysis without heterogeneity (pooled OR = 3.96 [95% CI 2.05-7.65], 1.24 [95% CI = 1.01-1.53], 1.19 [95% CI = 1.01-1.41], and 1.37 [95% CI = 1.15-1.62], respectively; meta OR = 4.59 [95% CI 2.74-7.70], 1.36 [95% CI = 1.09-1.70], 1.20 [95% CI = 1.00-1.44], and 1.32 [95% CI = 1.10-1.57], respectively). Risk allele of CRK rs7208768 had a significantly increased risk for gastric cancer at low phytoestrogen levels (p interaction<0.05). CONCLUSIONS: Our findings suggest that SRC, c-MET and CRK play a key role in gastric carcinogenesis by modulating CagA signal transductions and interaction between CRK gene and phytoestrogens modify gastric cancer risk.

Ecological study for refrigerator use, salt, vegetable, and fruit intakes, and gastric cancer.

We used an ecological approach to determine the correlation between vegetable, fruit and salt intakes, refrigerator use, and gastric cancer mortality in Korean population. Information on fruit and vegetable intakes per capita from the National Health and Nutrition Survey, death certificate data from the National Statistical office, refrigerator per household data from Korean Statistical Information Service, and salt/sodium intake data from a cross-sectional survey were utilized. Correlation coefficients were calculated between vegetable and fruit intakes, refrigerator per household, and gastric cancer mortality and between salt and sodium intakes, and gastric cancer mortality and incidence in the four areas. With 5, 10, and 15 years lag time, refrigerator usage and fruit intake were negatively associated with gastric cancer mortality (p < 0.01), but vegetable intake was not associated with gastric cancer mortality. When estimates of salt/sodium intake evaluated by 24-h urine collection in four areas of Korea were compared to the gastric cancer mortality and incidence in these regions, positive correlation was shown between salt/sodium intake, and gastric cancer incidence and mortality. Negative associations between refrigerator use, fruit intake, and gastric cancer mortality and positive associations between salt/sodium intake and gastric cancer mortality and incidence were suggested.

Oncogenic CagA promotes gastric cancer risk via activating ERK signaling pathways: a nested case-control study.

BACKGROUND: CagA cellular interaction via activation of the ERK signaling pathway may be a starting point in the development of gastric cancer. This study aimed to evaluate whether genes involved in ERK downstream signaling pathways activated by CagA are susceptible genetic markers for gastric cancer. METHODS: In the discovery phase, a total of 580 SNPs within +/-5 kbp of 30 candidate genes were genotyped to examine an association with gastric cancer risk in the Korean Multi-center Cancer Cohort (100 incident gastric cancer case-control sets). The most significant SNPs (raw or permutated p value<0.02) identified in the discovery analysis were re-evaluated in the extension phase using unconditional logistic regression model (400 gastric cancer case-control sets). Combined analyses including pooled- and meta-analysis were conducted to summarize all the results. RESULTS: 24 SNPs in eight genes (ERK, Dock180, C3G, Rap1, Src, CrkL, Mek and Crk) were significantly associated with gastric cancer risk in the individual SNP analyses in the discovery phase (p<0.05). In the extension analyses, ERK rs5999749, Dock180 rs4635002 and C3G rs7853122 showed marginally significant gene-dose effects for gastric cancer. Consistently, final combined analysis presented the SNPs as significantly associated with gastric cancer risk (OR = 1.56, [95% CI: 1.19-2.06], OR = 0.61, [95% CI: 0.43-0.87], OR = 0.59, [95% CI: 0.54-0.76], respectively). CONCLUSIONS: Our findings suggest that ERK rs5999749, Dock180 rs4635002 and C3G rs7853122 are genetic determinants in gastric carcinogenesis.

Reliability of quadruplicated serological parameters in the korean genome and epidemiology study.

OBJECTIVES: The aim of this study was to evaluate whether clinical test values from different laboratories in the Korean Genome and Epidemiology Study (KoGES) can be integrated through a statistical adjustment algorithm with appropriate intra- and inter-laboratory reliability. METHODS: External quality control data were obtained from the Korean Society for Laboratory Medicine and quadruplicated standardized serological samples (N=3,200) were manufactured in order to check the intra- and inter-laboratory reliability for aspartic acid transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transpeptidase (γ-GTP), blood urea nitrogen (BUN), creatinine, uric acid (UA), fasting blood sugar (FBS), cholesterol, and triglyceride (TG). As an index of inter- and intra-rater reliability, Pearson's correlation coefficient, intraclass correlation coefficients and kappa statistics were estimated. In addition, to detect the potential for data integration, we constructed statistical compensation models using linear regression analysis with residual analysis, and presented the R-square values. RESULTS: All correlation coefficient values indicated good intra- and inter-laboratory reliability, which ranged from 0.842 to 1.000. Kappa coefficients were greater than 0.75 (0.75-1.00). All of the regression models based on the trial results had strong R-square values and zero sums of residuals. These results were consistent in the regression models using external quality control data. CONCLUSION: The two laboratories in the KoGES have good intra- and inter-laboratory reliability for ten chemical test values, and data can be integrated through algorithmic statistical adjustment using regression equations.

Estimation of nationwide vaccination coverage and comparison of interview and telephone survey methodology for estimating vaccination status.

This study compared interview and telephone surveys to select the better method for regularly estimating nationwide vaccination coverage rates in Korea. Interview surveys using multi-stage cluster sampling and telephone surveys using stratified random sampling were conducted. Nationwide coverage rates were estimated in subjects with vaccination cards in the interview survey. The interview survey relative to the telephone survey showed a higher response rate, lower missing rate, higher validity and a less difference in vaccination coverage rates between card owners and non-owners. Primary vaccination coverage rate was greater than 90% except for the fourth dose of DTaP (diphtheria/tetanus/pertussis), the third dose of polio, and the third dose of Japanese B encephalitis (JBE). The DTaP4: Polio3: MMR1 fully vaccination rate was 62.0% and BCG1:HepB3:DTaP4:Polio3:MMR1 was 59.5%. For age-appropriate vaccination, the coverage rate was 50%-80%. We concluded that the interview survey was better than the telephone survey. These results can be applied to countries with incomplete registry and decreasing rates of landline telephone coverage due to increased cell phone usage and countries. Among mandatory vaccines, efforts to increase vaccination rate for the fourth dose of DTaP, the third dose of polio, JBE and regular vaccinations at recommended periods should be conducted in Korea.

Coinfection of hepatitis B and C viruses and risk of hepatocellular carcinoma: systematic review and meta-analysis.

A subadditive effect of hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection is possible because superinfection of one virus tends to inhibit infection of the other virus. However, studies have reported inconsistent findings, and two meta-analyses of studies from various countries (1998) and China (2005) reported a supraadditive effect for hepatocellular carcinoma (HCC) risk. Thus, we reevaluate HBV/HCV monoinfection and coinfection. Of 411 reports, we included 59 studies that assessed the association between HBV/HCV monoinfection and coinfection for HCC risk. HCC risk because of high/detectable HBV DNA and HBeAg infection was higher than HBsAg infection, whereas anti-HCV vs anti-HCV/HCV RNA was not different. Geographically, HCC risk was significantly higher in nonendemic than in HBV or HCV endemic areas. Subadditive effect for HCC risk was presented in recently published studies, cohort studies and studies conducted in HBV/HCV nonendemic areas; an additive effect was presented in studies conducted in HBV endemic areas; a supraadditive effect was presented in previously published studies, case-control studies and studies conducted in HCV endemic areas. Our results suggest HBV/HCV coinfection for HCC risk is not significantly greater than HBV/HCV monoinfection, and HCC risk due to HBV or HCV is higher in nonendemic than endemic areas. The p-heterogeneity was significant for most analyses, except HBV(+)/HCV(+) and HBV biomarker analyses. Prevention strategies targeted toward HBV or HCV monoinfected patients are needed. In addition, tailored prevention to reduce infectivity such as HBV markers (HBeAg, HBV DNA) is needed.

Reliability and data integration of duplicated test results using two bioelectrical impedence analysis machines in the Korean Genome and Epidemiology Study.

OBJECTIVES: The Korean Genome and Epidemiology Study (KoGES), a multicenter-based multi-cohort study, has collected information on body composition using two different bioelectrical impedence analysis (BIA) machines. The aim of the study was to evaluate the possibility of whether the test values measured from different BIA machines can be integrated through statistical adjustment algorithm under excellent inter-rater reliability. METHODS: We selected two centers to measure inter-rater reliability of the two BIA machines. We set up the two machines side by side and measured subjects' body compositions between October 2007 and December 2007. Duplicated test values of 848 subjects were collected. Pearson and intra-class correlation coefficients for inter-rater reliability were estimated using results from the two machines. To detect the feasibility for data integration, we constructed statistical compensation models using linear regression models with residual analysis and R-square values. RESULTS: All correlation coefficients indicated excellent reliability except mineral mass. However, models using only duplicated body composition values for data integration were not feasible due to relatively low R(2) values of 0.8 for mineral mass and target weight. To integrate body composition data, models adjusted for four empirical variables that were age, sex, weight and height were most ideal (all R(2)>0.9). CONCLUSIONS: The test values measured with the two BIA machines in the KoGES have excellent reliability for the nine body composition values. Based on reliability, values can be integrated through algorithmic statistical adjustment using regression equations that includes age, sex, weight, and height.

Cost-effectiveness analysis of 5 years of postoperative adjuvant tamoxifen therapy for Korean women with breast cancer: retrospective cohort study of the Korean breast cancer society database.

OBJECTIVE: This study aimed to evaluate the cost-effectiveness of postoperative adjuvant tamoxifen therapy using data from a Korean breast cancer registry. METHODS: In this retrospective, observational cohort study, patients were selected from the Korean Breast Cancer Society database. Women with stage I, II, or III breast cancer (diagnosed between 1981 and 2005), for whom information about tamoxifen use (20 mg/d for 5 years) and estrogen-receptor and/or progesterone-receptor status was available, were included. Cost-effectiveness was calculated from the perspective of Korean society. Using a decision analytic model based on standard clinical flow, incremental cost-effectiveness ratios (ICERs) for overall survival were calculated with stratification by disease stage and hormone-receptor status. One-way sensitivity analyses were also conducted. All results were represented as US dollars (US $1 approximately 1000 Korean won, in year-2005 values). RESULTS: A total of 17,579 patients were included in the analysis (10,694 tamoxifen users, 6885 nonusers). Among those with stage I or II breast cancer, ICERs for estrogen-receptor positive (ER+)/progesterone-receptor positive (PR+) tamoxifen users ranged from $739 to $1939. Tamoxifen use among those with either ER+ or PR+ status (but not both) remained cost-effective: $1217 to $3107 for 1 life-year gained. However, among estrogen-receptor negative (ER-)/progesterone-receptor negative (PR-) patients, tamoxifen use was more expensive and associated with shorter survival, and most ICERs were negative values, except for those aged >or=50 years (ICERs ranged from -$462 to -$3738 for 1 life-year gained). In contrast to those with stage I or II disease, tamoxifen use among patients with stage III disease was cost-effective regardless of hormone-receptor status. However, because of the small sample size, further studies are needed. CONCLUSIONS: In this analysis, postoperative adjuvant tamoxifen use was cost-effective for stage I or II ER+ and/or PR+ breast cancer, but not for ER-/PR- disease. Tamoxifen therapy appeared to be cost-effective for patients with stage III breast cancer regardless of hormone-receptor status. Seoul National University Hospital identifier: C-0702-019-198.

Isoflavones from phytoestrogens and gastric cancer risk: a nested case-control study within the Korean Multicenter Cancer Cohort.

BACKGROUND: The role of soybean products in gastric cancer risk is not clear in epidemiologic studies due to measurement error from dietary intake questionnaires and due to different degrees of bias according to study design. To examine the association between soybean products and gastric cancer risk, we measured phytoestrogen biological markers in a nested case-control study. METHODS: The study population was composed of 131 cases and 393 matched controls within the Korean Multicenter Cancer Cohort. The concentrations of the four biomarkers in the plasma samples were measured using time-resolved fluoroimmunoassay. Conditional and unconditional logistic regression models were used to compute the odds ratio (OR) and 95% confidence intervals (CI). RESULTS: Median plasma concentrations of genistein (229 nmol/L for controls, 181.8 nmol/L for cases; P=0.07) and daidzein (131.2 nmol/L for controls, 80.5 nmol/L for cases; P=0.04) in cases were lower than in controls, whereas equol concentrations were similar. Compared with the reference group, gastric cancer risk decreased in the highest groups for genistein (OR, 0.54; 95% CI, 0.31-0.93) and daidzein (OR, 0.21; 95% CI, 0.08-0.58). Higher equol concentrations were associated with a decreased risk for gastric cancer (OR, 0.50; 95% CI, 0.27-0.90). The combination of the highest concentrations for each isoflavone category was associated with a 0.09-fold decreased risk for gastric cancer compared with the combination of the lowest concentrations for each category. There was no association between plasma lignan concentrations and gastric cancer. CONCLUSIONS: High serum concentrations of isoflavones were associated with a decreased risk for gastric cancer. IMPACT: These results suggest a beneficial effect of high soybean product intake for gastric cancer risk.

Estrogen receptor-1 genetic polymorphisms for the risk of premature ovarian failure and early menopause.

BACKGROUND: The aim of this study was to investigate the role of the estrogen receptor 1 (ESR1) genetic polymorphisms for early menopause that was classified as premature ovarian failure (POF) and early menopause (EM) and to examine whether the associations of ESR1 genetic variants are different for POF and EM. METHODS: We selected 100 POF cases and matched 100 EM cases and 200 normal menopause (NM) controls from the Korean Multi-Center Cohort. Among them, we restricted idiopathic POF and EM cases vs NM controls by excluding POF/EM cases with medical/surgical causes. The XbaI (rs9340799) and PvuII (rs2234693) in the ESR1 gene were genotyped. The single-nucleotide polymorphism (SNP) and haplotype effects were analyzed by multivariate logistic regression and haplotype analysis. Also nominal polytomous logistic regression was used to find whether ESR1 genetic variants are differently associated with POF and EM. RESULTS: The global p values for idiopathic POF and EM were 0.08 and 0.39 (SNP-based), and <0.001 and 0.12 (haplotype-based), respectively. The XbaI genetic variant containing the X allele was marginally significantly associated with a reduced risk of idiopathic POF (OR = 0.6, 95% CI 0.3-1.0). The P-x haplotype and diplotypes significantly decreased the risk of idiopathic POF (OR = 0.5, 95% CI 0.2-0.9; OR = 0.4, 95% CI 0.2-0.9, respectively). In contrast from POF, the P-x haplotypes and diplotypes insignificantly increased the risk for both idiopathic EM (p(polytomous) = 0.009 for P-x haplotype; p(polytomous) = 0.02 for P-x diplotypes). CONCLUSION: Our results suggest that the ESR1 gene including PvuII and XbaI polymorphisms may modify the risk of idiopathic premature ovarian failure (POF) but not idiopathic early menopause (EM) risk.

Lung cancer risk and cigarette smoking, lung tuberculosis according to histologic type and gender in a population based case-control study.

We examined whether the strength of the association of cigarette smoking differs according to histological type and gender, and assessed other risk factors, in particular, tuberculosis. We recruited cases from the Korean Academy of Tuberculosis and Respiratory Diseases and controls from Chungju, a local site of the Korean Multi-Center Cancer Cohort. We matched one case to one control for females and two cases to one control for males according to age (or=70 years old). We used unconditional logistic regression to calculate the odds ratio (OR) and 95% confidence interval (CI) to estimate lung cancer risk by histologic type for males and females separately. The OR (95% CI) of 40 or more pack-years smoked relative to never smokers was 6.78 (4.17-11.00), 3.49 (1.83-6.33), and 2.72 (1.57-4.72) for males, and 13.72 (3.23-58.18), 12.18 (3.12-47.57), and 7.11 (1.78-28.43) for females for squamous cell, adenocarcinoma, and small cell carcinoma, respectively. Among males, the respective OR (95% CI) for past and current history of lung tuberculosis was 3.21 (2.12-4.90), 2.69 (1.63-4.45), and 1.52 (0.83-2.78), and for females was 2.40 (1.30-4.42), 4.20 (2.75-6.39), and 1.37 (0.61-3.06). Our findings provide additional evidence that women are more susceptible to the carcinogenic effects of tobacco, smoking has a higher risk for squamous cell and small cell carcinoma than adenocarcinoma, and tuberculosis is a potential risk factor for certain lung cancer histologic types.

The role of TNF genetic variants and the interaction with cigarette smoking for gastric cancer risk: a nested case-control study.

BACKGROUND: The aim of this study was to investigate the role of TNF genetic variants and the combined effect between TNF gene and cigarette smoking in the development of gastric cancer in the Korean population. METHODS: We selected 84 incident gastric cancer cases and 336 matched controls nested within the Korean Multi-Center Cancer Cohort. Six SNPs on the TNF gene, TNF-alpha-238 G/A, -308 G/A, -857 C/T, -863 C/A, -1031 T/C, and TNF-beta 252 A/G were genotyped. The ORs (95% CIs) were calculated using unconditional logistic regression model to detect each SNP and haplotype-pair effects for gastric cancer. The combined effects between the TNF gene and smoking on gastric cancer risk were also evaluated. Multi dimensionality reduction (MDR) analyses were performed to explore the potential TNF gene-gene interactions. RESULTS: TNF-alpha-857 C/T containing the T allele was significantly associated with an increased risk of gastric cancer and a linear trend effect was observed in the additive model (OR = 1.6, 95% CI 1.0-2.5 for CT genotype; OR = 2.6, 95% CI 1.0-6.4 for TT genotype). All haplotype-pairs that contained TCT or CCC of TNF-alpha-1031 T/C, TNF-alpha-863 C/A, and TNF-alpha-857 C/T were associated with a significantly higher risk for gastric cancer only among smokers. In the MDR analysis, regardless of smoking status, TNF-alpha-857 C/T was included in the first list of SNPs with a significant main effect. CONCLUSION: TNF-alpha-857 C/T polymorphism may play an independent role in gastric carcinogenesis and the risk for gastric cancer by TNF genetic effect is pronounced by cigarette smoking.

Soybean product intake modifies the association between interleukin-10 genetic polymorphisms and gastric cancer risk.

In this study, our aim was to investigate the association of inflammation-related genetic polymorphisms and gastric cancer risk and to examine whether the combined effect of soybean product intake modified cancer risk. Eighty-four incident gastric cancer cases and 336 matched controls were selected from the Korean Multi-Center Cancer Cohort. We selected 14 single nucleotide polymorphisms (SNP) from 5 genes [interleukin (IL)-1beta, IL-2, IL-4, IL-8, and IL-10] and used unconditional logistic regression model to calculate the odds ratios (OR) and 95% CI adjusting for H. pylori seropositivity, smoking, age, sex, enrollment year, and residential area. The risk for gastric cancer in relation to genetic polymorphisms and haplotypes were assessed according to soybean product intake levels. Although no single SNP effect was found, the combined effect between IL-10 gene variants of -592 GG/GA, -819 TC/CC, or -1082 AG/GG and low intake of soybean products had an increased risk for gastric cancer compared with the group with no risk gene variants and a high intake of soybean products (OR [95% CI] = 2.82 [1.04-7.62], 2.75 [1.02-7.44], and 4.34 [1.51-12.5], respectively). Among the low-soybean product intake group, IL-10 CCG haplotype had an increased risk of gastric cancer (OR = 3.38 [1.40-8.13]) relative to the ATA haplotype. Our results suggest that the association between IL-10 genetic polymorphisms and gastric cancer risk was modified by soybean product intake.