Large-scale Case-control Study Research Articles

Marital Status, Education, and Risk of Acute Myocardial Infarction in Mainland China: The INTER-HEART Study

BackgroundWe investigated the effects of marital status and education on the risk of acute myocardial infarction (AMI) in a large-scale case-control study in China.MethodsThis study was part of the INTER-HEART China case-control study. The main outcome measure was first AMI. Incident cases of AMI and control patients with no past history of heart disease were recruited. Controls were matching by age (±5 years) and sex. Marital status was combined into 2 categories: single and not single. Education level was classified into 2 categories: 8 years or less and more than 8 years.ResultsFrom 1999 to 2002, we recruited 2909 cases and 2947 controls from 17 cities. After adjustment for age, sex, BMI, psychosocial factors, lifestyle, other factors, and mutually for other risk factors, the odds ratio (OR) for AMI associated with being single was 1.51 (95% confidence interval: 1.18–1.93) overall, 1.19 (0.84–1.68; P = 0.072) in men and 2.00 (1.39–2.86; P < 0.0001) in women. The interaction of sex and marital status was statistically significant (P = 0.045). Compared with a high education level, a low education level increased the risk of AMI (1.45, 1.26–1.67); the odds ratios in men and women were 1.29 (1.09–1.52) and 1.55 (1.16–2.08), respectively. Single women with a low education level had a high risk of AMI (2.95, 1.99–4.37).ConclusionsBeing single was consistently associated with an increased risk for AMI, particularly in women. In addition, as compared with high education level, low education level was associated with a higher risk of AMI in both men and women.

Oral Disease and Risk of Pancreatic Cancer

To the Editor: Pancreatic cancer is characterized by a largely unknown etiology and poor survival, stressing the need to identify preventable risk factors. The few established risk factors (ie, tobacco smoking, chronic pancreatitis, diabetes, insulin resistance, and obesity) are only moderately or weakly associated with this tumor. A reported association between oral disease and pancreatic cancer remains to be confirmed in large and well-designed epidemiologic studies.1–5 Therefore, we conducted a large-scale case-control study, nested in a cohort comprising the nationwide Swedish Patient Register,6 during 1968–2008. Details of the study have been described elsewhere.7 All new cases of pancreatic cancer diagnosed during 1973–2008 with no prior cancer (except nonmelanoma skin cancer) were identified in the Swedish Cancer Register. Controls were frequency-matched using density-based sampling on the variables age, sex, calendar year, and year of the first record in the Patient Register. Hospitalization for a diagnosis of a defined disease of the oral cavity (ICD-8/9 codes 520–529 or ICD-10 codes K00–K14) since 1968, at least 5 years prior to inclusion, represented the study exposure. Estimates of risk of pancreatic cancer were calculated as odds ratios (ORs) with 95% confidence intervals (CIs), using unconditional logistic regression analysis with multivariable adjustment for confounding. Data on potential confounding factors were collected from diagnoses recorded in the Patient Register: alcoholism or alcohol-related disease; chronic obstructive pulmonary disease or bronchitis; obesity; diabetes; gastric or duodenal ulcer; and pancreatitis. The occurrence of disease of the oral cavity was slightly higher among the 29,218 pancreatic cancer cases than among the 99,992 control participants. The covariates pancreatitis, alcohol-related diseases, and diabetes were also overrepresented among cases compared with controls (data not shown). The adjusted odds ratio among patients with a history of oral disease was 1.2 (95% CI = 1.0–1.4) (Table).TABLE: Disease of the Oral Cavity and the Risk of Pancreatic Cancer in Sweden During the Period 1973–2008These data provide support for a modest association between diseases of subsequent oral cavity and the risk of pancreatic cancer. Strengths include the large sample size, complete nationwide coverage of hospitalizations for oral cavity disease and of all cancers, and adjustments for confounding. Moreover, the nationwide register-based design removes possible recall or selection bias. By considering only oral disease that occurred at least 5 years before inclusion, we also reduce bias from reverse causation. Among weaknesses, only the most severe forms of oral cavity disease are captured because the exposure is based only on in-hospital care. Tobacco use is the most consistent risk factor for pancreatic cancer, and a main risk factor for periodontal disease.8 The use of hospitalization for tobacco-related diseases (chronic obstructive pulmonary disease and bronchitis) as surrogate assessment of tobacco use is crude, and leaves open the possibility of residual confounding. However, adjustment for known tobacco-related diseases had no effect on the estimate (Table). The finding of an increased risk of pancreatic cancer after oral disease is supported by some previous research,3–5 whereas other studies have found no association.2 While more research is needed to establish an association, possible biologic mechanisms include an increased production of nitrosamines due to an altered oral flora or systemic inflammation. Rickard Ljung Upper Gastrointestinal Research Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm, Sweden National Board of Health and Welfare Stockholm, Sweden [email protected] Tomas Sjöberg Bexelius Lena Martin Upper Gastrointestinal Research Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm, Sweden Jesper Lagergren Upper Gastrointestinal Research Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm, Sweden Division of Cancer Studies King's College London, United Kingdom

Association of a common genetic variant in prostate stem‐cell antigen with gastric cancer susceptibility in a Korean population

A recent genome wide association study (GWAS) indentified a significant association between rs2294008 (C > T) polymorphism in prostate stem-cell antigen (PSCA) and increased risk of gastric cancer in Japanese and Korean populations. The aim of this study was to determine whether rs2294008 polymorphism is associated with risk of gastric cancer in a Korean population. We conducted a large-scale case-control study of 3,245 gastric cancer patients and 1,700 controls. The frequencies of the CC, CT, and TT genotypes of rs2294008 polymorphism were 17.8%, 49.9%, and 32.3% in the gastric cancer patients; and 24.4%, 48.1%, and 27.5% in the controls, respectively. We found that the CT and TT genotypes were associated with a significantly increased risk of gastric cancer (OR(CT) = 1.50, 95% confidence intervals, 95% CI: 1.28-1.76; OR(TT) = 1.71, 95% CI: 1.43-2.04), compared with the CC genotype. Further, stratified by tumor location and histological type, the effect of the rs2294008 T allele was larger in cardia (OR(TT) = 2.62, 95% CI = 1.42-4.85) than non-cardia (OR(TT) = 1.67, 95% CI = 1.40-2.00), in diffuse-type (OR(TT) = 2.00, 95% CI: 1.55-2.59) than in intestinal-type (OR(TT) = 1.51, 95% CI: 1.22-1.86). Our study showed that rs2294008 in the PSCA gene was associated with increased risks of gastric cancer in a Korean population, suggests that rs2294008 might play an important role in gastric carcinogenesis.

P53 codon 72 polymorphism in patients with gastric and colorectal cancer in a Korean population

The common p53 codon 72 polymorphism has been investigated as a risk factor for cancer in different populations; however, the results have been inconsistent. This study investigated the risk of developing gastric or colorectal cancer associated with the p53 codon 72 polymorphism in a Korean population. We conducted a large-scale case-control study that included 2,213 gastric cancer patients; 1,829 colorectal cancer patients; and 1,700 healthy controls. Genotyping was performed with real-time polymerase chain reaction (PCR), using a TaqMan single-nucleotide polymorphism (SNP) genotyping assay. The frequencies of Arg/Arg, Arg/Pro, and Pro/Pro genotypes of the p53 codon 72 polymorphism were 43.3, 42.0, and 13.0% in the gastric cancer patients; 40.5, 45.0, and 14.0% in the colorectal cancer patients; and 43.2, 45.6, and 11.2% in the controls, respectively. The Pro/Pro genotype was associated with an increased risk of gastric [age- and sex-adjusted odds ratio (OR) = 1.25, 95% confidence interval (CI) = 1.01-1.56, P = 0.04] and colorectal cancer (OR = 1.36, 95% CI = 1.07-1.72, P = 0.01). There were no significant interactions between the p53 codon 72 polymorphism and smoking or drinking. Our results suggest that the Pro/Pro genotype is associated with modest increases in the risks of gastric cancer and colorectal cancer in a Korean population.

The Same Chromosome 9p21.3 Locus Is Associated With Type 2 Diabetes and Coronary Artery Disease in a Chinese Han Population

OBJECTIVERecent genome-wide association studies (GWAS) revealed that a 9p21.3 locus was associated with type 2 diabetes. In this study, we carried out a large-scale case-control study in the GeneID Chinese Han population to 1) further replicate the association of 9p21.3 type 2 diabetes GWAS single nucleotide polymorphisms (SNPs) and 2) assess the association of these SNPs with coronary artery disease.RESEARCH DESIGN AND METHODSThree SNPs (rs2383208, rs10811661, and rs10757283) were genotyped in two GeneID cohorts of 3,167 Chinese Han individuals. Case-control association design was used to determine the association of the SNPs with type 2 diabetes and coronary artery disease. Gensini scores were calculated in the coronary artery disease subjects and were tested for association with the variants. Multivariate logistic regressions were performed on association studies.RESULTSThe association between two of the three SNPs and type 2 diabetes was replicated in the GeneID population (rs2383208, P = 0.936; rs10811661-T, P = 0.02, odds ratio [OR] = 1.23; rs10757283-C, P = 0.003, OR = 1.30). The same two SNPs also contributed to the risk of coronary artery disease (CAD) (rs10811661-T, P = 0.002, OR = 1.19; rs10757283-C, P = 0.003, OR = 1.18). In addition, rs10757283 was associated with severity of coronary atherosclerosis estimated by the Gensini scoring system (risk allele C, quantitative-trait regression adjusted P = 0.002).CONCLUSIONSFor the first time to our knowledge, our results indicated that the same 9p21.3 locus, represented by SNPs rs10811661 and rs10757283, contributed to the risk of type 2 diabetes and coronary artery disease in our GeneID Chinese Han population.

Impact of LIMK1, MMP2 and TNF-α variations for intracranial aneurysm in Japanese population

Genetic factors are known to have an important role in intracranial aneurysm (IA) pathogenesis. The purpose of this study is to identify single-nucleotide polymorphisms (SNPs) that are associated with IA in Japanese population. A total of 2050 IA patients and 1835 controls recruited in Biobank Japan, The University of Tokyo were used in this study. In all, 45 SNPs in 24 genes encoding proteins, which have been considered to be possible risk factors to IA pathogenesis, were genotyped using multiplex PCR-invader assay. Association analysis was evaluated by logistic regression analysis before and after adjustment of age, smoking and hypertension status. This case-control association study revealed a SNP, rs6460071 located on LIMK1 gene (P = 0.00069) to be significantly associated with increased risk of IA. In addition, two SNPs, rs243847 (P = 0.00086) and rs243865 (P = 0.00090), on matrix metallopeptidase 2 (MMP2) gene and one SNP rs1799724 (P = 0.0026) on tumor necrosis factor-α (TNF-α) gene, are marginally associated with IA in male- and female-specific manner, respectively. In conclusion, a large-scale case-control association study was conducted to verify genetic variations associated with IA in Japanese population. This study gave insights on the importance of stratified analysis between genders, and suggested that the underlying mechanism of IA pathogenesis might differ between females and males.

Dietary Benzo[a]pyrene Intake from Meat and the Risk of Colorectal Cancer

One possible mechanism for the postulated link between high consumption of meat and colorectal cancer (CRC) is the content of benzo[a]pyrene (BaP) in meat. We investigated this association in a population-based case-control study in Western Australia (567 cases and 713 controls). Participants' self-report of meat consumption and lifestyle was used in conjunction with the CHARRED carcinogen database to estimate their BaP intake. Dietary exposure to BaP from meat consumption was not associated with the risk of CRC. Our findings do not support the hypothesis that BaP exposure from meat consumption is a risk factor for CRC. IMPACT STATEMENT: This large-scale case-control study used a detailed meat questionnaire in conjunction with the CHARRED database in a large population with high meat intake but was unable to find any association between intake of BaP and colorectal cancer.

Alcohol and tea consumption in relation to the risk of nasopharyngeal carcinoma in Guangdong, China

To investigate whether alcohol and tea consumption has an etiological association with nasopharyngeal carcinoma (NPC) in a high-incident population, a large scale case-control study was conducted. The study included 2846 individuals in Guangdong Province, China, with 1387 newly diagnosed cases of NPC and 1459 frequency-matched controls. Exposure histories of alcohol and tea consumption were obtained via personal interviews. Information regarding socio-demographic characteristics (age, sex, education, dialect and household type), family history of NPC, Epstein-Barr virus (EBV) infection, dietary habits and other potential confounding factors was also studied. An analysis was performed using unconditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). The risk of NPC was found to be associated with habitual alcohol consumption and tea consumption. Tea consumption has been associated with a decreased occurrence of NPC (OR = 0.62), while consumption of alcohol was associated with a complex effect. Specifically, moderate consumption of alcohol was associated with decreased risk of NPC, while overuse, especially strong distillate spirits, appeared to be a risk factor.

Lifestyle factors and lumbar disc disease: results of a German multi-center case-control study (EPILIFT)

IntroductionIn the large-scale case-control study EPILIFT, we investigated the dose-response relationship between lifestyle factors (weight, smoking amount, cumulative duration of different sports activities) and lumbar disc disease.MethodsIn four German study regions (Frankfurt am Main, Freiburg, Halle/Saale, Regensburg), 564 male and female patients with lumbar disc herniation and 351 patients with lumbar disc narrowing (chondrosis) aged 25 to 70 years were prospectively recruited. From the regional population registers, 901 population control subjects were randomly selected. In a structured personal interview, we enquired as to body weight at different ages, body height, cumulative smoking amount and cumulative duration of different sports activities. Confounders were selected according to biological plausibility and to the change-in-estimate criterion. Adjusted, gender-stratified odds ratios with 95% confidence intervals were calculated using unconditional logistic regression analysis.ResultsThe results of this case-control study reveal a positive association between weight and lumbar disc herniation as well as lumbar disc narrowing among men and women. A medium amount of pack-years was associated with lumbar disc herniation and narrowing in men and women. A non-significantly lowered risk of lumbar disc disease was found in men with high levels of cumulative body building and strength training.ConclusionsAccording to our multi-center case-control study, body weight might be related to lumbar disc herniation as well as to lumbar disc narrowing. Further research should clarify the potential protective role of body building or strength training on lumbar disc disease.

Traditional Cantonese diet and nasopharyngeal carcinoma risk: a large-scale case-control study in Guangdong, China

BackgroundNasopharyngeal carcinoma (NPC) is rare in most parts of the world but is a common malignancy in southern China, especially in Guangdong. Dietary habit is regarded as an important modifier of NPC risk in several endemic areas and may partially explain the geographic distribution of NPC incidence. In China, rapid economic development during the past few decades has changed the predominant lifestyle and dietary habits of the Chinese considerably, requiring a reassessment of diet and its potential influence on NPC risk in this NPC-endemic area.MethodsTo evaluate the association between dietary factors and NPC risk in Guangdong, China, a large-scale, hospital-based case-control study was conducted. 1387 eligible cases and 1459 frequency matched controls were recruited. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were estimated using a logistic regression model, adjusting for age, sex, education, dialect, and habitation household type.ResultsObservations made include the following: 1) consumption of canton-style salted fish, preserved vegetables and preserved/cured meat were significantly associated with increased risk of NPC, with enhanced odds ratios (OR) of 2.45 (95% CI: 2.03-2.94), 3.17(95% CI: 2.68-3.77) and 2.09 (95% CI: 1.22-3.60) respectively in the highest intake frequency stratum during childhood; 2) consumption of fresh fruit was associated with reduced risk with a dose-dependent relationship (p = 0.001); and 3) consumption of Canton-style herbal tea and herbal slow-cooked soup was associated with decreased risk, with ORs of 0.84 (95% CI: 0.68-1.03) and 0.58 (95% CI: 0.47-0.72) respectively in the highest intake frequency stratum. In multivariate analyses, these associations remained significant.ConclusionsIt can be inferred that previously established dietary risk factors in the Cantonese population are still stable and have contributed to the incidence of NPC.

The 'headache' of assessing a link between PFO and migraine

The relationship between patent foramen ovale and migraine is a hotly debated issue. Conflicting data on the association or independence of these conditions have been reported by various study groups around the world. Now, a large-scale case-control study has shown no association between the two entities; however, there were a number of methodological flaws in this study and we are unlikely to see the end of the controversy in the near future.

Methylenetetrahydrofolate reductase C677T polymorphism in patients with gastric and colorectal cancer in a Korean population

BackgroundThis study was designed to investigate an association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of gastric and colorectal cancer in the Korean population.MethodsWe conducted a population-based large-scale case-control study involving 2,213 patients with newly diagnosed gastric cancer, 1,829 patients with newly diagnosed colorectal cancer, and 1,700 healthy controls. Genotyping was performed with peripheral blood DNA for MTHFR C677T polymorphisms. The statistical significance was estimated by logistic regression analysis.ResultsThe MTHFR C677T frequencies of CC, CT, and TT genotypes were 35.2%, 47.5%, and 17.3% among stomach cancer, 34%, 50.5%, and 15.5% in colorectal cancer, and 31.8%, 50.7%, and 17.5% in the controls, respectively. The MTHFR 677TT genotype showed a weak opposite association with colorectal cancer compared to the homozygous CC genotype [adjusted age and sex odds ratio (OR) = 0.792, 95% confidence interval (CI) = 0.638-0.984, P = 0.035]. Subjects with the MTHFR 677CT showed a significantly reduced risk of gastric cancer compared whose with the 677CC genotype (age- and sex-adjusted OR = 0.810; 95% CI = 0.696-0.942, P = 0.006). We also observed no significant interactions between the MTHFR C677T polymorphism and smoking or drinking in the risk of gastric and colorectal cancer.ConclusionsThe T allele was found to provide a weak protective association with gastric cancer and colorectal cancer.

L-Type Voltage-Dependent Calcium Channel Alpha Subunit 1C Is a Novel Candidate Gene Associated with Secondary Hyperparathyroidism: An Application of Haplotype-Based Analysis for Multiple Linked Single Nucleotide Polymorphisms

Background and Methods: We conducted a large-scale case-control study that explored the association of 358 single nucleotide polymorphisms (SNPs) in 185 patients with end-stage renal disease. A variety of SNPs were recognized as significant in simple association studies. In addition, haplotype analysis identified the gene for the alpha 1C subunit of the voltage-dependent L-type calcium channel (CACNA1C) as having a significant association with secondary hyperparathyroidism (intact parathyroid hormone level >200 pg/ml) among 61 haplotypes. Since CACNA1C is a relatively large molecule, we examined 84 SNP markers from the CACNA1C region located on chromosome 12 by haplotype case-control association analysis. Results: Sixteen SNPs of 14 genes were significant according to allelic and/or genotypic studies (p < 0.05 by Fisher’s exact test). Three different SNPs were from the CACNA1C gene. Next, we performed haplotype-based association testing with a focus on the CACNA1C region, revealing an odds ratio (OR) of 1.63 and 95% confidence interval (CI) of 1.05–2.52. The second major haplotype with a frequency of 27% was also significant and acted as a protective haplotype (p = 0.022 by Fisher’s exact test, with an OR of 0.55 and 95% CI of 0.33–0.90). Conclusion: These results suggest that CACNA1C may be associated with secondary hyperparathyroidism. In addition, the haplotype-based approach may be useful to screen for key molecules associated with complex traits.

Abstract 976: Consumption of vitamins and calcium reduces breast cancer risk by their regulation of the DNA repair capacity

Abstract Background- Breast cancer (BC) is the most common cancer in women with over one million new cases diagnosed annually worldwide. The capacity of the DNA to repair itself (DRC) is a complex biological process involving over 200 proteins. This process involves at least five pathways and is critical in maintaining genomic stability. The objective of this study was to examine the association of DRC and BC risk in terms of consumption of vitamin and calcium supplements by means of a large scale case-control study. Methods.- This was an incident-case case-control study design involving Puerto Rican women. The selection of potential predictors under study was based on previous published research in BC including information on vitamins, calcium, and variables that could provide an estimate of BC risk including age, BMI, family history, gynecological history, hormonal and environmental factors. The host reactivation assay with a luciferase reporter gene was used to measure the DRC in the lymphocytes from all participants. Cases were compared to controls, regarding diet supplement intake, DRC, and other selected covariates. The crude and multiple logistic regression adjusted Odds Ratio (OR) were used as measures of association and the 95% confidence interval of the OR was utilized to asses the precision of this estimate. Results.- A total of 268 breast cancer cases and 457 controls were included in this analysis. Statistically significant associations were found between BC and ageing, low DRC levels, family history of BC, and no breastfeeding. Vitamins and calcium intake were found to be protective reducing 30% and 40% the odds of having BC respectively. Calcium reduced considerably its protective effect becoming negligibly and not statistically significant when DRC was included in the logistic regression model. This suggests that DRC explains this association. In contrast, vitamin's intake did not show an important change in the association with BC when adjusting for DRC. Calcium and vitamins’ intake were strongly associated with higher levels of DRC. Discussion.- Vitamins and calcium intake are protective for breast cancer and are associated with higher DRC levels. Vitamins’ intake is an independent protective factor for BC while the protective effect of calcium may be explained by an increased DRC. DRC can be used to monitor the protective effect of calcium in terms of breast cancer risk. This study is supported by grants from the NCI Center to Reduce Health Disparities and NIH-MBRS Program grant #: S06 GM008239-23. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 976.

Abstract 879: Mitochondrial DNA content and its association with lung cancer risk and clinical outcomes

Abstract Mitochondrion is an essential cellular organelle generating energy, and also plays a key role in the initiation and regulation of apoptosis. Impaired mitochondria function may inhibit apoptosis; enhance reactive oxygen species and generate cancer related proteins. The difference in mitochondrial DNA (mtDNA) content (also termed mtDNA copy number) may contribute to cancer predisposition as well as variations in clinical outcomes. To test this hypothesis, we conducted a large-scale case-control study to investigate the role of mtDNA content in lung cancer etiology and clinical outcomes. MtDNA content in 2,442 newly diagnosed lung cancer patients and 2,417 matched controls were measured by quantitative real-time polymerase chain reaction. Clinical outcome data were collected for non-small cell lung cancer (NSCLC) patients (2,020 subjects). We analyzed the association of MtDNA copy number with the risk of developing lung cancer and also the clinical outcomes in NSCLC patients. MtDNA content was significantly lower in patients than controls (mean=1.17 vs. 1.23, P=4.28×10−4). Compared to higher mtDNA content (above the median value in the controls), lower mtDNA content was associated with a significantly increased risk for lung cancer (OR=1.25, 95%CI=1.11-1.41, P=1.52×10−4). In the trend analysis, we detected a significant dose-response relationship between mtDNA content and risk, as lower mtDNA content was associated with a progressively increased risk for lung cancer (P-trend=1.40×10−4). In the analysis of clinical outcomes, a significant difference in mtDNA content was observed between death and survival groups (mean=1.12 vs. 1.27, P=6.62×10−4) in early stage (stage I and II) NSCLC patients. Compared to those who have higher mtDNA content, patients who have lower mtDNA content had a 45% higher risk for death (HR=1.34, 95%CI=1.05-1.71, P=0.019), and a dramatically shorter survival time (58 months vs. 96 months, log-rank P=5.68×10−4). A dose-response effect of increased risk for death was found with decreased mtDNA content (P-trend=0.048) in this group of patients. No significant results were found in advance stage (stage III and IV) patients. To our knowledge, this is the first study to evaluate the association of MtDNA copy number with lung cancer risk and clinical outcomes. Our results suggested that lower mtDNA content is associated with increased lung cancer risk and poor prognosis in early stage NSCLC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 879.

NRG1 gene in recurrent major depression: No association in a large‐scale case–control association study

The Neuregulin 1 (NRG1) gene was initially implicated in schizophrenia (SZ) and has recently been associated with bipolar disorder (BPD) in two studies. An association with major depressive disorder (MDD) has not yet been investigated but is warranted in view of the genetic overlap between MDD and BPD. We have performed a large-scale case-control study investigating the association between NRG1 polymorphisms and MDD, genotyping a selection of 14 single nucleotide polymorphisms (SNPs) spanning the NRG1 gene in a sample of 1,398 patients of White European ancestry with a diagnosis of MDD and 1,304 ethnically matched controls from three clinical sites in the UK. We found no single marker or haplotype associations that withstood correction for multiple testing. Our findings do not provide evidence that NRG1 plays a role in MDD or that this gene explains part of the genetic overlap with BPD.

Abstract C29: Bladder cancer-associated single nucleotide polymorphisms of vascular endothelial growth factor in 12 human cell lines

Abstract Introduction: Vascular endothelial growth factor (VEGF), critical in angiogenesis, is important for solid tumor growth and metastasis. Three single nucleotide polymorphisms (SNP) in the promoter (rs833052, rs1109324 and rs1547651) and one in the 5′-UTR regions (rs25648) of VEGF have been associated with increased risk for bladder cancer, and one at intron 2 (rs3024994) with decreased risk in a large-scale case-control study. The genotype frequency of the five bladder cancer-associated SNPs among various ethnic groups is similar based on the dbSNP and the SNP500Cancer databases. The objective of this study was to determine the presence of these variants in a panel of 12 human bladder cancer cell lines. Methods: Twelve bladder cancer cell lines, commonly used in urological research and derived from various ethnic groups, were included in the study. Genotypes of the five SNPs were determined for the12 cell lines by direct PCR sequencing. The basal VEGF secretion by these cell lines in culture was measured by ELISA using a microsphere-based array (Millipore) and Luminex® xMAP technology. Results: The SNP genotype frequency was in agreement with that reported in the databases. The only bladder cancer-associated variant (rs833052: C&amp;gt;A) was detected in UM-UC-3, a cell line with many other genetic alterations. The secreted VEGF level in these cell lines as determined by ELISA varied considerably. No correlation between VEGF production and any particular SNP genotype could be established. Conclusions: The reported bladder cancer associated variants in VEGF was detected in only one of the twelve cell lines. Though these SNPs are all located in the regulatory regions, it appears that they have no effect on basal VEGF production in the cultured cells. Considering the low prevalence of these variants reported, the role of these SNPs in VEGF production and bladder cancer remains to be defined. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C29.

Active and Involuntary Tobacco Smoking and Upper Aerodigestive Tract Cancer Risks in a Multicenter Case-Control Study

Several important issues for the established association between tobacco smoking and upper aerodigestive tract (UADT) cancer risks include the associations with smoking by cancer subsite, by type of tobacco, and among never alcohol drinkers and the associations with involuntary smoking among nonsmokers. Our aim was to examine these specific issues in a large-scale case-control study in Europe. Analysis was done on 2,103 UADT squamous cell carcinoma cases and 2,221 controls in the Alcohol-Related Cancers and Genetic Susceptibility in Europe project, a multicenter case-control study in 10 European countries. Unconditional logistic regression was done to obtain odds ratios (OR) and 95% confidence intervals (95% CI). Compared with never tobacco smoking, current smoking was associated with UADT cancer risks (OR, 6.72; 95% CI, 5.45-8.30 for overall; OR, 5.83; 95% CI, 4.50-7.54 for oral cavity and oropharynx; OR, 12.19; 95% CI, 8.29-17.92 for hypopharynx and larynx; and OR, 4.17; 95% CI, 2.45-7.10 for esophagus). Among never drinkers, dose-response relationships with tobacco smoking pack-years were observed for hypopharyngeal and laryngeal cancers (P(trend) = 0.010) but not for oral cavity and oropharyngeal cancers (P(trend) = 0.282). Among never smokers, ever exposure to involuntary smoking was associated with an increased risk of UADT cancers (OR, 1.60; 95% CI, 1.04-2.46). Our results corroborate that tobacco smoking may play a stronger role in the development of hypopharyngeal and laryngeal cancers than that of oral cavity and oropharyngeal cancers among never drinkers and that involuntary smoking is an important risk factor for UADT cancers. Public health interventions to reduce involuntary smoking exposure could help reduce UADT cancer incidence.

Acute generalized exanthematous pustulosis

The purpose of the present review is to update knowledge on acute generalized exanthematous pustulosis (AGEP) in terms of epidemiology, pathogenesis, cause, clinical features, diagnosis, and treatment. AGEP is a rare reaction pattern attributed mainly to drugs. Drug-specific T cells (CD4+ and CD8+) and the production of interleukin-8/CXCL8 play an important role in its pathogenesis. A large-scale case-control study (EuroSCAR study) revealed a broad spectrum of drugs strongly associated with AGEP characterized by different time patterns (latent periods). Recent publications have supported the recognized role of individual drugs in the induction of AGEP and some have reported newly incriminated drugs. Many recent publications on AGEP have used the AGEP validation score (EuroSCAR group criteria) to establish the diagnosis. The value of in-vivo tests (mainly patch tests), in-vitro tests (the lymphocyte transformation test and cytokine release tests), or both for the identification of causative drugs has been demonstrated. Infections do not play a prominent role in the development of AGEP. There is no evidence for the assumption that AGEP is a variant of pustular psoriasis. Unique observations related to AGEP include a marked female predominance, a possible role for seasonality and a causal role for spider bites. A broad spectrum of drugs is associated with AGEP, a T cell-mediated reaction. Genetic susceptibility and the possible role of other risk factors in AGEP should be further evaluated in larger studies of AGEP patients with a validated diagnosis.

Meta-Analysis of the ACE Gene Polymorphism in Cerebral Infarction

The angiotensin-1 converting enzyme (ACE) gene is known to have two polymorphic alleles insertion/deletion (I/D). People with the DD genotype have been shown to be at greater risk of cerebral infarction, but only in some studies. Identification of cerebral infarction susceptibility genes and quantification of associated risks have been hampered by conflicting results from underpowered case-control studies. This meta-analysis was made to look specifically into the genetics of cerebral infarction among Han Chinese population. Genetic associations studies published from January 1, 1990 to December 30, 2007 were collected from databases of MEDLINE, EMBASE, CBM and CNKI. Data were extracted using standardised forms and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Twenty-nine original case-control studies of Han Chinese population, comprising 3654 patients with cerebral infarction and 3058 controls were included in the meta-analysis. Using the random effects model, the pooled ORs of ACE DD genotype VS ID+ II was 1.91 (95% CI 1.56 to 2.34, P<0.00001). These data suggest that the ACE DD genotype may be a risk factor for cerebral infarction in Han Chinese population. A large scale case-control study is needed to clarify the functional effect of the polymorphism of the ACE I/D gene in the pathogenesis of cerebral infarction in Han Chinese population.