Meta-analysis Of Case-control Studies Research Articles

RETRACTED ARTICLE: SELP genetic polymorphisms may contribute to the pathogenesis of coronary heart disease and myocardial infarction: a meta-analysis

We conducted a meta-analysis of case-control studies to determine whether SELP genetic polymorphisms contribute to the pathogenesis of coronary heart disease (CHD) and myocardial infarction (MI). A range of electronic databases were searched: MEDLINE (1966-2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980-2013), CINAHL (1982-2013), Web of Science (1945-2013) and the Chinese biomedical database (1982-2013) without language restrictions. Meta-analysis was performed with the use of the STATA statistical software. Nine case-control studies with a total of 3,154 CHD patients, 1,608 MI patients and 17,304 healthy controls were involved in this meta-analysis. Six common polymorphisms in the SELE gene were assessed, including -1969G/A (rs1800805 G>A), -1817T/C (rs1800808 T>C), -2123C/G (rs1800807 C>G), Thr715Pro (rs6136 A>C), Leu599Val (rs6133 G>T), and Ser290Asn (rs6131 C>T). Our findings illustrated significantly positive associations of SELE genetic polymorphisms with the development of CHD and MI. The results of subgroup analysis by SNP type indicated that -1969G/A, -1817T/C, -2123C/G, Thr715Pro and Ser290Asn in the SELP gene might be strongly correlated with CHD and MI risk, but no similar results were found in SELP Leu599Val polymorphism. In the subgroup analysis by ethnicity, our results indicated significant relationships between SELE genetic polymorphisms and the pathogenesis of CHD and MI among Asians and Caucasians. However, we observed no significant associations between SELP genetic polymorphisms and the risk of CHD and MI among Africans. Our findings provide empirical evidence that SELE genetic polymorphisms may contribute to the pathogenesis of CHD and MI, especially among Asians and Caucasians. Thus, SELP genetic polymorphisms could be potential and practical biomarkers for early diagnosis of CHD and MI.

RETRACTED ARTICLE: Correlations of SELE genetic polymorphisms with risk of coronary heart disease and myocardial infarction: a meta-analysis

This meta-analysis of case-control studies was conducted to determine whether SELE genetic polymorphisms contribute to the pathogenesis of coronary heart disease (CHD) and myocardial infarction (MI). The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched for relevant articles published before November 1st, 2013 without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Twenty case-control studies met the inclusion criteria, with a total of 2,292 CHD patients, 901 MI patients and 3,233 healthy controls. Six common polymorphisms in the SELE gene were evaluated, including 554L/F, 98G/T, 128S/R, 2692G/A, 1901C/T, and 1856A/G. The results of our meta-analysis suggest that SELE genetic polymorphisms might be strongly correlated with an increased risk of CHD (allele model: OR 2.08, 95% CI 1.67-2.58, P<0.001; dominant model: OR 2.12, 95% CI 1.68-2.68, P<0.001; respectively), especially the SELE 554L/F, 98G/T and 128S/R polymorphisms. Furthermore, our findings indicated that SELE genetic polymorphisms were closely linked to the risk of CHD in Asians but not Caucasians. However, our findings reveal no positive correlations between SELE genetic polymorphisms and MI risk (allele model: OR 1.39, 95% CI 1.00-1.94, P=0.054; dominant model: OR 1.40, 95% CI 0.96-2.04, P=0.081; respectively). The current meta-analysis suggests that SELE genetic polymorphisms may contribute to an increased risk of CHD, especially the SELE 554L/F, 98G/T and 128S/R polymorphisms in Asians. However, SELE genetic polymorphisms may not be important determinants of susceptibility to MI.

Effect of statins on gastric cancer incidence: A meta-Analysis of case control studies

Gastric cancer is among the leading causes of cancer-related death worldwide, especially in Eastern Asia, Eastern Europe and South America. Statin is one of the most widely used medications for hypercholesterolemia. Several meta-analyses have failed to determine the relationship between statins and gastric cancer. A meta-analysis of case control studies is conducted to evaluate the association of statin exposure and risk of gastric cancer. Eight electronic databases (The Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 12, 2012), PubMed, EMBASE, ISI Web of Knowledge, CNKI, CBM, CSJD and Wanfang Database) were searched for relevant publications through September 2013. Two reviewers determined the eligibility of articles and abstracted the data independently. RevMan 5.2 software was used for statistical analysis. 146 items were retrieved from the databases and 6 studies were identified in this meta-analysis, which included 5,993 cases and 54,800 matched controls. RESULTS from the meta-analysis demonstrated that statins were inversely related to the risk of gastric cancer (RR=0.56, 95% CI: 0.35-0.90). There was no significant difference for cumulative duration of statin exposure and gastric cancer, nor participants from Asia, Europe, or USA. This meta-analysis suggests that statins have favorable effects on gastric cancer, rigorously designed and executed observational studies and randomized control trials with longer duration of follow-up are warranted to determine effects in clinical practice.

Alzheimer's disease and HLA-A2: linking neurodegenerative to immune processes through an in silico approach.

There is a controversial relationship between HLA-A2 and Alzheimer's disease (AD). It has been suggested a modifier effect on the risk that depends on genetic loadings. Thus, the aims of this study were to evaluate this relationship and to reveal genes associated with both concepts the HLA-A gene and AD. Consequently, we did first a classical systematic review and a meta-analysis of case-control studies. Next, by means of an in silico approach, we used experimental knowledge of protein-protein interactions to evaluate the top ranked genes shared by both concepts, previously found through text mining. The meta-analysis did not show a significant pooled OR (1.11, 95% CI: 0.98 to 1.24 in Caucasians), in spite of the fact that four of the included studies had a significant OR > 1 and none of them a significant OR < 1. In contrast, the in silico approach retrieved nonrandomly shared genes by both concepts (P = 0.02), which additionally encode truly interacting proteins. The network of proteins encoded by APP, ICAM-1, ITGB2, ITGAL, SELP, SELL, IL2, IL1B, CD4, and CD8A linked immune to neurodegenerative processes and highlighted the potential roles in AD pathogenesis of endothelial regulation, infectious diseases, specific antigen presentation, and HLA-A2 in maintaining synapses.

Correlation between IRGM genetic polymorphisms and Crohn's disease risk: a meta-analysis of case-control studies.

This meta-analysis was performed to evaluate the relationships between single-nucleotide polymorphisms (SNPs) in the immunity-related GTPase M (IRGM) gene and the risk of Crohn's disease (CD). Eleven case-control studies were included, for a total of 5183 CD patients and 5571 healthy controls. Three common SNPs (rs13361189 C>T, rs10065172 C>T, and rs4958847 A>G) in the IRGM gene were assessed. We found that the IRGM rs13361189 polymorphism was significantly associated with an increased risk of CD [C allele vs T allele: odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.05-1.61, P = 0.017; CC + CT vs TT: OR = 1.32, 95%CI = 1.06-1.64, P = 0.013]. However, we observed no correlation between the rs10065172 and rs4958847 polymorphisms in the IRGM gene with susceptibility to CD (all P > 0.05). Subgroup analysis by ethnicity revealed significant associations between IRGM genetic polymorphisms and an increased risk of CD among Caucasian populations (C allele vs T allele: OR = 1.22, 95%CI = 1.07-1.40, P = 0.004; CC + CT vs TT: OR = 1.22, 95%CI = 1.05-1.41, P = 0.009), but not among Asian populations (all P > 0.05). Meta-regression analysis also confirmed that ethnic differences may be an important source of heterogeneity (P = 0.003). Our meta-analysis results indicate that the IRGM rs13361189 polymorphism contributes to the susceptibility to CD. Thus, the IRGM rs13361189 polymorphism is promising as a biomarker for early diagnosis of CD. However, the IRGM rs10065172 and rs4958847 polymorphisms may not be the major determinants of CD risk.

The role of polyphenols in the development of colorectal cancer: a systematic review and meta-analysis of case-controlled studies

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HIF1A gene Pro582Ser polymorphism and susceptibility to digestive tract cancers: a meta-analysis of case-control studies.

Many existing studies have demonstrated that common polymorphisms in the hypoxia inducible factor-1α (HIF-1A) may contribute to the development of digestive tract cancers, but individually published studies showed inconclusive results. This meta-analysis aimed to derive a precise estimation of the relationships between HIF1A Pro582Ser polymorphism and the risk of digestive tract cancers. We searched CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from inception through May 1, 2013. Meta-analysis was performed using the STATA 12.0 software. We assessed 6 case-control studies that included a total of 911 digestive tract cancer patients and 2774 healthy controls. Our meta-analysis indicated that HIF1A Pro582Ser polymorphism was associated with an increased risk of digestive tract cancer. Subgroup analysis by ethnicity suggested that HIF1A Pro582Ser polymorphism might increase an individual's susceptibility to digestive tract cancer in Asian populations. However, similar association was not observed in Caucasian populations. In conclusion, our findings suggest that HIF1A Pro582Ser polymorphism may contribute to the risk of digestive tract cancers, especially in Asian populations.

IGF1(CA)19 and IGFBP-3-202A/C Gene Polymorphism and Cancer Risk: A Meta-analysis

Insulin-like growth factor 1 (IGF1)(CA)19 and insulin-like growth factor-binding protein-3 (IGFBP-3)-202A/C gene polymorphisms had been focused by many epidemiological studies recently, which were associated with common cancer risk including colorectal, breast, prostate, and lung cancer. However, the findings of epidemiological investigations are not coincident. We did a systematic review and meta-analysis of case-control studies, including studies nested in cohorts, of the association between IGF1(CA)19 and IGFBP-3-202A/C gene polymorphism and prostate, colorectal, premenopausal and postmenopausal breast cancer. We identified 17 eligible studies (24 datasets), which included 9,744 cases and 11,332 controls. The result displays that individuals carrying (CA)19 allele had a subtly decreased risk of all cancer sites [OR(95% CI) 0.92(0.87,0.97); 0.882(0.809,0.962); 0.902(0.849,0.958)] and postmenopausal breast cancer [OR(95% CI) 0.893(0.832,0.959); 0.834(0.719,0.968); 0.862(0.776,0.958)] in allele contrast model, CA19/CA19 vs. non-CA19/non-CA19 model, and recessive genetic model. In subgroup analysis according to ethnicities, (CA)19 repeat polymorphism had an increased risk of common cancers in Asian [OR (95% CI) of allele contrast model: 1.105(1.000,1.224); additive model: 1.103(0.844,1.441), 1.197(1.013,1.413); recessive model: 1.039(0.831,1.300); and dominant model: 1.191(1.030,1.376)]. On the other hand, IGFBP-3-202A/C gene polymorphism did not seem to be associated with all the cancer sites in any genetic model and ethnicity. In conclusion, the result of this meta-analysis indicates that the IGF1(CA)19 polymorphism is a candidate gene polymorphism for cancer susceptibility regardless of environmental factors, especially in Asian.

Lack of Association between Cytotoxic T-Lymphocyte Antigen-4 −318C/T Polymorphism and Cancer Risk: A Meta-Analysis of Case-Control Studies

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is important for the down regulation of T-cell activation. Number of studies assessed the association between CTLA-4 -318C/T polymorphisms and cancer in different populations. However, the studies have provided conflicting results. We performed a meta-analysis to examine the association between CTLA-4 -318C/T polymorphisms and cancer susceptibility. Eligible studies were identified by searching several databases for relevant reports published up to September 30, 2012. Sixteen eligible studies with a total of 6190 patients and 6560 controls were included to summarize the association between CTLA-4 -318C/T polymorphisms and the risk of cancer. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Overall, no significant associations were found in all genetic models when all studies were pooled into the meta-analysis (for -318C/T polymorphisms as estimated using a fixed effect model: TT vs. (CC + CT), OR = 1.02, 95% CI = 0.83-1.24; (TT + CT) vs. CC, OR = 1.20, 95% CI = 1.00-1.44; TT vs. CC, OR = 1.09, 95% CI = 0.74-1.59; CT vs. CC, OR = 1.21, 95% CI = 1.00-1.46). In further subgroup analyses for the -318C/T polymorphisms, stratified by design of ethnicity, cancer types, solid tumors to non-solid tumors, epithelial tumors to non-epithelial tumors, no significant associations were found in any subgroup of the population. This meta-analysis strongly suggests that -318C/T polymorphisms in CTLA-4 are not associated with an increased risk of cancer.

Effectiveness of Haemophilus influenzae Type b Vaccines Administered According to Various Schedules

Conjugate vaccines against Haemophilus influenzae type b (Hib) are widely used. The full implications of Hib vaccination schedule for vaccine effectiveness (VE) are unclear. We searched the literature for observational studies reporting the effectiveness of conjugate Hib vaccines administered according to different schedules. We summarized dose-specific VE estimates, where appropriate, using random effects meta-analysis. Thirty-one eligible articles (reporting 30 studies conducted in 17 countries) were identified. Meta-analysis of case-control studies using community controls produced VE estimates against Hib meningitis of 55% (95% confidence interval: 2-80%, based on 3 studies), 96% (86-99%, 3 studies) and 96% (86-99%, 4 studies) after 1, 2 and 3 doses of vaccines other than the polyribosyl ribitol phosphate outer membrane protein vaccine. Estimates were similar using hospital controls. VE against invasive Hib disease in case-control studies was estimated as 59% (30-76%, 3 studies) and 97% (87-99%, 3 studies) for 1 and 3 doses (insufficient data were identified to estimate 2-dose VE). Point estimates from 2 studies suggested VE>90% after 1 dose of the polyribosyl ribitol phosphate outer membrane protein vaccine, but meta-analysis was not possible. Using data from 4 cohort studies, 3-dose VE was estimated as 94% (88-97%). There was some evidence that Hib vaccine was less effective when administered with acellular (rather than whole cell) pertussis vaccine. Weak evidence from 2 studies suggested that a booster confers some additional protection following full primary vaccination and may compensate for an incomplete primary series. Observational data suggest that ≥2 doses of Hib vaccine are required for high effectiveness, but do not strongly favor any particular schedule.

CYP2D6 phenotypes and Parkinson's disease risk: A meta-analysis

BackgroundCYP2D6 polymorphisms have been reported to be associated with Parkinson's disease (PD) susceptibility, but the results of these previous studies were inconsistent. ObjectivesTo explore whether PD patients with CYP2D6 gene variation have different risk to PD to those with normal function of CYP2D6. MethodsSystematic review with meta-analysis of case-controlled studies on the association between CYP2D6 and PD risk was conducted. Studies published up to August 1, 2013 were identified by searching electronic databases PubMed and Embase. Odds ratios (ORs) together with their corresponding 95% confidence intervals (CIs) were used to estimated the association between CYP2D6 polymorphisms and PD risk in different phenotype models. Meta-regression, subgroup analysis, sensitivity analysis and publication bias were also performed. ResultsA total of 3521 PD Patients and 4476 controls from 29 case–control studies were identified. Overall, a borderline significant influence of the CYP2D6 polymorphisms on PD risk was observed (OR: 1.07, 95%CI: 0.99–1.16, p=0.106). Significant association was found when comparisons were performed in different phenotypes in PM versus EM (OR=1.33, 95% CI=1.01–1.74, p=0.044) and PM versus IM+EM (OR=1.32, 95% CI=1.11–1.56, p=0.002). In subgroup analysis stratified by country, significant association was demonstrated in British but not in other white subjects. No significant association was detected in subgroup analysis according to the age of onset and the source of patients. ConclusionThe present meta-analysis demonstrated that the poor metabolizer phenotype of CYP2D6 confers a significant genetic susceptibility to PD in Caucasians, especially in British white subjects.

The Influence of Angiotensin Converting Enzyme and Angiotensinogen Gene Polymorphisms on Hypertrophic Cardiomyopathy

Some studies have reported that angiotensin converting enzyme (ACE) and angiotensinogen (AGT) genes have been associated with hypertrophic cardiomyopathy (HCM). However, there have been inconsonant results among different studies. To clarify the influence of ACE and AGT on HCM, a systemic review and meta-analysis of case-control studies were performed. The following databases were searched to indentify related studies: PubMed database, the Embase database, the Cochrane Central Register of Controlled Trials database, China National Knowledge Information database, and Chinese Scientific and Technological Journal database. Search terms included “hypertrophic cardiomyopathy”, “angiotensin converting enzyme” (ACE) or “ACE” and “polymorphism or mutation”. For the association of AGT M235T polymorphism and HCM, “angiotensin converting enzyme” or “ACE” was replaced with “angiotensinogen”. A total of seventeen studies were included in our review. For the association of ACE I/D polymorphism and HCM, eleven literatures were included in the meta-analysis on association of penetrance and genotype. Similarly, six case-control studies were included in the meta-analysis for AGT M235T. For ACE I/D polymorphism, the comparison of DI/II genotype vs DD genotype was performed in the present meta-analysis. The OR was 0.73 (95% CI: 0.527, 0.998, P = 0.049, power = 94%, alpha = 0.05) after the study which deviated from Hardy-Weinberg Equilibrium was excluded, indicating that the ACE I/D gene polymorphism might be associated with HCM. The AGT M235T polymorphism did not significantly affect the risk of HCM. In addition, ACE I/D gene polymorphism did not significantly influence the interventricular septal thickness in HCM patients. In conclusion, the ACE I/D polymorphism might be associated with the risk of HCM.

Smoking and carpal tunnel syndrome: A meta‐analysis

We assessed the association between smoking and carpal tunnel syndrome (CTS) and estimated the magnitude of the association with meta-analysis. The PubMed, Embase, Scopus, and SciVerse databases were searched through December 2012. Thirteen studies were included in the meta-analysis. Cross-sectional studies reported an association between current smoking and CTS (pooled odds ratio (OR) = 1.99, 95% confidence interval (CI) 1.38-2.60, I-squared = 0%). Meta-analyses of case-control studies did not, however, show an association between smoking and CTS (pooled OR = 1.04, 95% CI 0.95-1.12, I-squared = 0.0%) or surgery due to CTS (pooled OR = 0.99, 95% CI 0.82-1.15, I-squared = 0%). Moreover, smoking was not associated with CTS in the meta-analysis of cohort studies (pooled OR = 0.97, 95% CI 0.45-1.50, I-squared = 0%). We found an association between smoking and CTS in cross-sectional studies. This association should be explored further in appropriately designed case-control and cohort studies. Muscle Nerve 49:345-350, 2014.

XRCC1 Gene Polymorphisms and the Risk of Differentiated Thyroid Carcinoma (DTC): A Meta-Analysis of Case-Control Studies

BackgroundPrevious studies investigating the association between X-ray repair cross-complementing group 1 (XRCC1) polymorphisms and thyroid cancer risk have yielded inconsistent results. This meta-analysis was performed to derive a more precise estimation of the relationship between three XRCC1 polymorphisms and thyroid cancer risk.Methods/Principal FindingsPubMed and EMBASE database were systematically searched to identify relevant studies. 10 publications were selected for this meta-analysis, including 11 studies for Arg399Gln polymorphism (1726 cases and 3774 controls), 7 studies for Arg194Trp polymorphism (1037 cases and 2487 controls) and 8 studies for Arg280His polymorphism (1432 cases and 3356 controls). The results in total population did not show any significant association between these three polymorphisms and the risk of DTC for all genetic models. However, when stratified by ethnicity, the results showed that Arg280His polymorphism was associated with an increased risk of DTC among Caucasians (Arg/His vs. Arg/Arg: OR = 1.45, 95% CI = 1.09–1.93; dominant model: OR = 1.43, 95% CI = 1.08–1.89; additive model: OR = 1.38, 95% CI = 1.05–1.80), whereas individuals carrying Arg/His genotype have a significantly reduced risk of DTC among Asians (Arg/His vs. Arg/Arg: OR = 0.71, 95% CI = 0.51–0.98). We also detected that 399Gln variant allele carriers might presented an overall decreased risk of DTC in mixed population. Furthermore, subgroup analyses by histological subtype revealed that Arg194Trp polymorphism was significantly associated with reduced risk for papillary thyroid carcinoma (PTC) (dominant model: OR = 0.71, 95% CI = 0.50–0.99).ConclusionsThis meta-analysis suggests that Arg280His polymorphism might contribute to the susceptibility of DTC among Caucasians, whereas it might provide protective effects in Asians against the risk of DTC. Additionally, our results support the protective role of Arg194Trp polymorphism in developing PTC, and show evidence of an association between Arg399Gln polymorphism and decreased risk of DTC in mixed population.

Decreased TGFBR1 signaling and breast cancer.

1548 Background: We previously identified TGFBR1*6A (rs11466445), a hypomorphic TGF-beta type 1 receptor variant that is associated with cancer risk, has impaired TGF-beta signaling capability, and enhances the migration and invasion of breast cancer cells (Cancer Res 2008, 68:1319). Two recent large meta-analyses of case control studies have found a significant association between TGFBR1*6A and risk of breast cancer (Mol Biol Rep 2010 37:3227; PLoS One 2012,7(8). Rs7034462 is a single nucleotide polymorphism (SNP) in a noncoding region more than 9 kilobases upstream of TGFBR1 exon 1, which has been shown to be associated with decreased TGFBR1 expression similar to TGFBR1*6A (J Exp Clin Cancer Res 2010, 29:57). In this study we tested the hypothesis that rs7034462 may be associated with breast cancer risk. Methods: rs7034462 was genotyped in DNA obtained from patients with breast cancer and their unaffected sisters recruited by the Breast Cancer Family Registry (B-CFR). Results: The median age of cases and controls was 48.8 and 47.6 years, respectively. Using a simple case-control genetic association analysis for this family-matched population, rs7034462 was found to be associated with breast cancer risk. Conclusions: TGFBR1 rs7034462 is emerging as a low penetrance breast cancer susceptibility allele suggesting that two distinct TGFBR1 SNPs, each associated with decreased TGFBR1 expression, may modulate breast cancer risk. [Table: see text]

Surgery and risk for multiple sclerosis: a systematic review and meta-analysis of case-control studies.

BackgroundAlthough the precise etiology of multiple sclerosis is largely unknown, there is some speculation that a prior history of surgery may be associated with the subsequent risk for developing the disease. Therefore, we aimed to examine surgery as a risk factor for the diagnosis of multiple sclerosis.MethodsWe searched for observational studies that evaluated the risk for developing multiple sclerosis after surgery that occurred in childhood (≤ 20 years of age) or “premorbid” (> 20 years of age). We specifically included surgeries classified as: tonsillectomy, appendectomy, adenoidectomy, or “surgery”. We performed a systematic review and meta-analyses and calculated odds ratios (OR) and their 95% confidence intervals (CIs) using a random effects model.ResultsWe identified 33 case–control studies, involving 27,373 multiple sclerosis cases and 211,756 controls. There was a statistically significant association between tonsillectomy (OR = 1.32, 95% CI 1.08-1.61; 12 studies, I2 = 44%) and appendectomy (OR = 1.16, 95% CI 1.01-1.34; 7 studies, I2 = 0%) in individual’s ≤ 20 years of age and the subsequent risk for developing multiple sclerosis. There was no statistically significant association between risk for multiple sclerosis and tonsillectomy occurring after age 20 (OR = 1.20, 95% CI 0.94-1.53; 9 studies, I2 = 32%), in those with appendectomy at > 20 years (OR = 1.26, 95% CI 0.92-1.72; 5 studies, I2 = 46%), and in those with adenoidectomy at ≤ 20 years of age (OR = 1.06, 95% CI 0.68-1.68; 3 studies, I2 = 35%). The combined OR of 15 studies (N = 2,380) looking at “surgery” before multiple sclerosis diagnosis was not statistically significant (OR = 1.19, 95% CI 0.83-1.70; I2 = 71%).ConclusionsWe found a small but statistically significant and clinically important increased risk for developing multiple sclerosis, in those with tonsillectomy and appendectomy at ≤ 20 years of age. There was no convincing evidence to support the association of other surgeries and the risk for multiple sclerosis. Well-designed prospective etiological studies, pertaining to the risk for developing multiple sclerosis, ought to be conducted and should include the examination of various surgeries as risk factors.

Abstract 4856: Association between breast cancer and constitutively decreased TGFBR1 signaling.

Abstract Background: We previously identified a hypomorphic TGF-β type 1 receptor variant (TGFBR1*6A) that is associated with cancer risk, has impaired TGF-β signaling capability and enhances the migration and invasion of breast cancer cells. Two recent large meta-analyses of case control studies have found a significant association between TGFBR1*6A and risk of breast cancer (ORs 1.16,1.01-1.34; 1.15,1.01-1.31). Rs7034462 is a single nucleotide polymorphism (SNP) in a noncoding region more than 9 kilobases upstream of TGFBR1 exon 1, which has been shown to be associated with decreased TGFBR1 expression. In this study we tested the hypothesis that rs7034462 may be associated with breast cancer risk. Methods: rs7034462 was genotyped in DNA obtained from patients with breast cancer and healthy controls recruited by the Breast Cancer Family Registry. The samples in this multinational cohort were primarily from younger patients (average age 49.4 and 48.1 years for cases and controls, respectively, at time of interview). Results: Using the Cockerham model, rs7034462 was found to be associated with breast cancer risk under the dominance genetic effect but, unexpectedly, there was a significant decreased association with breast cancer for this SNP under the additive genetic effect for this model. SNP Cases Controls Cockerham Model Genetic Effect Odds Ratio 95% CI P rs7034462 (n = 2,934) 1509 1425 Additive 0.60 0.38-0.93 0.020 Dominance 2.09 1.29-3.38 0.002 Conclusion: rs7034462 heterozygotes have an increased risk of breast cancer but rare homozygotes have a decreased risk. This is the first evidence in humans that constitutively decreased TGFBR1-mediated TGF-β signaling is associated with breast cancer risk. Citation Format: John C. Henegan, Lakisha Moore-Smith, Nengjun Yi, Kui Zhang, Habibul Ahsan, Alice S. Whittemore, Boris Pasche, BCFR Co-Investigators. Association between breast cancer and constitutively decreased TGFBR1 signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4856. doi:10.1158/1538-7445.AM2013-4856

Abstract 1406: Tgfbr1 haploinsufficiency is a potent modifier of breast cancer risk.

Abstract Background: We previously identified a hypomorphic TGF-β type 1 receptor variant (TGFBR1*6A) that is associated with cancer risk and has impaired TGF-β signaling capability. Two recent large meta-analyses of case control studies have found a significant association between TGFBR1*6A and risk of several types of cancer, including breast cancer (ORs 1.16,1.01-1.34; 1.15,1.01-1.31). To investigate the effects of constitutively decreased TGFBR1 signaling on cancer development, we developed a novel mouse model of Tgfbr1 haploinsufficiency to mimic the decreased TGFBR1 signaling observed in individuals with higher risk of cancer. Using this model, we demonstrated that Apcmin;Tgfbr1+/- mice develop more than twice as many intestinal tumors as Apcmin controls. The aim of the current study was to assess the effects of Tgfbr1 haploinsufficiency on breast carcinogenesis by crossing Tgfbr1+/- mice with the MMTV-c-Neu mouse model. Methods: Fully congenic (100%) FVB/N-Tgfbr1+/- mice were crossed with FVB/N-Neu mice, and female virgin progeny were kept for analysis. Mammary glands were collected from 10, 12, and 40 week-old Neu and Neu;Tgfbr1+/- mice. Mice assessed for tumor development were sacrificed 80 days after the initial tumor palpation or at the earliest sign of morbidity. Whole lungs, tumor tissue, and primary tumor cells were collected for additional analysis. Long-term evaluation of 2-year-old Tgfbr1+/+ and Tgfbr1+/- mice was also conducted to directly assess the impact of Tgfbr1 haploinsufficiency on mammary gland and lung development. Results: Mammary gland whole mounts revealed that Neu;Tgfbr1+/- mice have more ductal branching at all time points compared to Neu mice. In the assessment of breast tumor development, Neu;Tgfbr1+/- mice were observed to have a significantly shorter tumor latency period (171 days) compared to Neu mice (220 days) (p=0.004). Seventy percent of Neu;Tgfbr1+/- mice (14/20) developed surface lung metastases, while 36.4% were observed in Neu mice (8/22), a borderline significant difference (p=0.061). The TGF-β-mediated growth inhibition of Neu;Tgfbr1+/- primary tumor cells was 32.2% lower than that of Neu tumor cells (p=0.007). Neu;Tgfbr1+/- tumor cells and tissue had significantly reduced Smad2/3 phosphorylation and total Cdkn1b (p27Kip1) expression compared to Neu mice. Long-term evaluation of Tgfbr1+/- and wild-type mice revealed no signs of mammary gland hyperplasia or differences in lung fibrosis in either group. Conclusion: This study is the first in vivo evidence that Tgfbr1 haploinsufficiency promotes breast carcinogenesis by increasing breast cancer proliferation. The relevance of this data to human breast cancer warrants additional investigations into the effects of decreased TGFBR1 signaling on tumor development and progression and identifies potential targets for prevention and treatment. Citation Format: Michael J. Pennison, Diana S. Rosman-Balzer, Lakisha Moore-Smith, Jacquelyn W. Zimmerman, Trenton R. Schoeb, Andra R. Frost, Ming Zhang, Peter M. Siegel, Boris C. Pasche. Tgfbr1 haploinsufficiency is a potent modifier of breast cancer risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1406. doi:10.1158/1538-7445.AM2013-1406 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Association of Tumor Necrosis Factor-α Gene G-308A Polymorphism with Dilated Cardiomyopathy: A Meta-Analysis

Published data on the association between tumor necrosis factor-α (TNF-α) G-308A gene polymorphism and dilated cardiomyopathy (DCM) risk are inconclusive. To clarify the association of TNF-α G-308A gene polymorphism and DCM, a meta-analysis of case-control studies was performed. Some databases, such as PubMed and Embase, were searched to indentify related studies. Search terms included dilated cardiomyopathy, tumor necrosis factor-alpha or TNF-α or TNF alpha or tumor necrosis factor alpha, and polymorphism or mutation. Eight case-control studies involving 1487 DCM cases and 1734 normal controls were included in the meta-analysis to assess the purported association between the TNF-α G-308A gene polymorphism and the risk of DCM. A dominant genetic model was used and the comparison of GA/AA genotype versus GG genotype was performed in the present meta-analysis. The odds ratio was 1.42 (95% confidence interval: 1.05, 1.93, P=0.02), manifesting frequency of the TNF-α-308 GA/AA genotype was higher in DCM patients than the control group. TNF-α G-308A nucleotide transition might be associated with the risk of DCM.

Methylenetetrahydrofolate Reductase Genetic Polymorphisms and Esophageal Squamous Cell Carcinoma Susceptibility: A Meta-analysis of Case-control Studies

Genetic factors and environmental factors play a role in pathogenesis of esophageal squamous cell carcinoma (ESCC). Previous studies regarding the association of folate intake and Methylenetetrahydrofolate reductase C677T polymorphism with ESCC was conflicting. We conducted a meta-analysis to investigate the association of MTHFR C677T and folate intake with esophageal cancer risk. MEDLINE, EMBASE and the Chinese Biomedical Database were searched in our study. The quality of studies were evaluated by predefined scale, and The association of polymorphisms of MTHFR C677T and folate intake and ESCC risk was estimated by Odds ratio (ORs) with 95% confidence intervals (CIs). 19 studies (4239 cases and 5575 controls) were included for meta-analysis. A significant association was seen between individuals with MTHFR 677 CT [OR(95%)=1.47(1.32-1.63)] and TT [OR(95%)=1.69(1.49-1.91)] genotypes and ESCC risk (p<0.05). Low intake of folate had significantly higher risk of esophageal cancer among individuals with CT/TT genotype [OR(95%)=1.65(1.1-2.49)], while high intake of folate did not find significant high risk of esophageal cancer among individuals with CT/TT genotype [OR(95%)=1.64 (0.82-3.26)]. Our meta-analysis indicated the folate intake and MTHFR 677CT/TT are associated with the risk of ESCC, and folate showed a significant interaction with polymorphism of MTHFR C677T.