PLCE1) rs2274223 A>G and risk of digestive tract cancer (DTC) remains inconclusive. To derive a more precise estimation of the association, we conducted a meta-analysis on all eligible case–control studies involving 8281 cases and 10,532 controls.To date, the association between phospholipase C epsilon 1 (PLCE1 rs2274223 polymorphism and digestive tract cancer risk. The pooled odds ratio (OR) and the 95% confidence interval (95% CI) were calculated using a fixed or random effect model. Heterogeneity, publication bias, and sensitivity analysis were also explored.A comprehensive search was conducted to identify all eligible studies of PLCE1 rs2274223 A>G polymorphism was associated with risk of DTC in all genetic models . The recessive model did not reach statistically significance when the P values were Bonferroni corrected to 0.0125. In the stratified analysis by cancer type, ethnicity, and source of controls, significantly increased risk was observed for esophagus cancer, Asians in three genetic models , population-based studies in all genetic models, and for gastric cancer in the heterozygote comparison and dominant model after Bonferroni correction. However, in the subsite of gastric cancer, no significant association was found either in cardia or non-cardia gastric cancer.Overall, the PLCE1 rs2274223 A>G polymorphism was significantly associated with increased risk of DTC, especially among Asian populations. Due to some minor limitations, our findings should be confirmed in further studies.Our study indicated that  Digestive tract cancer (DTC) referring to a group of malignancies  is the most common cancer worldwide. It has been estimated that there were nearly 316,970 new diagnosed cases and 147,150 deaths caused by DTC in the United States in 2011 Helicobacter pylori (HP) infection in gastric cancer, human papillomavirus (HPV) is recognized as a major risk factor for oropharygeal cancer It has been suggested that DTC carcinogenesis is a combined effect of multiple factors, which contains environmental factors, dietary habits and inherited susceptibility PLCE1 gene, located on chromosome 10q23, is a unique member of the phospholipase family PLCE1 encodes the phospholipase C epsilon 1 (PLCε1) that catalyses the hydrolysis of phosphatidylinositol-4,5-bisphosphate into the secondary messengers inositol 1,4,5-trisphosphate and diacylglycerol (DAG), which participate in cell growth, differentiation and gene expression PLCE1 has been speculated to be a effector of small GTPases of the Ras, Rap and Rho families, and contains a guanine nucleotide exchange factor domain for Ras-like small GTPases at its N-terminus and two Ras-binding domains at its C-terminus PLCE1 plays crucial roles in carcinogenesis and progression of several types of cancers, including cancers of the intestine, skin, bladder, colorectal and head and neck The PLCE1 gene and result in the amino acid change from histidine (His) to arginine (Arg) at codon 1927 of PLCE1. In 2010, two large-scale genome-wide association studies (GWASs) simultaneously reported that the new and notable low-penetrance susceptibility locus rs2274223 was strongly associated with risk of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) in Chinese population PLCE1 rs2274223 SNP plays a role in esophageal adenocarcinoma (EAC) or ESCC susceptibility Rs2274223 (A>G) is a non-synonymous single nucleotide polymorphism (SNP) located in 26th exon of the To date, the association between the rs2274223 (A>G) and the susceptibility of DTC are inconclusive in different cancer types and ethnicities, partially because of the different effects of the polymorphism on variants of DTC risk and the relatively small sample size in each of published studies. Hence, we conducted a meta-analysis on all eligible case–control studies involving 8281 cases and 10,532 controls to estimate the overall DTC risk of the rs2274223 (A>G) polymorphism.PLCE1”, “10q23”, “genetic susceptibility”, “SNP”, “polymorphism” or “variation”, and “cancer” or “carcinoma” or “neoplasia”. The search was limited to English-language articles. We also used a hand search of references of original studies on this topic in order to identify additional studies. Studies included in our meta-analysis have to meet the following inclusion criteria: (a) evaluated the PLCE1 rs2274223 polymorphism and cancer risk, (b) used a case–control design and (c) contained available genotype frequency.We searched PubMed and Embase (updated to 28th February 2013) using the following search terms: “rs2274223”, “Two investigators independently extracted data and reached a consensus on all the items in cases of discordance. For each eligible study, the following data were extracted: the first author’s name, year of publication, ethnicity, country of origin, cancer type, value of Hardy–Weinberg equilibrium (HWE), source of controls, genotyping method,and numbers of genotyped cases and controls. Ethnic descents were categorized as European and Asian (the only one African study was excluded). For studies including subjects of different sites of gastric cancer (cardia and non-cardia), data were extracted separately whenever possible.PLCE1 rs2274223 polymorphism and cancer risk was assessed by the odds ratio (OR) and the 95% confidence interval (95% CI). Pooled ORs were obtained from the combination of individual studies by heterozygote comparison (GA vs. AA), homozygote comparison (GG vs. AA), a dominant model (AA/GA vs. GG), and a recessive model (AA vs. GA/GG). The significance of pooled ORs was determined using the Z-test. Bonferroni correction was utilized for multiple testing. Because multiple comparisons were performed 4 times respectively, the P value lesser than 0.05/4 (0.0125) was accepted for statistical significance after Bonferroni correction. Both the Cochran’s Q statistic to test for heterogeneity and the I2 statistic to quantify the proportion of the total variation due to heterogeneity were calculated to estimate heterogeneity among the included studies P value of the Q test was <0.05, indicating a lack of heterogeneity across studies, the summary OR estimate of each study was calculated by the fixed effects model (the Mantel–Haenszel method) P values.The strength of the association between the PLCE1 rs2274223 polymorphism and the susceptibility to digestive tract cancer is presented in P<0.001, I2 = 35.70%; homozygote comparison, GG vs. AA: OR = 1.30, 95% CI = 1.06–1.60, P = 0.012, I2 = 65.60%; dominant model, GG/GA vs. AA: OR = 1.20, 95% CI = 1.10–1.32, P<0.001, I2 = 57.60%; recessive model, GG vs. GA/AA: OR = 1.21, 95% CI = 1.01–1.46, P = 0.040, I2 = 60.00%). However, after Bonferroni correction, this association in recessive model did not reach statistically significance when the P values were correction to 0.0125.The evaluation of the association between the PLCE1 rs2274223 polymorphism was significantly linked to a higher risk for esophageal cancer . However, the recessive model did not reach statistically significance when the P values were Bonferroni corrected. We also observed increased susceptibility of gastric cancer in heterozygote comparison  and dominant model . No significant associations were found in the “others” group .Additionally, in the analysis stratified by cancer types , the PLCP<0.001, I2 = 28.00%; GG vs. AA: OR = 1.51, 95% CI = 1.13–2.00, P = 0.005, I2 = 62.20%; GG/GA vs. AA: OR = 1.29, 95% CI = 1.15–1.44, P<0.001, I2 = 53.20%; GG vs. GA/AA: OR = 1.39, 95% CI = 1.06–1.80, P = 0.016, I2 = 57.80%), but the recessive model did not reach statistically significance Bonferroni correction, whereas no significant associations were detected among the European group . By contrast, studies with hospital-based controls only presented significant associations in heterozygote comparison  and dominant model comparisons , but this did not reach statistically significance when the P value was Bonferroni corrected. In the subgroup analysis by tumor sites of gastric cancer, there was no significant association detected in any genetic comparisons either in cardia or non-cardia gastric cancer.For the Asian group, every genetic comparison produced significantly increased risks , dominant model comparison  and recessive model comparison  but not for the heterozygote comparison . Thus, we assessed the source of heterogeneity for the dominant model comparison by examining cancer type, ethnicity, source of controls and genotyping method. Meta-regression analyses showed that none of these concomitant variables could account for the substantial heterogeneity observed .When evaluating the association between the In order to reflect the influence of the individual dataset to the pooled ORs, we deleted a single study involved in the meta-analysis each time, but the corresponding pooled ORs were not altered materially (data not shown), suggesting that our results were statistically robust.P = 0.205; GG/GA vs. AA: P = 0.137).Begg’s funnel plot and Egger’s test were performed to assess the publication bias of the literature. The shape of the funnel plots did not reveal any evidence of obvious asymmetry  PLCE1 protein calcium-dependent lipid-binding (C2) domain.The PLCE1 protein is a member of the phospholipase family and functions as an effector of guanosine triphosphatases (GTPases) such as Ras, Rap1 and Rap2 involving regulation of cell growth, differentiation and apoptosis PLCE1 rs2274223 SNP played a role in EAC or ESCC susceptibility in American and Dutch PLCE1 rs2274223 AG/GG genotypes had a higher survival rate than those carrying the AA genotype, which suggested that the rs2274223-G allele may be associated with the prognosis of the gastric cancer patients Wang et al. and Abnet et al. simultaneously reported the strong association of the new and notable low-penetrance susceptibility locus rs2274223 with the increased risk of ESCC and GCA in the Chinese population by two large-scale GWASs PLCE1 rs2274223 polymorphism on the risk of variants of DTC had been conducted, the results were conflicting and inconclusive because of various reasons, such as different ethnicities, resident areas, sample size, environmental factors and diet habits. To provide a more comprehensive analysis on the association, we carried out this meta-analysis based on eleven case–control studies with 18,813 participants and indicated that G allele of the PLCE1 rs2274223 A>G polymorphism was associated with increased risk of DTC.Although many epidemiological studies regarding the In the analysis stratified by cancer type, we observed increased susceptibility to esophageal cancer in the three genetic comparisons  and to gastric cancer in the heterozygote comparison (GA vs. AA) and the dominant model comparison (GG/GA vs. AA) after Bonferroni correction. The results were consistent with the conclusions of most previous studies PLCE1 rs2274223 A>G polymorphism might be masked or magnified by the presence of other genes which were unidentified yet in the development of cancer. Other factors such as selection bias, different matching criteria and limited number of studies with available data may have insufficient statistical power to detect a slight difference and may also generate a fluctuated risk estimate.When compared by ethnicity, statistically significantly increased risks were found among Asians for three genetic comparison  but not Europeans after Bonferroni correction. Although the exact mechanism for these ethnic differences is still unknown, one possible reason is due to differences in genetic backgrounds and in the environmental and lifestyle context  We also observed a significantly increased DTC risk among studies using population-based controls in every genetic model, but not using hospital-based controls. Some biases may exist in hospital-based studies, for such controls may represent a sample of an ill-defined reference population instead of the general population, particularly when the genotypes investigated were associated with the disease that the hospital-based controls may have. Thus, a proper and representative cancer-free control subject is very important in reducing biases in such genotype association studies.Several previous studies showed that the association between rs2274223 and the risk of gastric cancer was stronger in the cardia than in the non-cardia gastric cancer HP infection. Lacking of information may cause serious confounding bias.Some limitations of this meta-analysis may have affected the objectivity of the conclusions and should be considered in interpreting the results. First, the quantity of published studies was not sufficiently large for a comprehensive analysis, and the lack of original data in some studies limited our further evaluation of potential interactions, such as ethnicity, anatomic subsite and pathological subtype of cancer. Second, although perfect searching strategy was used to identify eligible studies for current meta-analysis, it was still possible that a few studies meeting inclusion criteria were not included. Third, the overall outcomes were based on unadjusted estimates, while a more precise evaluation should be conducted if more detailed individual data were available, such as age, sex, histological types and PLCE1 rs2274223 A>G polymorphism and DTC risk, and further showed the significant association especially among Asians rather than Europeans. This study may also provide a potential genetic marker and a new insight into the etiology of DTC. Second, we pooled a substantial number of cases and controls from different studies, which greatly increased the statistical power of the analysis. Third, no publication biases were detected, which indicated that the results were likely unbiased.In spite of these limitations, our present meta-analysis also had some advantages. First, we estimated the association conclusively between the PLCE1 rs2274223 A>G polymorphism is associated with DTC risk, especially with gastric cancer and esophageal cancer. The PLCE1 rs2274223 A>G polymorphism is an independent risk factor for the development of DTC, and will probably be a potential therapeutic target for new drugs. Nevertheless, larger and well-designed multicentric studies including other potential DTC risks  should be carried out to validate our findings. Furthermore, research based on the non-DTCs  should be performed to explore the association between PLCE1 gene polymorphisms and cancer risks.In conclusion, our meta-analysis suggests that the Checklist S1A PRISMA checklist for this meta-analysis.(DOC)Click here for additional data file.


The methylenetetrahydrofolate reductase (MTHFR) enzyme catalyzes the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and methyl donors. The methyl donors are required for the conversion of homocysteine to methionine. Mutation of MTHFR 677 C > T disrupts its thermostability therefore leads to defective enzyme activities and dysregulation of homocysteine levels.12 and folic acid levels.This case-control study (n = 367) was conducted to investigate the correlation of the MTHFR gene polymorphism [NM_005957] and psoriasis vulgaris amongst the Malaysian population. Overnight fasting blood samples were collected from a subgroup of consented psoriasis vulgaris patients and matched controls (n = 84) for the quantification of homocysteine, vitamin Bχ2 = 0.733, p = 0.392). No significant association between homocysteine levels and MTHFR gene polymorphism in cases and controls were observed . However, homocysteine levels in cases were negatively correlated with vitamin B12 (r = -0.173) and folic acid (r = -0.345) levels. Vitamin B12 and folic acid levels in cases were also negatively correlated (r = -0.164).There was no significant increase of the MTHFR 677 C > T mutation in patients with psoriasis vulgaris compared with controls (Our results indicate that there was no significant association between the MTHFR gene polymorphism and psoriasis vulgaris in the Malaysian population. There was no significant increase of the plasma homocysteine level in the psoriasis patients compared to the controls. Psoriasis vulgaris also known as chronic plaque psoriasis, is a common subtype of psoriasis that affects about 80% of psoriatic patients worldwide . Psorias12 and folic acid. Therefore, the deficiencies of the Vitamin B12 and folic acid will lead to hyperhomocysteinaemia and hypomethioninaemia [The MTHFR gene NM_005957) is located at chromosome 1 (1p36.3). It catalyses the conversion of 5,10-methylenetetrahydrofolate to 5-methylenetetra-hydrofolate, which then leads to the remethylation of homocysteine to methionine ,9. This 57 is locninaemia -16.MTHFR gene polymorphism has been reported to be associated with psoriasis vulgaris. Significant association of the polymorphism of the MTHFR gene and psoriasis vulgaris was reported in the Chinese population by Wang et al., 2000 . This ChRecent studies also postulated hyperhomocysteinaemia as a risk factor for coronary heart disease, cerebrovascular accident and peripheral vascular diseases . An incrHowever to date, there is no other study that we are aware of which investigate the polymorphism of the MTHFR gene and psoriasis vulgaris on other ethnic groups of the Asian origin. We hypothesized that the functional polymorphism of the MTHFR gene might be associated with psoriasis vulgaris and hyperhomocysteinaemia. The purpose of this hospital-based case-control study was to determine the association of the MTHFR gene polymorphism and psoriasis vulgaris in the Malaysian population which comprises of the 3 major Asian populations: the Chinese, Indian and Malay ethnicities. This study also aim to investigate whether MTHFR 677 C > T polymorphism might play a role in the homocysteine level of the psoriasis vulgaris patients from Malaysia.12 and folic acid levels after fasting for ~ 8 hours. Cases and controls with previous history of ischaemic heart disease, myocardial infarction, cerebrovascular accident, thromboembolic events were excluded from this study. The blood samples were sent to a commercial laboratory  for the measurement of homocysteine, vitamin B12 and folate levels. The protocol of this study was designed according to the Declaration of Helsinki and was approved by the ethics committee of the International Medical University, Malaysia.The cases and controls were recruited from General Hospital Kuala Lumpur and Tuanku Ja'afar Hospital, Seremban, Malaysia from April 2009 to April 2010. All the psoriasis vulgaris patients, cases (n = 200) recruited were Malaysian with either Chinese, Indian or Malay ethnicity. The patients with psoriasis vulgaris were examined and diagnosed by the dermatologists based on clinical examination. The severity of the disease was then scored according to Psoriasis Area and Severity Index (PASI). A mixture of early and late onset of psoriasis vulgaris patients was included in this study (mean age 45.12 ± 14.20). The healthy controls (n = 167) were those without psoriasis vulgaris and were age- (± 5 years), gender- and ethnicity-matched with the respective patients. The samples were determined based on the criteria of 95% confidence and 85% statistical power in determining the confidence intervals of the parameters estimated in this study. The patients and controls were well informed about the nature of this study and their participations were voluntary. Informed consent was obtained from each subject. Approximately 5 mL of blood samples were withdrawn from each case or control. A subgroup (n = 41) of consented patients with homozygous CC, heterozygous CT and homozygous TT genotypes were subsequently selected or recruited for further study. Among the cases recruited (n = 200), only 41 cases consented for the subsequent skin biopsy procedure. The age- (± 5 years), gender- and ethnicity-matched healthy controls (n = 43) were those with homozygous CC, heterozygous CT and homozygous TT genotypes but without psoriasis vulgaris. Their blood samples were collected for the measurement of plasma homocysteine, vitamin BDNA samples were extracted from the whole blood of the cases and controls using DNA extraction kit  according to the manufacturer's protocol. The amount of the DNA was quantified and the quality of the DNA was determined. The MTHFR gene was amplified in a final volume of 25 μL using the following primers: 5'-GAA GCA GGG AGC TTT GAG GC-3' and 5'-CCC ATG TCG GTG CAT GCC TT-3' [12 and folic acid levels between cases and controls irregardless of the genotypes. The association between the plasma homocysteine, vitamin B12 and folic acid levels and the MTHFR polymorphisms were analyzed using 3-way ANOVA. P values were considered statistically significant if they were less than 0.05. The sample size was determined using the power analysis, with the α error and β error set at 0.05 and 0.20 respectively. Approximately 40 subjects per group were sufficient for parametric test  whilst for non-parametric test such as Chi-Square test, the expected frequency of a minimum 5 for each category was sufficient . The measure of skewness and kurtosis were used to assess the normality of the distribution of the parameters .The association between the genotypes of the MTHFR polymorphism and allelic frequencies with the demographic variables was analyzed with Chi-square test. T-test was used to determine the association of homocysteine, vitamin BIn this study, great attention was given to the selection of the cases and the controls. The matching process was conducted to ensure that the cases and controls have similar demographic characteristics. Two hundred psoriasis vulgaris patients, diagnosed clinically by the dermatologists were age-, sex- and ethnicity- matched with 167 healthy controls. Table χ2 = 0.733, p = 0.392). The occurrence of genotype CT was higher amongst cases compared with controls (adjusted odds ratio (OR) 1.11; 95% confidence interval (CI) 0.47 - 2.60). However this was not statistically significant (p = 0.812). The genotype TT was not detected in the cases but was found in two controls as such no further statistical analysis was performed. The frequencies of distribution of the T allele in cases and controls were comparable. No statistically significant difference in the frequency of allelic distribution between cases and controls was seen .The distribution of the MTHFR gene polymorphism amongst cases and controls are shown in Table The association between MTHFR gene polymorphism (CC and CT) and ethnicities  was analyzed. The frequencies of the genotype CT were significantly higher in the Malay population p < 0.002) in the cases compared with controls. The Chi-square test for Goodness-of-Fit was used, since each cell has an expected frequency of at least 5 subjects. Table  in the c12 and folic acid levels of the selected cases (n = 41) and controls (n = 43) were summarized in Table 12 and folic acid levels of cases regardless of the MTHFR gene genotype were compared with the controls. There was no significant difference between these two groups on all the three parameters assessed with t-test analysis . The cases with genotype CT had the highest homocysteine levels, followed by controls with genotype CC, cases with genotype CC and controls with genotype CT. No significant association between homocysteine levels and MTHFR gene polymorphism in cases and controls were seen . Similarly, no significant association between vitamin B12 levels and MTHFR gene polymorphism in both cases and controls was seen . There was no significant association between folic acid levels and MTHFR gene polymorphism in cases and controls  and folic acid (r = -0.345) levels. Similarly, vitamin B12 and folic acid levels in cases were negatively correlated (r = -0.164). Homocysteine levels in controls were negatively correlated with vitamin B12 (r = -0.439) and folic acid (r = -0.598) levels. However, vitamin B12 and folic acid levels in controls were positively correlated (r = 0.250).The correlation between homocysteine, vitamin B12 and folic acid levels in cases and controls were summarized in Table 12 and folic acid levels were analyzed with Three Way ANOVA. Gender was the only variable that was significantly associated with homocysteine levels . Males (mean = 17.00 and SD = 4.06) have significantly (p = 0.001) higher homocysteine levels compared with female (mean = 12.43 and SD = 3.10). It can be concluded that plasma homocysteine levels were not associated with psoriasis vulgaris, MTHFR gene polymorphism and ethnicity.The homocysteine, vitamin B12, similar results were seen as of homocysteine levels. Nonetheless vitamin B12 levels were associated with gender.As for vitamin BBoth cases and controls of the Chinese ethnicity had significantly (p = 0.000) higher folic acid levels  compared with Indians  and Malays . However, folic acid levels in different ethnic groups were not associated with gender (p = 0.062) and MTHFR gene (p = 0.128).The association between MTHFR gene polymorphism and psoriasis vulgaris was reported by Wang et al. (2000)  and was The association of the MTHFR gene polymorphism and psoriasis vulgaris in the Malaysian population i.e. Chinese, Indian and Malay ethnic groups was investigated in this case-control hospital based study. Two hundred patients and 167 controls were recruited. The methodology of this study was conducted according to Wang et al. (2000) . Our resThe prevalence of the MTHFR 677 C > T is variable depending on the geography and ethnicity . Botto e12 and folic acid levels in selected 41 cases and 43 controls. We demonstrated that there was no significant relationship between the MTHFR gene polymorphism and homocysteine, vitamin B12 or folic acid levels in this subset of subjects.The MTHFR gene polymorphism was reported to be associated with hyperhomocysteinaemia which has deleterious effects on the cardiovascular system ,28. Henc12 and folic acid levels compared with the ethnicities and the MTHFR gene polymorphism was analyzed using 3-way ANOVA. We did not find any statistically significant relationship amongst these groups. Nonetheless, males irregardless of the polymorphism of the MTHFR gene have a higher homocysteine levels when compared to the females (p = 0.001). Overall, the Indian males and Malay males have higher homocysteine levels than the Chinese males and a significantly lower folic acid level compared to the Chinese (p = 0.000).The relationship of homocysteine, vitamin BIn Malaysia, the dietary intakes varied amongst the ethnic groups and also varied amongst the genders ,30. The The limitation of this study was the centrality of the recruitment of the subjects in the area of Kuala Lumpur and Seremban and we did not recruit subjects from the northern, eastern or southern states of Malaysia. Perhaps, there would have been a difference in the genotypes distribution in these places compared with the ones we have recruited. Future studies might be warranted to investigate the variation of the MTHFR 677 C > T gene geographically, perhaps on other Asian populations using a bigger sample size and a larger population. The inclusion of other single nucleotide polymorphism of the MTHFR gene would be beneficial to investigate the association of the presence of synergistic effects of the haplotypes and psoriasis vulgaris.This study has again pinpointed the independent hyperhomocysteinaemia irrespective of the possession of psoriasis vulgaris, mutation of the MTHFR gene and its prevalence in the male gender. With the prior knowledge of hyperhomocysteinaemia as a risk for cardiovascular and thromboembolic events, routine homocysteine and folic acid screening should be included as part of psoriasis vulgaris and cardiovascular disease management. The routine supplementation of folic acid in the diet of the psoriasis vulgaris patients could be of benefit to them.In summary, we concluded that the MTHFR 677 C > T gene polymorphism and the T allele occurrence were not significantly associated with psoriasis vulgaris in the Malaysian population. We also concluded that there was no significant association between the plasma homocysteine levels and psoriasis vulgaris with or without the MTHFR gene polymorphism.bp: base pair; DNA: deoxyribose nucleic acid; PCR: polymerase chain reaction; RFLP: reaction fragment length polymorphism; SD: standard deviation; SDS: sodium dodecyl sulphate; SDS-PAGE: sodium dodecyl sulphate polyacrylamide gel electrophoresis; U: unit; Val: Valine; V: volt; vs.: versus.The authors declare that they have no competing interests.SCL participated in the conception of the study, the inception of the study design, carried out the patients sampling, molecular genetic study  and drafting of the manuscript. EDG, SFW, NS, AJ participated in the conception of the study, the inception of the study design, carried out the patients sampling and drafting of the manuscript. N Lee participated in the conception of the study, the inception of the study design and performed the statistical analysis. All authors read and approved the final manuscript.S.C.L is a medical doctor and is currently pursuing her Master of Science (MSc) at the International Medical University. This research paper covered part of her MSc project. E.D.G, S.F.W and N.S are her supervisors for this project. N.L is the statistician overseeing this project and A.J is the co-investigator for this project.


CYP2A6*4) polymorphism and risk of lung cancer.To assess the association between the variant of Cytochrome P450 2A6 whole gene deletion  and a random-effects model (the DerSimonian and Laird method) when appropriate.Two investigators independently searched the PubMed, Elsevier, EMBASE, Web of Science, Wiley Online Library and Chinese National Knowledge Infrastructure (CNKI). Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) for CYP2A6*4 was associated with the risk of lung cancer . When stratifying for population, significant association was observed in Asian . In the overall analysis, a comparably significant decrease in the frequency of *4/*4 genotype was detected between cases and controls in Asian while no *4/*4 genotype was detected in Caucasian in collected data.This meta-analysis included seven eligible studies, which included 2524 lung cancer cases and 2258 controls (cancer–free). Overall, CYP2A6*4 polymorphism is associated with susceptibility of lung cancer in Asian. The whole gene deletion of CYP2A6 may decrease the risk of lung cancer in Asian samples.This meta-analysis suggests that the  Lung cancer is the most common cancer in the world, representing approximately 12% of all new cancer cases, with over 1 million deaths annually, which is the leading cause of cancer death Tobacco carcinogens are the most significant factors for smoking induced cancers. To exert their effects, most tobacco carcinogens require metabolic activation, which is generally carried out by cytochrome P450 (CYP) enzymes. Short-lived electrophile agents produced in metabolic activation process react with DNA, thus causing DNA damage and inducing tumors. Such process, mostly, only happen in tissues where it is generated. Therefore, tissue-specific metabolic activation is of vital importance for tissue susceptibility to carcinogen-induced tumors. Among tobacco's potent carcinogens, tobacco-specific nitrosamines (TSNA) and other nitrosamines are activated by CYP2A enzymes, nicotine is also metabolized by CYP2A enzymes CYP2A6, CYP2A7 and CYP2A13) and one pseudogene (CYP2A18)CYP2A7 so far. CYP2A6 expression is mainly found in the liver, but its protein or mRNA is also expressed in other tissues such as nasal epithelium, trachea, lung and esophagus www.cypalleles.ki.se/cyp2a6.htm). CYP2A6*4 presents a gene deletion that accounts for the majority of poor metabolizer individuals (PM) in Asian populations, and various alleles have been described CYP2A6*4. CYP2A6*4A lacks the 3′-UTR of the CYP2A7 gene and the whole CYP2A6 gene is deleted and an unequal crossover junction is located in the 3′-UTR. CYP2A6*4B has a normal CYP2A7 gene, while the whole CYP2A6 gene is deleted. In CYP2A6*4D, an unequal crossover junction is located at the end of the CYP2A7 gene in either exon 8 or 9 and the whole CYP2A6 gene is deleted. Formerly, a CYP2A6*4C allele is recognized, but subsequent observations reveal that this allele is the same as the CYP2A6*4A allele. Because all these variants result in a whole gene deletion of CYP2A6, most studies do not discriminate between the variants and the term ‘CYP2A6*4’ is designated to all deletions There are three CYP2A genes in humans  AND (‘lung cancer’). The date of the last search was Sep 20, 2012. Publication date and publication language were not restricted in our search. Reference lists were examined manually to further identify potentially relevant studies. Unpublished reports were not considered. If more than one article was published by the same author using the same case series, we selected the study where the most individuals were investigated.The PubMed, Elsevier, EMBASE, Web of Science, Wiley Online Library and Chinese National Knowledge Infrastructure (CNKI) for all articles were searched with the following search terms:  Providing available genotype data of CYP2A6*4; (4) Control group is cancer-free. Studies were excluded if one of the following factors existed: (1) the design is based on family or sibling pairs or case-only; (2) the genotype frequency of CYP2A6*4 is not reported; or (3) there is insufficient information for extraction of data.Abstracts of all citations and retrieved studies were reviewed. Studies meeting the following criteria were included: (1) Using a case – control design; (2) Detecting the relationship between variant All data were extracted independently by two reviewers (XXX and XXX) according to the inclusion criteria listed above. Disagreements were resolved by discussion between the two reviewers. The following characteristics were collected from each study: first author, year of publication, country of sample, ethnicity, number of cases and controls, main background of samples, matching criteria, and genotyping methods .The statistical analysis was conducted using STATA 11.0 ; P-value <0.05 was considered statistically significant. Hardy Weinberg Equilibrium (HWE) in the controls was tested by the chi-square test for goodness of fit, and a P –value <0.05 was considered as significant disequilibrium. Pooled ORs were calculated for allele frequency comparison (*4 vs. non-*4), dominant model (*4/*4+*4/non-*4 vs. non-*4/non-*4), and recessive model ((*4/*4 vs.*4/non-*4 +non-*4/non-*4)), respectively. The significance of pooled ORs was determined by Z-test and P-value <0.05 was considered statistically significant.2 -based Q testing and 2I statistics 2-based Q testing and I2 was interpreted as the proportion of total variation contributed by between-study variation. If there was a significant heterogeneity , a random-effects model (the DerSimonian and Laird method) was selected to pool the data. If not, a fixed-effects model (the Mantel-Haenszel method) was selected to pool the data. Heterogeneity was also quantified using the 2I metric  The OR and 95% CI were estimated for each study in a random-effects model or a fixed-effects model. Heterogeneity among studies was examined with the χA total of 52 papers were retrieved after the first search. After our selection, 7 case-control studies including 2524 lung cancer cases and 2258 controls fulfilled the inclusion criteria CYP2A6*4 polymorphism and lung cancer risk. Results of the meta-analysis are shown in CYP2A6*4 polymorphism and lung cancer risk . But no significant association was observed under dominant model .There were seven case-control studies When studies were divided according to the population, the results indicated that significant associations were observed in Asian samples under all models . Reversely, no significant associations were observed in Caucasian samples under any model . Results of the meta-analysis are shown in The influence of a single study on the overall meta-analysis estimate was investigated by omitting one study at a time, and the omission of any study made no significant difference, indicating that our results were statistically reliable.2I >50%). Then subgroup analysis was carried out. Studies were divided according to the population. For Caucasian, no statistically significant heterogeneity was observed under either additive model  or dominant model . For Asian, no statistically significant heterogeneity was observed under recessive model , but significant heterogeneity was still observed under both additive model  and dominant model . However, when Tan's study was excluded, no statistically significant heterogeneity was observed anymore under either additive model  or dominant model . Funnel plot and Egger's test were performed to assess the publication bias of the literature. No publication bias was observed  and symmetrical funnel plots were obtained. Results of heterogeneity and publication bias are shown in For all studies, statistically significant heterogeneity was observed  Number of studies and number of subjects in the studies included in the meta-analysis are still small; and (5) Meta-analysis is a retrospective research that is subject to some methodological limitations. In order to minimize the bias, we used explicit methods for study selection, data extraction and data analysis. Nevertheless, our results should be interpreted with caution.However, there are still some limitations in this meta-analysis. (1) In seven studies included for our analysis, only two of them are Caucasian samples; (2) The samples from 4 countries and controls are not uniform; (3) CYP2A6*4 polymorphism is associated with susceptibility of lung cancer in Asian and the whole gene deletion of CYP2A6 may decrease the risk of lung cancer. The pooled ORs in this study suggest that *4/*4 genotype has a modest but definite genetic effect in Asian. Larger and well-designed studies based on different ethnic groups are needed to confirm our results.This meta-analysis suggests that the Checklist S1PRISMA Checklist.(DOC)Click here for additional data file.


Objective. It has been stated that brain cancers are an increasingly serious issue in many parts of the world. The aim of our study was to determine a possible relationship between Vitamin D receptor (VDR) gene polymorphisms and the risk of glioma and meningioma. Methods. We investigated the VDR Taq-I and VDR Fok-I gene polymorphisms in 100 brain cancer patients (including 44 meningioma cases and 56 glioma cases) and 122 age-matched healthy control subjects. This study was performed by polymerase chain reaction-based restriction fragment length polymorphism (RF LP). Results. VDR Fok-I ff genotype was significantly increased in meningioma patients (15.9%) compared with controls (2.5%), and carriers of Fok-I ff genotype had a 6.47-fold increased risk for meningioma cases. There was no significant difference between patients and controls for VDR Taq-I genotypes and alleles. Conclusions. We suggest that VDR Fok-I genotypes might affect the development of meningioma. The term of brain cancer is a heterogeneous group of neoplasms which occurs in intracranial tissue and the meninges. The incidence of malignant brain tumors is rare and approximately 2% of all cancers in adults , 2. Acco2D is one of potent regulators of cell growth and differentiation, which is an effect on cell death, tumor invasion, and angiogenesis, which makes it a candidate compound for cancer regulation [Vitamin D is a steroid hormone that regulates several endocrine functions and cell functions such as, proliferation and differentiation. , 9. The gulation . The nucgulation . The vitgulation , 13. Thegulation . Variousgulation –17. One gulation . It has gulation , 19. It gulation . Synthetgulation –26. The gulation , 25. SevSubject Selection. We investigated the VDR Taq-I and VDR Fok-I gene polymorphisms in 100 brain cancer patients (including 44 meningioma cases and 56 glioma cases) and 122 age-matched healthy control subjects who were in the follow-up Cerrahpaşa Faculty of Medicine: Department of Neurosurgery in Istanbul University. The mean ages of glioma and meningioma patients and control group were 44.75 ± 15.63, 50.26 ± 12.68, and 47.22 ± 10.63 years, respectively.The specimens were taken after obtaining informed consent, and the study was conducted prospectively. The Medical Ethics Committee of Istanbul Medical Faculty approval was obtained for the study. The protocol followed was consistent with the World Medical Association Declaration of Helsinki .2, 0.2 mM of each dNTP, 0.2 mM of each primer, and Taq polymerase in a 50 μL reaction volume. The PCR conditions were as follows: Initial denaturation step of 94°C for 4 min followed by 5 cycles of 94°C for 45 sec, 64°C for 60 sec, and 72°C for 2 min, and a further 25 cycles of 94°C for 30 sec, 64°C for 30 sec, and 72°C for 45 sec. PCR products were digested with TaqI restriction enzyme at 65°C, electrophoresed on 2% agarose gels, and stained with ethidium bromide. Genotypes were determined as TT , Tt , or tt  for Taq-I polymorphism [2, 0.2 mM of each dNTP, 0.25 mM of each primer, and Taq polymerase  in a 50 μL final volume. The PCR conditions involved an initial denaturation of 4 min at 94°C and followed by 30 cycles of 94°C for 1 min, annealing at 60°C for 1 min, and extension at 72°C for 1 min. A final extension step at 72°C for 4 min was also studied. PCR products were digested with FokI restriction enzyme  at 37°C for 3 h followed by electrophoresis in a 2% agarose gel. The FF genotype  shows only one band of 272 bp in agarose gel. The ff genotype  generates two fragments of 198 and 74 bp. The heterozygote displays three fragments  [Blood specimens were collected in tubes containing EDTA, and DNA samples were extracted from the whole blood by a salting out procedure  . Genotypmorphism . The priP < 0.05 were considered statistically significant. Haplotype frequencies D′ and r2 were calculated using Haploview 4.0 programme.Statistical analyses were performed using the SPSS software package . Data are expressed as means + SD. Differences in the distribution of genotypes or alleles between cases and controls were tested using the chi-square statistic. Odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated to estimate the risk of glioma and meningioma. Values of P > 0.05) (P = 0.004) . The VDR Taq-I genotype frequencies for meningioma, glioma, and control cases were not significantly different (P > 0.05). In addition, vitamin D haplotypes were evaluated for association with brain cancers. Haplotype analysis revealed that there was no relationship between VDR polymorphisms and brain cancers   . VDR FokFor the first time, we demonstrated the positive association of VDR Fok-I gene variants with meningioma cases. We also determined that VDR Fok-I ff genotype might affect development of meningioma, but we found that there was no statistically significant difference between VDR polymorphisms with glioma.Vitamin D is an important factor in the regulation of cell division and differentiation. The VDR gene is a member of nuclear receptor superfamily. The VDR gene located on chromosome 12. For a long time, several polymorphisms in VDR gene have been investigated for functional significance and potential effects on disease susceptibility . Many stSadetzki et al. reported that the genotype of KRAS was related to the increased the risk of (nearly 2 fold) meningioma . VDR expDespite an extensive literature study, there was no study that reported the relationship between VDR polymorphisms and brain cancer susceptibility. In conclusion, the present results suggest that the Fok-I polymorphism in the VDR gene may be related to the risk of meningioma. However, further studies with large number of subjects are needed to explain this kind of relationship between VDR-Fok-I genetic variants and meningioma risk.


Lung cancer is the most commonly diagnosed cancer and leading cause of cancer mortality in the world. A single nucleotide polymorphism (SNP), rs402710, located in 5p15.33, was firstly identified to be associated with the lung cancer risk in a genome-wide association study. However, some following replication studies yielded inconsistent results.A case-control study of 611 cases and 1062 controls in a Chinese population was conducted, and then a meta-analysis integrating the current and previously published studies with a total 31811 cases and 36333 controls was performed to explore the real effect of rs402710 on lung cancer susceptibility. Significant associations between the SNP rs402710 and lung cancer risk were observed in both case-control study and meta-analysis, with ORs equal to 0.77 (95%CI = 0.63–0.95) and 0.83 (95%CI = 0.81–0.86) in dominant model, respectively. By stratified analysis of our case-control study, the associations were also observed in never smoker group and non-small cell lung cancer(NSCLC) group with ORs equal to 0.71 (95%CI = 0.53–0.95) and 0.69 (95%CI = 0.55–0.87), which was remarkable that larger effect of the minor allele T was seen in the two groups than that in overall lung cancer. Besides, the sensitive and cumulative analysis indicated the robust stability of the current results of meta-analysis.The results from our replication study and the meta-analysis provided firm evidence that rs402710 T allele significantly contributed to decreased lung cancer risk, and the case-control study implied that the variant may yield stronger effect on NSCLC and never smokers. However, the mechanism underlying the polymorphism conferring susceptibility to lung cancer is warranted to clarify in the follow-up studies. Lung cancer is the most commonly diagnosed cancer and leading cause of cancer mortality worldwide, with 1.61 million newly confirmed cases and 1.38 million death from lung cancer annually CLPTM1L), was firstly identified in a GWAS set of 3,259 cases and 4,159 controls and a replication set of 2,899 cases and 5,573 controls by McKay JD et al CLPTM1L, alias CRR9, which was found to express in various tissue, including lung tissue and overexpress in cisplatin-resistant cell lines, encodes an enzyme—cleft lip and palate trans-membrane 1-like that may be associated with apoptosis Genome-wide association studies (GWAS), which aim to cover most genetic variation by genotyping up to 1,000,000 single nucleotide polymorphisms (SNPs) and do not require prior knowledge of gene function, are efficiently applied to identify the association between common genetic variants and complex disease Between 2009 and 2011, a total of 611 newly confirmed cases and 1062 cancer-free controls were obtained from the Tongji Hospital of Huazhong University of Science and Technology (HUST). All of them were genetically unrelated ethnic Han Chinese residing in Wuhan City or surrounding regions in Hubei Province of central China. The 611 cases were histopathologically confirmed without any treatment (such as radiotherapy or chemotherapy) prior to blood samples collection. All controls were randomly selected from the individuals who participated in a health check-up program at the same hospital during the same period as the cases were recruited. The controls had no history of cancer and were frequency matched to the cases by age (±5 years), sex, gender and residential area . After a written informed consent was obtained, a 5-ml peripheral blood sample and a questionnaire were collected from each subject. Smoker was defined as one person who had smoked at least one cigarette per day>1 year or longer at any time in their life, while never-smokers were defined as those who had not. This study was approved by ethics committee of Tongji Hospital of Huazhong University of Science and Technology.Genomic DNA was extracted from 5-mL of peripheral blood sample using the Relax Gene Blood DNA System DP319-02  according to the manufacturer's instructions. The genotypes of rs402710 SNP was performed by the TaqMan SNP Genotyping Assay using the 7900HT Fast Real-Time PCR System  without knowing the subjects' case or control status. To validate the results, 5% duplicated samples were randomly selected to assess the reproducibility, with a concordance rate of 100%.2χ test and t test. The Hardy–Weinberg equilibrium (HWE) was tested by a goodness of fit 2χ test in the control subjects. Unconditional logistic regression was used to estimate crude odds ratio (OR), adjusted OR and their 95% confidence intervals (CIs) for the effect of rs402710 genotypes on lung cancer risk, with adjustment for age, sex and smoking status, where appropriate. In order to avoid the assumption of genetic models, dominant (TT plus CT vs CC), recessive (TT vs CT plus CC) and additive models were also analyzed. All the analyses were performed using SPSS version 19.0. The criterion of statistical significance except for heterogeneity test was P<0.05, and all statistical tests were two sided.Differences in the distributions of demographic characteristics, selected variables and genotypes between cases and controls were examined by rs402710, 5q15.33 or CLPTM1L, combined with lung cancer, lung neoplasia, lung adenoma, lung carcinoma, or lung tumor in the PubMed, Embase and ISI Web of Knowledge databases for published studies without language restriction. References cited by the retrieved articles were also scanned for additional information. Eligible studies had to meet the following criteria: (a) a case-control or nested case-control study assessing the association between rs402710 and lung cancer risk; (b) contained sufficient information about genotype or allele frequency for risk estimates, or original data through which we can calculate what we need; (c) genotypes in controls were in Hardy-Weinberg equilibrium (P>0.01); (d) studies of humans. If there was parallel publication, we selected the study with larger sample size. If more than one ethnic population were involved in one report, each population was considered separately.Followed the methods proposed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2χ-based Cochran's Q statistic test was utilized to test heterogeneity (true variance of effect size across studies), and we considered that the heterogeneity was significant if P<0.100 for Q statistic 2I statistic, which reveals the proportion of the variability in effect estimation, was employed to quantify heterogeneity among studies  P>0.1 for Q statistic), we pooled the data from studies by a fix-effects model using Mantel-Haenszel method, otherwise, we employed a random-effects model using DerSimonian and Laird method P<0.05 for Egger's test or Begg's test), was applied. All statistical analyses were carried out by Stata Version 11.0. All P values are two-tailed with a significant level at 0.05. If we got a significant association between the SNP and lung cancer risk, bioinformatics analyses were further carried out to predict the function of rs402710 using three comprehensive bioinformatics tools “FastSNP” (http://fastsnp.ibms.sinica.edu.tw/pages/input_CandidateGeneSearch.jsp), “SNP Info” (http://manticore.niehs.nih.gov/snpfunc.htm) and “F-SNP” (http://compbio.cs.queensu.ca/F-SNP/).The following data were extracted from eligible study by two independent authors (Xuzai Lu & Xia Luo): first author, year of publication, geographic location, ethnicity of study population, study design, genotyping method, numbers of cases and controls, male/female rate, mean age, family history of cancer, source of control group, frequencies of genotypes in cases and controls. ORs and 95% CIs as the metrics of effect size were re-calculated for the allele T versus C, genotypes CT versus CC and TT versus CC and so were the dominant, recessive and additive models respectively. The P = 0.475). The mean age was 60.97 (±10.76) years for cases and 61.71 (±9.36) years for controls (P = 0.145). There was also no significant difference in distribution of age . More smokers were observed in cases compared with subjects in control group (P<0.001), considering that most lung cancers are attributable to smoking. 421 (68.9%) of the cases were histopathologically confirmed as non-small-cell lung cancer (NSCLC), including squamous cell carcinomas, adenocarcinomas and large cell lung carcinomas, meanwhile NSCLC accounts for approximately 80% of primary lung cancers in general.A total of 611 lung cancer cases and 1062 cancer-free controls were enrolled in our study. The characteristics of all subjects were listed in P = 0.955). Significant difference was observed in distribution of genotypes between cases and controls .The call rate of genotyping was 99.6% for the SNP rs402710. The distribution of the SNP genotypes in cases and controls was showed in By multivariate logistic regression model adjusted for age, sex and smoking status, the significant association between rs402710 and lung cancer was observed in heterozygote model , which indicated that the individuals with the CT genotype had a significantly decreased risk of lung cancer compared to the CC genotype carriers. Likewise, significant associations were found in dominant and additive models . A dominant model was a T carrier (TT plus CT) group which was combined the TT carriers with the CT carriers to increase statistical power. The per-T-allele OR could be calculated in an additive model. Considering smoking is a major factor contributing to lung cancer, we respectively stratified the cases and controls into two groups, smoker and never smoker, to detect the association between rs402710 and lung cancer. The same effect between rs402710 and lung cancer was also observed in heterozygote and dominant models in never smoker group . However, no valid associations were found under any models of smoker group, suggesting that the T carriers who never smoke might have less risk of lung cancer than those smokers.To explore the rs402710's effect on NSCLC, we also compared the genotype distribution between the NSCLC cases and controls. Like total lung cancers, similar positive association and stronger genetic effect were found in three models of NSCLC . It is remarkable that larger effect of the minor allele T was seen in NSCLC than that in overall lung cancer. But beyond that, in the allelic model, T allele carriers also showed significantly protective effect compared to those with the C allele . Subsequently, the NSCLC and controls were once again stratified into two groups: smoker and never smoker Likewise, under the same four models of never smoker group, positive association and stronger genetic effect were found. However, significant associations were still not detected under any models of smoker group.As show in HapMap database displayed that the T allele frequencies of rs402710 in Caucasians, Chinese and Japanese were 36.5%, 31.5% and 30.9% respectively. And we similarly found the pooled T allele frequencies were 35.0% (95%CI = 34.5%–35.4%) in Caucasian controls and 31.7% (95%CI = 30.6%–32.9%) in Asian controls in our meta-analysis, under fixed and random model respectively.P>0.10), therefore a fix-effects model was employed to pool the OR for all models. In allelic model, as shown in As shown in heterogeneityP >0.1, all 2I = 0%), meanwhile the heterogeneity in heterozygous (2I = 38.7%) and recessive (2I = 39.3%) model among Asian studies slightly increased from no heterogeneity grade to moderate grade. It might be due to that the heterogeneity largely came from Asian studies and the heterogeneity in Caucasian studies was little. Even the heterogeneity in Asian studies which could be accounted for different study design and genotyping methods reached moderate grade, the values of P for heterogeneity were all greater than 0.10. In other words, the results of meta-analysis in Asian studies were credible and representative. In spite of this, the significant association between the SNP rs402710 and lung cancer risk was still identified in all genetic models of both Caucasian and Asian groups. Subsequently, the data of genotypes was stratified by sample size, which was defined large group when it was more than 1000, otherwise was small group. In the two subgroups, all genetic models exhibited significant association with decreased lung cancer risk, and showed no significant between-study heterogeneity.We performed stratified analyses to explore the potential source of heterogeneity by ethnicity and sample size . After s2I = 45.7%) and dominant (2I = 35.8%) model among NSCLC studies was moderate, which might be due to different study design and genotyping methods. Under fixed-effects model, the significant association with decreased lung cancer risk was exhibited in all genetic models.To provide a more precise estimate of the effect of rs402710 on NSCLC, we combined our current study and previously published studies which displayed detailed information about NSCLC, including 5 studies of 6060 NSCLC cases and 8678 controls. The heterogeneity in heterozygous  and funnel plot was visually symmetrical.As reflected by the funnel plot, the Egger's test and the Begg's test, there was no publication bias under all genetic models  and CLPTM1L. The copy number gain of this region of chromosome 5p is the most frequent cytogenetic event in the early stages of NSCLC CLPTM1L gene were poorly understood, and it was observed as a cisplatin-resistance factor in ovarian cancer-cell lines which can't be taken as a function of CLPTM1L gene on oncogenesis CLPTM1L, as an overexpressed protein in lung tumor cells, protected from genotoxic stress induced apoptosis through regulation of Bcl-xL, which implicated that the anti-apoptotic CLPTM1L function may be a potential mechanism of susceptibility to lung tumorigenesis.The rs402710 is located in intron 4 of the CLPTM1L gene variant rs402710 is associated with higher DNA adduct formation in tumor adjacent lung tissue CLPTM1L gene is not clear. Through bioinformatics analysis, we found that this variant may participate in transcriptional regulation. But the effect of the SNP in lung tumorigenesis needs to be affirmed by further studies.The The susceptibility locus rs402710 was firstly identified in a GWA study of Caucasian population by Mckay JD et al Although no heterogeneity was detected in all genetic models among included studies, stratified analyses was still performed to explore the differences between ethnicities or study sample size. In Caucasians, no significant heterogeneity was detected, whereas the heterogeneity in heterozygous and recessive model among Asian studies increased from no heterogeneity grade to moderate grade. The same phenomenon, that the heterogeneity between large sample size studies removed and the small group increased, existed after stratified by study sample size, which may be due to the sampling error in small studies. Furthermore, the sensitivity analysis and publication bias estimation illustrated the current results of this meta-analysis were robust.Despite the clear strength of the current study possessing enough power, some limitations should be seriously considered. Firstly, the sample size of our case-control study was relatively small. Secondly, absent data or insufficient data restricted us to perform further analysis. Thus we couldn't analysis the association between the SNP rs402710 and lung cancer subtypes including adenocarcinoma, non-small cell lung cancer, small cell lung cancer and others. Finally, lung cancer is a complex disease caused by both genetic and environmental factors, but the gene-environment interaction can't be evaluated owing to the absence of environmental information.In conclusion, the current case-control study and the follow-up meta-analysis helped to strongly clarify the significant association between rs402710 and lung cancer, and our study implied that the variant may yield stronger effect on NSCLC and never smokers. However, it is needed to implement fine-mapping of 5p15.33 region or function analysis to identify causal variant.Figure S1Follow chart of study selection.(TIF)Click here for additional data file.Checklist S1PRISMA checklist.(DOC)Click here for additional data file.


A lot of studies have investigated the correlation between x-ray repair cross-complementing group 3 (XRCC3) Thr241Met polymorphism and clinical outcomes in non-small cell cancer (NSCLC), while the conclusion is still conflicting.We conducted this meta-analysis to evaluate the predictive value of XRCC3 Thr241Met polymorphism on response and overall survival of patients with NSCLC. Pooled odds ratios (ORs) and hazard ratios (HRs) and corresponding 95% confidence intervals (95% CIs) were used to estimate the association strength.heterogeneity = 0.968 and ThrMet+MetMet vs. ThrThr, OR = 1.476, 95% CI: 1.087–2.004, Pheterogeneity = 0.696). This significant association was observed in Caucasian population but not in Asian population. On the other hand, there was no significant association of XRCC3 Thr241Met polymorphism with survival , and there was no difference between Asian and Caucasian population.A total of 14 eligible studies with 2828 patients were identified according to our inclusion criteria. Meta-analysis results showed that carriers of the variant 241Met allele were significantly associated with good response, compared with those harboring the wild 241Thr allele (Met vs. Thr, OR = 1.453, 95% CI: 1.116–1.892, PThese findings suggest a predictive role of XRCC3 Thr241Met polymorphism on response to platinum-based chemotherapy in patients with advanced NSCLC. Additionally, we first report that the XRCC3 Thr241Met polymorphism is associated with response to platinum-based chemotherapy and highlights the prognostic value of the XRCC3 Thr241Met polymorphism. Non-small cell lung cancer (NSCLC) accounts for about 80% of primary lung cancers, most of which were diagnosed at the advanced stage A lot of clinical studies have suggested that genetic factors can influence treatment efficacy of lung cancer and are correlated with prognosis of patients Therefore, this present meta-analysis was carried out to evaluate the predictive value of XRCC3 Thr241 polymorphism by analyzing the relationship between XRCC3 Thr241Met polymorphism and response to platinum-based chemotherapy and survival of NSCLC.This meta-analysis was conducted and reported in accordance with the PRISMA guidelines  NSCLC patients; 2) investigating the relationship between XRCC3 Thr241Met polymorphism and response to chemotherapy or survival; 3) for response to chemotherapy, the regimen was restricted to platinum-based chemotherapy; 4) for survival, there was no limitation on treatment methods; 5) available data for quantitative synthesis, namely genotype distribution data for response or hazard ratio (HR) and 95% confidence intervals (CIs) for survival. Conference abstracts were excluded and only full-text published articles were included. Studies without available data were excluded. All searching records were screened by two authors (Qiu and Yang), with discrepancies resolved by discussion with another author (Yin).Response to platinum-based chemotherapy and overall survival were the primary outcomes in this meta-analysis. Response to chemotherapy was assessed with RECIST  criteria, namely, “good response” was defined as “complete response + partial response” and “poor response” was “stable disease + progressive disease”. Data of overall survival (HR and 95% CIs) were extracted from studies directly according to studies' own definition.Data of eligible studies were extracted by two authors (Qiu and Xu) independently in duplicate with a pre-designed data collection form. The two authors reached consensus on each item. The following data was collected, name of first author, year of publication, country, ethnicity, treatment (chemotherapy regimens), number of patients, TNM stages, age, percentage of male, SNPs investigated, genotype distribution data among responders and non-responders and HR and corresponding 95% CIs of OS. For OS, we collected HR and CIs of each comparison. Ethnicity descents were simply categorized as Asian or Caucasian. In three studies Pooled odds ratio (OR) and corresponding 95% CIs were calculated to estimate the association strength of XRCC3 Thr241Met polymorphisms with response to platinum-based chemotherapy. The 95% CIs were utilized for statistical significance test and a 95% CI without 1 suggested significant difference. For response, a total of 5 genetic comparison models were calculated . The genotype distribution data was directly used to estimate the pooled ORs and 95% CIs. For OS, HRs and CIs retrieved from each study were calculated to estimate the pooled HRs and 95% CIs. Also, the 95% CIs pooled HRs were used for statistical test. Pooled HRs for homozygote comparison, heterozygote comparison and dominant model were calculated.Between studies heterogeneity was measured by chi-square based Q test, and p<0.10 indicated the existence of significant heterogeneity All statistical analyses were carried out with STATA software . All p values are two-side.After primary screening, 774 potentially relevant full-text articles were identified, of which 14 studies met the inclusion criteriaEight studies For overall survival, we did not restrict the treatment methods. Thus, 10 studies In this meta-analysis, we provided evidence that, in patients with advanced NSCLC, the variant XRCC3 241Met allele could predict good response to platinum-based chemotherapy, especially in Caucasian population; while there was no significant association of XRCC3 Thr241Met polymorphism with survival. Additionally, it was reported for the first time that the XRCC3 Thr241Met polymorphism is associated with response to platinum-based chemotherapy.It has been well documented that impaired DNA repair capacity caused by functional SNPs of DNA repair genes is associated with survival of platinum-based chemotherapyThe correlation between XRCC3 Thr241Met polymorphism and response to platinum-based chemotherapy has been extensively investigatedFor overall survival, we did not find any significant association between XRCC3 Thr241Met polymorphism and survival of NSCLC patients in overall analysis . In the subgroups of platinum-based chemotherapy and radiotherapy+chemotherapy, there was no significant association either. Notably, in the heterozygote comparison, we observed a significant association of ThrMet genotype with poor survival with random-effects model but not with fixed-effects model. It has been demonstrated that, compared with random-effects model, fixed-effects model increases statistical power of meta-analysesPublished evidence showed that the XRCC3 Thr241Met polymorphism may predict survival of NSCLC patients in a chemotherapy regimen-dependent manner Despite the effort to perform a comprehensive meta-analysis, limitations of our meta-analysis should be noted. For analysis of overall survival, we included patients with surgery or radiotherapy in addition to platinum-based chemotherapy, which may introduce heterogeneity among studies. As shown in To summary, results from our meta-analysis show that the XRCC3 Thr241Met polymorphism can predict good response to platinum-based chemotherapy in patients with advanced NSCLC, especially in Caucasian population; while there is no significant association of XRCC3 Thr241Met polymorphism with survival of NSCLC. Well-designed studies with large sample size are warranted to validate our findings and evaluate the predictive value of XRCC3 Thr241Met polymorphism on toxicity.Figure S1Funnel plot of the comparison of ThrMet+MetMet vs. ThrThr for response to platinum-based chemotherapy. The each circle represent one included study and its weight. p = 1 for Begg's test and p = 0.934 for Egger's test.(TIF)Click here for additional data file.Figure S2Forest plot of the comparison of ThrMet vs. ThrThr for overall survival estimated by random-effects model. HR = 1.220, 95% CI: 0.957–1.555, p = 0.056 for heterogeneity.(TIF)Click here for additional data file.Figure S3Forest plot of the comparison of ThrMet vs. ThrThr for overall survival estimated by fixed-effects model. HR = 1.357, 95% CI: 1.211–1.521, p = 0.056 for heterogeneity.(TIF)Click here for additional data file.Checklist S1PRISMA Checklists.(DOC)Click here for additional data file.


Aggregatibacter actinomycetemcomitans has recently been shown to cause abundant secretion of IL-1β from macrophages. The aim of the present study was to compare the prevalence of systemic immunoreactivity to A. actinomycetemcomitans leukotoxin in myocardial infarction (MI) cases (n = 532) and matched controls  in a population-based case and referents study in northern Sweden.Chronic infections and associated inflammatory markers are suggested risk factors for cardiovascular disease (CVD). The proinflammatory cytokine, interleukin (IL)-1β, is suggested to play a role in the regulation of local inflammatory responses in both CVD and periodontitis. The leukotoxin from the periodontal pathogen A. actinomycetemcomitans leukotoxin was analyzed in a bioassay with leukocytes, purified leukotoxin, and plasma. Plasma samples that inhibited lactate-dehydrogenase release from leukotoxin-lysed cells by ≥50% were classified as positive.Capacity to neutralize A. actinomycetemcomitans leukotoxin was detected in 53.3% of the plasma samples. The ability to neutralize leukotoxin was correlated to increasing age in men  but not in women (n = 450). There was no correlation between presence of systemic leukotoxin-neutralization capacity and the incidence of MI, except for women (n = 146). Women with a low neutralizing capacity had a significantly higher incidence of MI than those who had a high neutralizing capacity.Neutralizing capacity against A. actinomycetemcomitans leukotoxin was found at a high prevalence in the analyzed population of adults from northern Sweden. The results from the present study do not support the hypothesis that systemic leukotoxin-neutralizing capacity can decrease the risk for MI.Systemic immunoreactivity against  Aggregatibacter actinomycetemcomitans is a bacterium associated with aggressive forms of periodontitis, and it produces a leukotoxin that specifically affects human leukocytes [Chronic inflammations, such as periodontitis, are suggested to be risk factors for the development of cardiovascular diseases . It has ukocytes . Individukocytes . The proukocytes ,12,13 anukocytes .A. actinomycetemcomitans varies depending on geographic origin and periodontal condition of the subjects [A. actinomycetemcomitans' leukotoxin had a significantly decreased incidence of stroke [A. actinomyctemcomitans bacteria [A. actinomycetemcomitans infection late in life might be a risk factor for stroke and contribute to the negative association between stroke and the presence of these neutralizing antibodies. The aim of the present study was to analyze if the presence of systemic immunoreactivity to A. actinomycetemcomitans leukotoxin also interferes with the incidence of a future myocardial infarction (MI).The proportion in a population that harbor subjects . It has subjects -17. Dataf stroke . This sybacteria . We hypoThe study population was derived from the Northern Sweden Health and Disease Study (NSHDS), which consists of three sub-cohorts: The Västerbotten Intervention Programme (VIP) , the WHOIncident cases and matching controls were identified through 13 years of follow-up (1985-1999) from the Västerbotten Intervention Program and the Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study. Study participants were from the Västerbotten and Norrbotten counties in northern Sweden. Participants with a history of MI, stroke or cancer were excluded from this study. Participants were followed from baseline examination until first MI or death. There was an average time period of 4 years between the time of inclusion and the MI event.Fatal and nonfatal cases of MI occurring from October 1, 1994 to December 31, 1999 were identified through the Northern Sweden Monica Incidence Registry . ThroughA. actinomycetemcomitans leukotoxin-neutralizing capacity in the plasma samples was detected as a reduction of leukocyte damage and subsequent leakage of lactate dehydrogenase (LDH) upon exposure to purified leukotoxin, as described previously [The eviously . This as6 cells/ml. The blood was taken from donors visiting the University Hospital blood bank in Umeå, Sweden. Informed written approval was given by all subjects, and authorization for the study was granted by the Human Studies Ethical Committee of Umeå University, Sweden .Briefly, human polymorphonuclear leukocytes (PMNs) were isolated from human peripheral blood as described previously . The iso2. Activity of the released LDH into the culture supernatant was quantified as described previously [null", plasma that neutralized leukotoxin at 10% plasma concentration but not at 1% was classified as "low", and plasma that neutralized the leukotoxin at both 10% and 1% concentrations was classified as "high".For detection of leukotoxin-neutralizing capacity, purified leukotoxin (450 ng/mL)  was mixeeviously . Plasma 2-test for trend was used to analyze the association between age and antibodies. To investigate if the presence of leukotoxin antibodies  affects the risk of having an MI, conditional logistic regression appropriate for the matched design, was used. A multivariable model was used to adjust for smoking, self-reported diabetes, systolic blood pressure and apoB/apoA1. Results are presented as p-values, odds ratios (ORs) and corresponding 95% confidence intervals (CIs). No correction for multiple testing was performed. SAS version 9.1 was used for the statistical analyses.The Mantel-Haenszel χThe study population was classified into 4 different age groups, and the distribution in relation to age and gender is shown in Figure A. actinomycetemcomitans leukotoxicity in the neutralization assay. Further dilution of the plasma samples resulted in loss of the capacity to neutralize leukotoxin in 526 of these samples, and they were classified as samples with low neutralizing capacity. The 291 samples that neutralized leukotoxin also at the higher dilution were classified as high. The distribution of the study population in relation to their systemic capacity to neutralize leukotoxin was 46.7% negative, 34.3% low and 19.9% high. There were no significant differences between men and woman in capacity to neutralize the leukotoxin  could neutralize The proportion of subjects with capacity to neutralize leukotoxin increased with increasing age Figure . This agWomen with low capacity to neutralize leukotoxin had a significantly  higher incidence of MI than women without the capacity to neutralize leukotoxin  in adults from northern Sweden. The prevalence of leukotoxin-neutralizing capacity increased with increasing age, significantly for men but not for women.The results from the present study do not support the hypothesis that systemic leukotoxin-neutralizing capacity can decrease the risk for MI. In addition, the prevalence of systemic The authors declare that they have no competing interests.AJ conceptualized the study, conducted the analyses, and wrote the first draft of the manuscript. A-MÅ and AJ performed the analyses and made a first draft of the result calculations. J-HJ and KB planned and supervised data collection. GH and IJ coordinated data collection, and ME performed the statistical calculations. All approved the final version of the submitted manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/11/55/prepub


Obesity is a multifactorial disease caused by the interaction between genotype and environment, and it is considered to be a type of addictive alteration. The A1 allele of the DRD2/ANKK1-TaqIA gene has been associated with addictive disorders, with obesity and with the performance in executive functions. The 7 repeat allele of the DRD4 gene has likewise been associated with the performance in executive functions, as well as with addictive behaviors and impulsivity. Participants were included in the obesity group (N = 42) if their body mass index (BMI) was equal to or above 30, and in the lean group (N = 42) if their BMI was below 25. The DRD2/ANKK1-TaqIA and DRD4 VNTR polymorphisms were obtained. All subjects underwent neuropsychological assessment. Eating behavior traits were evaluated. The ‘DRD2/ANKK1-TaqIA A1-allele status’ had a significant effect on almost all the executive variables, but no significant ‘DRD4 7R-allele status’ effects were observed for any of the executive variables analyzed. There was a significant ‘group’ x ‘DRD2/ANKK1-TaqIA A1-allele status’ interaction effect on LN and ‘group’ x ‘DRD4 7R-allele status’ interaction effect on TMT B-A score. Being obese and a carrier of the A1 allele of DRD2/ANKK1-TaqIA or the 7R allele of DRD4 VNTR polymorphisms could confer a weakness as regards the performance of executive functions. Obesity is a chronic multifactorial disease caused by the interaction between genotype and environment, and it is considered the second cause of premature and avoidable mortality, after tobacco DRD2 is a gene encoding the D2 dopamine receptor, which is mainly expressed in the striatum The A1 allele of the DRD2/ANKK1-TaqIA gene has been associated with both addictive disorders Further to these findings, imaging studies have reported that the reductions in D2 receptors are associated with decreased metabolism in prefrontal cortical regions in obese subjects There are controversial results regarding the relationship between DRD2/ANKK1-TaqIA polymorphisms and cognitive processes. Berman and Noble As regards frontal functions some studies in healthy adult samples have found that carriers of the A1 allele (who have a lower density of D2 receptors) display better behavioural flexibility than do A1 non-carriers Another gene encoding dopamine receptors is DRD4, which is highly expressed in the prefrontal cortex and other brain regions that are involved in the reward circuits that mediate the reinforcing properties of food, such as the hippocampus, amygdala and hypothalamus The DRD4 gene has been associated with addictive behaviours Research into the link between DRD4 and cognitive functions has also yielded mixed results. Some studies have reported associations between being a carrier of 7R allele and impairment on executive function tasks in healthy children Since the DRD2 and DRD4 genes have been associated with susceptibility to obesity and anomalous eating behaviour, and given that polymorphisms of these genes seem to affect the performance of executive functions, which appear to be altered in obesity, it would seem logical to ask whether there is any relationship between these polymorphisms and executive function in obese subjects. No study to date has examined a possible effect of DRD2/ANKK1-TaqIA and DRD4 VNTR polymorphisms on executive performance in the obese population. However, it must be taken into account that depression is the most frequent co-morbidity of obesity Thus, the purpose of the present study was to assess the association between two dopamine genes and executive function and their potential interactions with obesity. The relationship between these polymorphisms and eating behaviour variables was also studied.http://www.ub.edu/recerca/comissiobioetica.htm) and the research was conducted in accordance with the Helsinki Declaration. Written informed consent was obtained from each participant prior to taking part in the study. The demographic and clinical characteristics of the obese and control groups are shown in Participants were randomly selected from a population base of 1539 people living within the catchment area of three public medical centres belonging to the Consorci Sanitari de Terrassa. The recruitment process continued until two samples with similar demographic features were obtained. Specifically, 816 potential participants were contacted by telephone  according to the manufacturer’s protocol. The DRD2/ANKK1 TaqIA (rs1800497) and DRD4 VNTR (rs1805186) polymorphisms were analysed as described below.5′-GGCTGGCCAAGTTGTCTA-3′) and reverse (5′-CCTTCCTGAGTGTCATCA-3′) primers, 1× PCR buffer, 1 mM MgCl2, 200 µM of dNTPs and 2.5 units of BioTaq DNA polymerase . The PCR programme was 95°C for 5 min followed by 35 cycles of 94°C for 30 s, 59°C for 30 s and 72°C for 1 min. The 302 bp PCR product was digested with TaqαI enzyme  for 90 min at 65°C and visualized under ultraviolet light on an 8% ethidium bromide acrylamide gel. The DRD2-A2 allele was cleaved into two fragments of 176 and 126 bp, whereas the DRD2-A1 allele was not cleaved.The DRD2/ANKK1-TaqIA polymorphism was amplified by polymerase chain reaction (PCR) containing 100 ng of genomic DNA from each subject, 0.5 µM each of forward (5′-GCGACTACGTGGTCTACTCG-3′ as forward and 5′-AGGACCCTCATGGCCTTG-3′ as reverse), 1× PCR buffer, 1 mM MgCl2, 5% DMSO, 200 µM of dATP, dCTP and dTTP, 140 µM of dGTP, 60 µM of 7-deazaGTP and 2.5 units of BioTaq DNA polymerase (Bioline). Cycling conditions were 35 cycles at 94°C for 30 s, 63°C for 30 s and 72°C for 1 min. Amplification products were resolved by 5% acrylamide gel electrophoresis and were subsequently stained with ethidium bromide and visualized under ultraviolet light. Fragment sizes were determined by comparison with molecular length standards. A 4-repeat PCR product has a length of 475 bp. Genotyping was successful in all participants. Each genotype was recoded as carrier versus non-carrier of the allele of interest.The DRD4 48-bp VNTR polymorphism was amplified by PCR containing 100 ng genomic DNA, 0.5 µM of each primer  was used to assess processing speed and verbal and visuo-spatial working memory (WM) Eating behaviour traits were assessed using the Three-Factor Eating Questionnaire (3FEQ) Statistical analyses were performed by means of PASW Statistics 18.0 . The Kolmogorov-Smirnov test was used to test whether all continuous variables followed a normal distribution. Frequencies of polymorphisms and alleles were calculated. Chi-square analysis tested for goodness-of-fit to the Hardy-Weinberg equilibrium. The Mann-Whitney U test was used to compare categorical variables between the genetic groups, whereas the continuous variables were compared via the Student’s t-test for independent samples. Factorial ANCOVA was performed to determine the effect of group (obesity), allele status (carrier vs. non carrier) and their interaction on executive function and eating behaviour variables controlling for confounding variables (score in HADS depression questionnaire and sex). Given the low number of participants who were simultaneously carriers of A1 (DRD2/ANKK1-TaqIA) and 7R (DRD4 VNTR), we did not examine the interaction between these two genes; instead, separate ANCOVAs were performed for each allele status (carrier vs non carrier). Finally, the effect size was calculated according to the value of eta squared (ή2). The interpretation of this statistic is as follows: ή2 = 0.0099, small effect; ή2 = 0.0588, medium effect; ή2 = 0.1379, large effect Comparisons between obese and control subjects in demographics, neuropsychological and questionnaire scores are shown in Frequencies of DRD2/ANKK1-TaqIA alleles and genotypes, and the frequencies of DRD4 VNTR alleles and genotypes in obese and control subjects are shown in Although age, education and estimated intelligence were equivalent for all genetic subgroups, the DRD4-7R carriers group contained significantly more females than did the group comprising non-carriers of 7R : F = 0.15; p = 0.693; sex: U = 584; p = 0.47; DRD4-7R subgroups: age: F = 0.02; p = 0.869; years of education: F = 0.00; p = 0.950; vocabulary (WAIS): F = 0.50; p = 0.479; sex: U = 390; p = 0.032). Therefore, to rule out the effect of sex on the DRD4 7R allele comparisons we introduced additionally this variable in the ANCOVA analysis.As expected, there was a significant ‘group’ effect on all the eating behaviour variables. Interestingly, however, the results also revealed a significant effect of ‘allele status’ on two of these variables , as well as a significant ‘group’ x ‘DRD2/ANKK1-TaqIA A1-allele status’ interaction effect on BITE symptoms .The purpose of this study was to examine the association between two dopamine genes and executive function and their potential interactions with obesity. Specifically, the two dopamine system genes chosen were the DRD2/ANKK1-TaqIA and DRD4 48 bp VNTR polymorphisms. Both have been associated with psychiatric disorders involving impulsivity and obesity. In addition, these polymorphisms appear to exert a functional influence on dopamine D2 and D4 receptors, which are densely located in the corticostriatal-mesolimbic system Previous studies have demonstrated altered executive function in obese subjects Studies of frontal function and the DRD2/ANKK1-TaqIA polymorphism in healthy adult samples have yielded conflicting results. Some recent investigations have revealed carriers of the A1 allele to have better cognitive flexibility than A1 non-carriers Our results also revealed a significantly ‘group’ x ‘DRD2/ANKK1-TaqIA A1-allele status’ interaction effect on the LN variable. In the obese group, A1 carriers performed worse than did A1 non-carriers, whereas among controls the performance of A1 carriers and non-carriers was similar. This suggests that possession of the A1 allele among obese subjects is associated with worse performance on working memory, and it could therefore confer a disadvantage in terms of executive performance. Other studies with pathological samples involving the dopaminergic system have yielded discordant results regarding frontal function. In a sample of alcoholic males those subjects bearing at least one copy of the A1 allele showed lower attention and less inhibitory control than did those without the A1 allele The A1 allele of the DRD2/ANKK1-TaqIA gene has been associated with addictive disorders No significant ‘group’ or ‘DRD4 VNTR 7R-allele status’ effects were observed for any of the executive variables analysed. In this regard, our data partially support the results of previous studies that found no differences among ADHD patients in relation to the DRD4 VNTR polymorphism and cognitive functions At all events the strengths and limitations of the present study should be considered when interpreting the findings. The study sample size was modest, and research designed to identify genes that are associated with specific behaviours usually requires a much larger sample. Nevertheless, this sample size did provide enough statistical power to detect a significant interaction and main effect of gene variants on our measures of executive function, even though the effect sizes were small. The results should, however, be interpreted with caution in view of the numerous statistical comparisons, the risk being that some of the findings may be spurious. The present results therefore require confirmation by studies that are adequately powered to detect the effect of DRD2-A1 and DRD4-7R on executive performance.Ideally one would also have investigated all possible interactions among the two polymorphisms studied here. However, for the DRD4 48-bp VNTR and the DRD2/ANKK1-TaqIA polymorphisms the genotype frequencies involving the minor allele were too low to test for meaningful interactions. Future studies should therefore address the question of all potential interactions between these two (and other) polymorphisms in dopamine system genes in a larger, adult, obese cohort.To conclude, despite the methodological limitations, we found that obese subjects carriers of the A1 allele of the DRD2/ANKK1 TaqA1 and carriers of the 7R allele of the DRD4 48-bp VNTR polymorphism performed worse on certain tests of executive functions. These results provided new knowledge on the effect of two genes that are crucial for dopamine neurotransmission, which underlies several psychiatric disorders. The study of the genes related to dopamine transmission, with respect to both its elimination and its release or receptor binding, may shed light on the role of this system in mental disorders.Figure S1The figure shows detailed information on data inclusion.(TIF)Click here for additional data file.