FTO rs9939609 and MC4R rs17782313, that are linked to increased body weight and obesity. We examined the association of FTO rs9939609 and MC4R rs17782313 with endometrial cancer risk in a pooled analysis of nine case-control studies within the Epidemiology of Endometrial Cancer Consortium (E2C2). This analysis included 3601 non-Hispanic white women with histologically-confirmed endometrial carcinoma and 5275 frequency-matched controls. Unconditional logistic regression models were used to assess the relation of FTO rs9939609 and MC4R rs17782313 genotypes to the risk of endometrial cancer. Among control women, both the FTO rs9939609 A and MC4R rs17782313 C alleles were associated with a 16% increased risk of being overweight . In case-control analyses, carriers of the FTO rs9939609 AA genotype were at increased risk of endometrial carcinoma compared to women with the TT genotype . However, this association was no longer apparent after adjusting for body mass index (BMI), suggesting mediation of the gene-disease effect through body weight. The MC4R rs17782313 polymorphism was not related to endometrial cancer risk . FTO rs9939609 is a susceptibility marker for white non-Hispanic women at higher risk of endometrial cancer. Although FTO rs9939609 alone might have limited clinical or public health significance for identifying women at high risk for endometrial cancer beyond that of excess body weight, further investigation of obesity-related genetic markers might help to identify the pathways that influence endometrial carcinogenesis.Overweight and obesity are strongly associated with endometrial cancer. Several independent genome-wide association studies recently identified two common polymorphisms,  Endometrial cancer is the most common invasive gynecologic cancer in U.S. women with an estimated 43,470 new cases expected in 2010 fat mass and obesity associated  and melanocortin-4 receptor  gene polymorphisms with obesity and BMI in Caucasian populations FTO rs9939609 A and MC4R rs17782313 C alleles was estimated to increase the risk of obesity by 31% Recently, several independent large-scale genome-wide association studies (GWAS) reported an association of FTO has been described as a Fe(II)- and 2-oxoglutarate-dependent oxygenase that might operate as a DNA demethylase. The human FTO gene is expressed in many tissues including mesenteric fat, pancreas, liver and adipose tissue, with the highest concentrations found in the hypothalamus FTO underlies obesity FTO gene expression in the arcuate nucleus of the hypothalamus is regulated by fasting MC4R gene encodes the MC4 protein, a ubiquitously expressed G-protein-coupled receptor that binds α-melanocyte stimulating hormone (α-MSH) MC4R is a key regulator of energy balance, influencing food intake and energy expenditure through functionally divergent central melanocortin neuronal pathways The protein encoded by FTO rs9939609 and MC4R rs17782313 and endometrial cancer risk, we utilized pooled data within the Epidemiology of Endometrial Cancer Consortium (E2C2) FTO rs9939609 A allele and MC4R rs17782313 C allele and risk of the endometrioid type of endometrial carcinoma than with nonendometrioid types.To examine the relation between the obesity-associated FTO rs9939609 minor allele (A) frequency among pooled controls was 0.40 (range by study: 0.39 to 0.47) (Table S1). The MC4R rs17782313 minor allele (C) frequency among controls was 0.25 (range: 0.23 to 0.28).The FTO rs9939609 and MC4R rs17782313 were associated with a 16% per allele increased risk of being overweight   Table 1.FTO rs9939609 AA genotype was associated with an increased risk of endometrial cancer  compared to women with the TT genotype . No heterogeneity of effects was observed between the TORONTO study and studies including incident cases only (p = 0.78). In the subset of women with BMI data available, the association of the FTO rs9939609 AA genotype with risk remained the same . The majority of cases were diagnosed with endometrioid carcinomas . In the analyses restricted to the endometrioid histological subtype, the FTO rs9939609 AA versus TT genotype was slightly strengthened  .In the pooled analysis, the genotype Table 2.FTO rs9939609 AA genotype were at increased risk of endometrial carcinoma. This genetic association appears to be mediated through a relation of rs9939609 to a woman's weight, as no independent effect of this SNP was observed after accounting for BMI.In this pooled analysis of non-Hispanic white women from the United States, Poland, Canada and Australia, we found that carriers of the FTO gene are associated with altered gene expression FTO transcript levels in unspliced heterogeneous nuclear DNA preparations from blood and fibroblasts of individuals heterozygous for rs9939609. The FTO transcripts containing the A (‘risk’) allele were more abundant than those with T allele .Experimental evidence suggests that obesity associated SNPs in intron 1 of the FTO rs9939609 SNP is related to body weight through an influence on energy intake and satiety TA and AA rs9939609 genotypes had significantly lower postprandial responses to hunger and satiety compared to TT carriers. Wardle et al. FTO alleles ate less than those with one or two higher-risk alleles and concluded that the T allele is protective against overeating by promoting responsiveness to internal signals of satiety. In addition, two studies reported an association of the rs9939609 A allele with decreased lipolysis The MC4R rs17782313 SNP was unexpected and needs further investigation. Although the power of our MC4R analysis was modest, odds ratios were close to one, providing no suggestion of an association of this SNP with endometrial cancer risk among non-Hispanic white women. Further study of additional genetic correlates of body weight will assist in clarifying whether the FTO relation to endometrial cancer risk is unique among ‘obesity-associated’ genes.The lack of an independent effect of the FTO remains the strongest genetic determinant of common obesity characterized to date. A limitation of this analysis was that histology was available for only 62% of women. Furthermore, we did not have detailed information on menopausal hormone use, weight at different periods in life, body fat distribution, or other factors that may influence endometrial cancer risk FTO genotype with menopausal status or menopausal hormone use was observed in the subset of women for whom this information was available. Finally, the use of self-reported height and weight might have resulted in nondifferential misclassification and thus underestimation of the true effects.A strength of this pooled analysis was the large sample size available within the E2C2. A large number of genetic variants and quantitative trait loci that potentially predispose to obesity have been reported, but only a few have been convincingly confirmed in multiple independent large scale investigations FTO rs9939609 AA genotype is associated with endometrial cancer risk among non-Hispanic white women. As more common genetic variants associated with overweight and obesity are identified, these might help to identify the pathways that influence endometrial carcinogenesis.Although important gaps exist in our understanding of the molecular pathways leading to increased weight and obesity, our data provide novel evidence that the All participating studies were approved by the review boards and ethics committees of their parent institutions and participating hospitals, including Queensland Institute of Medical Research, Brisbane, Australia, for the Australian National Endometrial Cancer Study (ANECS); the Institutional Review Board (IRB) at Memorial Sloan-Kettering Cancer Center, NJ, USA, for the Estrogen, Diet, Genetics, and Endometrial Cancer (EDGE) study; the IRB of the Fred Hutchinson Cancer Research Center, WA, USA, for the Fred Hutchinson Cancer Research Center Case-Control Study (FHCRC); the IRB of the University of Hawaii, HI, USA, for the Hawaii Endometrial Cancer Study (HAW); the IRBs of the Universities of Hawaii and Southern California, for the Multiethnic Cohort Study (MEC); the Committee on Use of Human Subjects of the Brigham and Women's Hospital, MA, USA for the Nurses' Health Study (NHS); the National Cancer Institute Central IRB, Bethesda, MD, USA, the Ethical Committee of The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology , and the Bioethical Committee of the Nofer Institute of Occupational Medicine  for the Polish Endometrial Cancer Study (PECS); the Research Ethics Board of the Women's College Research Institute, Toronto, ON, Canada, for the Toronto Case-Control Endometrial Cancer Study; the Committee on Studies Involving Human Subjects of the University of Pennsylvania, PA, USA, for the Women's Insights and Shared Experiences Study (WISE).Written informed consent was obtained from all participants. and S4) included 3601 women with primary incident endometrial carcinoma and 5275 women who were free of endometrial cancer and did not have history of hysterectomy. Six studies were population-based case-control studies, two studies were case-control studies nested within a cohort, and one study was hospital-based. All studies except the TORONTO study included incident endometrial cancer cases exclusively. Epidemiological data were collected using structured questionnaires. All data were combined in the E2C2 coordinating center. Age at diagnosis for cases or age at interview for controls was available for all study participants. FTO rs9939609 genotype data were available for 8728 women (3561 cases and 5167 controls) and MC4R rs17782313 genotype data were available for 7895 women (3120 cases and 4775 controls). Self-reported BMI data were available for 7459 (84%) of women; data were missing for women from the Toronto study  and for 1.5% of women from other studies. Histology data were available for 2243 (62%) cases. Data on menopausal status were available for 907 cases and 885 controls (20%) and use of any menopausal hormones were available for 3050 cases and 3803 controls (77% of women).Based on Epidemiology of Endometrial Cancer Consortium (E2C2) procedures, we submitted a formal proposal describing our hypothesis and methods to the steering committee and to all consortium members. Genotyping of the proposed SNPs was performed in the individual laboratories of investigators expressing an interest in collaboration, following a similar protocol. All data were combined in the E2C2 coordinating center. Nine studies participating in this pooled analysis (MC4R rs17782313 genotype data were not available for the PEC study (417 cases and 407 controls).Genotyping was performed in the individual laboratories using 5′ nuclease TaqMan allelic discrimination assay  following the same protocol. We used the following criteria to measure the acceptability of the genotyping results: (1) inclusion of ≥3% sample duplicates, (2) concordance rate for duplicate samples ≥99%, (3) overall call rate by study ≥95% and (4) intermixing of cases and controls on each plate. All studies met these criteria. Genotyping quality was also assessed using tests for Hardy-Weinberg equilibrium (HWE). The genotype distribution for both SNPs among controls was consistent with HWE in all but one study  for rs9939609 and one study  for rs17782313. Exclusion of these studies did not appreciably affect the reported results. 2) and overweight women (BMI ≥25 kg/m2). The genotype for each SNP was treated as a non-ordered categorical variable to test for heterogeneity and as an ordered categorical variable  to test for an allele-dose effect. Homozygous carriers of the common FTO rs9939609 and MC4R rs17782313 T alleles were used as the reference group for these models. Heterogeneity of effects by study was examined using two different methods. First, we included study site as a fixed effect covariate and evaluated heterogeneity of the association of genotypes with risk by study, using a Wald test of the genotype-study interaction term. Second, we included study site as a random effect using SAS GLIMMIX procedure (the results were the same). To evaluate potential confounders, the distributions of genotypes among controls were examined by factors associated with ovarian cancer risk  (Table S5). Age (continuous variable) was included in all models to account for residual confounding by imperfect matching. A Wald test was used to compare the associations of genotypes with endometrial cancer risk by study and BMI strata. Power calculations were performed using QUANTO software (http:hydra.usc.edu/gxe) and were based on population incidence rates of endometrial cancer of 24.4 per 100,000 women per year. These rates are based on cases diagnosed in 2001–2005 from 17 Surveillance Epidemiology and End Results (SEER) geographic areas Table S6.All analyses were completed in the SAS statistical software package version 9.2 . Fisher's goodness-of-fit test was used to assess whether allele frequency distributions among controls were consistent with HWE. Unconditional multiple logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of genotype with endometrial cancer risk and BMI, calculated as the ratio of weight in kilograms divided by the square of height in meters. BMI was used as continuous variable, as well as categorical with two levels: lean women Click here for additional data file.Table S2FTO rs9939609 and MC4R rs17782313 SNPs with endometrial carcinoma risk among non-Hispanic white women by study.Association of the (DOC)Click here for additional data file.Table S3FTO rs9939609 and MC4R rs17782313 with endometrial carcinoma risk among white-non-Hispanic women by BMI strata.Association of (DOC)Click here for additional data file.Table S4Case ascertainment and selection of controls.(DOC)Click here for additional data file.Table S5FTO rs9939609 and MC4R rs17782313 genotypes.Frequency distribution of age, menopausal status, and menopausal hormone use by (DOC)Click here for additional data file.Table S6FTO rs9939606 and MC4R rs17782313 at power 80%, type I error = 0.05.Minimal detectable ORs (MDORs) for (DOC)Click here for additional data file.


Gastric cancer is a major contributor to cancer deaths in Zambia but, as elsewhere, no preventive strategies have been identified. We set out to investigate the possibility of reducing gastric atrophy, a premalignant lesion, using micronutrient-antioxidant supplementation.We analysed 215 archival samples from a randomised controlled trial of micronutrient-antioxidant supplementation carried out from 2003 to 2006. Participants were randomised to receive either the supplement or placebo and had been taking the allocated intervention for a mean of 18 (range 14–27) months when the samples used in this study were taken. We used low pepsinogen 1 to 2 (PEP1:2) ratio as a surrogate marker of gastric atrophy. A PEP 1:2 ratio of less than three was considered low. HIV serology, age, nutritional status, smoking, alcohol intake and gastric pH were also analysed. Ethical approval was obtained from the University of Zambia Biomedical Research Ethics Committee (011-04-12). The randomized trial was registered (ISRCTN31173864).P = 0.79). The presence of low PEP 1:2 ratio was not influenced by HIV infection  or nutritional status but it inversely correlated with gastric pH . Age above 40 years was associated with atrophy, but neither alcohol nor smoking had any influence.The overall prevalence of low PEP 1:2 ratio was 15/215 (7%) and it did not differ between the placebo  and micronutrient groups (7/112, 6.3%; HR 1.24; 95% CI 0.47-3.3; Short term micronutrient supplementation does not have any impact on PEP 1:2 ratio, a serological marker of gastric atrophy. PEP 1:2 ratio inversely correlates with gastric pH. Gastric cancer is a major contributor to cancer deaths in Zambia but, as elsewhere, no appreciable preventive strategies have been identified. Low intake of fruits and vegetables has been associated with increased risk of gastric adenocarcinoma in the United States of America . This apThe sequence of gastric premalignant lesions was first defined by Correa in 1975 . PremaliHelicobacter pylori (H. pylori) gastritis or gastric premalignancy [et al.[There is conflicting evidence regarding the benefit of micronutrient supplementation in premalignant gastric lesions. Most studies have failed to sufficiently prove any beneficial effect of this supplementation on the progression to gastric cancer -12. Vitalignancy . Beno ety [et al. reportedThese studies mainly investigated the effects of vitamins C, E, A and selenium, and did not include other micronutrients. These studies also used histological changes to assess gastric atrophy. We set out to test the hypothesis that micronutrient and antioxidant supplementation could lead to the regression of gastric atrophy determined by low PEP 1:2 ratios in a Zambian population.H. pylori infection of 81% [This was a retrospective analysis of samples from a randomised, placebo-controlled trial of multiple micronutrient and antioxidant supplementation which was conducted in Misisi Township in Lusaka, Zambia between 2003 and 2006 . Misisi n of 81% . For thiDuring the controlled trial, all consenting residents above the age of 18 years, living in the designated area were eligible to participate in the study. There were no exclusion criteria. In total, 500 residents volunteered to participate in the study, half of whom were randomly allocated to receiving either micronutrient supplementation or placebo. The multiple micronutrient and the placebo tablets were both prepared and supplied by Dnask Farmaceutic Industri . The supplement tablets contained multiple micronutrients at around 1.5-2 times Recommended Nutrient Intakes  and the manufacturer’s instructions were followed. A ratio less than 3.0 was used to signify the presence of severe gastric atrophy. VK and MC were completely blinded to the allocations while running the samples. The coding of these samples was only broken by PK after completion of data entry.Statistical analysis was carried out using STATA 12.1 (STATA Corp. College Station. TX). For continuous variables showing Gaussian distribution, the Kruskal-Wallis test was used to compare the two groups. For categorical variables, Fisher’s exact test was used. Backwards step wise unconditional logistic regression was used to assess the contributions of different factors to gastric atrophy.A total of 226 serum samples collected in 2005 were available for analysis. Eleven samples were, however, left out of the analysis as three were not clearly labelled and eight were collected after crossover from micronutrient to placebo in the original trial , leavingP = 0.79. Analysis of the PEP 1:2 ratios of all the samples as continuous variables did not yield any statistically significant difference (P = 0.32). The mean ratio among the supplementation group was 5.8 (IQR 4.3-6.9), while that among the placebo group was 5.9 (IQR 4.5-8.0).The overall prevalence of gastric atrophy in these healthy volunteers was 15/215 (7%). There was no significant difference in the prevalence of low PEP 1:2 ratios between the participants on micronutrient supplementation, 8/103(7.8%) and those on placebo, 7/112 (6.3%) Hazard Ratio (HR) 1.24; 95% CI 0.47-3.3; P =0.89).Of the serum samples analysed, 180 had HIV tests performed in the previous trial, and 66 (37%) were positive. Of these subjects with HIV infection, 5/66 (7.6%) had gastric atrophy, which did not differ significantly from HIV negative subjects among whom 8/114 (7.0%) had atrophy . Of the 60 participants randomised to placebo for whom pH measurements were available, 19 (32%) had a fasting gastric pH of more than 4 (which was taken as significant hypochlorhydria) compared to 26 of 61 (43%) participants allocated to micronutrient-antioxidant supplementation .Measurements of pH in gastric aspirates taken while fasting were available on 121 participants. Gastric pH and low PEP 1:2 ratios were inversely correlated . If the supplementation had any effect on development of atrophy, this difference would still have been seen despite the longer follow-up in the placebo group. It seems unlikely that this difference in duration of follow-up (which is determined by the date the sample was collected) could explain a lack of apparent benefit. On the other hand, 18 months might be too short to demonstrate the effect of these supplementations and it is possible that a longer follow-up (5–10 years) might yield different results.The study participants were randomly allocated to either supplementation or placebo in the main trial. We made a reasonable assumption at since the participants were randomly allocated at enrolment then the prevalence of atrophy was not significantly different in the two groups. It is well understood that any differences in groups that have been randomly allocated are merely due to chance . This isGastroscopies were done on some of the participants in the main trial to determine the fasting gastric pH. Unfortunately, no gastric biopsies were obtained as this was not part of that study protocol. We therefore, did not have any data on the histological diagnosis of gastric atrophy or the degree of atrophic changes. Analysis of PEP 1:2 ratios as continuous variables did not yield any statistically significant difference between the two groups.H. pylori antibodies is very common in this population [H. pylori infection has an influence on the presence and persistence of gastric atrophy but it was not tested in the main trial and we did not have the appropriate samples to test for active infection. Therefore, the presence of H. pylori infection was not checked in this retrospective analysis of stored serum samples. This could not have affected the results as none of the patients received treatment to eradicate the infection during the study follow-up.We know from our previous work that the presence of pulation . H. pyloThe adherence (pill count) of the subjects was at more than 95%, as reported in the main trial . ParticiThe population prevalence of gastric atrophy in Zambia is unknown, but in a hospital based case–control study , we founHIV positive patients have in the past been reported to have higher gastric pH than their HIV negative counterparts . NeitherWe were also interested to see if alcohol and smoking had any influence on gastric atrophy. It remains unclear at which exact stage  of the carcinogenic pathway alcohol and smoking influence gastric carcinogenesis. We found that these two factors have no influence on gastric atrophy.There is a shortage of data on gastrointestinal malignancies in Africa, and further work is needed to determine if there might be any scope for nutritional interventions to reduce risk.An average of 18 months of micronutrient-antioxidant supplementation has no impact on the occurrence of low PEP 1:2 ratio, which is a surrogate marker of gastric atrophy. The presence of HIV infection has no influence on atrophy. Low PEP 1:2 ratios were more likely among participants above the age of 40 years, while there was an inverse correlation with fasting pH. Alcohol and smoking also did not show any influence on gastric atrophy.The authors declare that they have no competing interest.VK and PK designed the study; VK collected and sorted the serum samples; VK and MC did the Enzyme-linked Immunoabsorbant Assays on the samples; PK performed the statistical analysis; VK and PK analysed the data; VK, MC and PK contributed to the write-up of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-230X/14/52/prepub


FTO A/T polymorphism (rs9939609) is a strong candidate to influence obesity-related traits. Elite athletes from many different sporting disciplines are characterized by low body fat. Therefore, the aim of this study was to assess whether athletic status is associated with the FTO A/T polymorphism.The FTO A/T polymorphism (rs9939609) and athletic status. A total of 551 athletes were divided by type of sport  as well as by level of competition . The control group consisted of 1,416 ethnically-matched, non-athletic participants, all Europeans. Multinomial logistic regression analyses were conducted to assess the association between FTO A/T genotypes and athletic status/competition level.A large cohort of European Caucasians from Poland, Russia and Spain were tested to examine the association between There were no significantly greater/lesser odds of harbouring any type of genotype when comparing across athletic status . These effects were observed after controlling for sex and nationality. Furthermore, no significantly greater/lesser odds ratios were observed for any of the genotypes in respect to the level of competition .FTO A/T polymorphism is not associated with elite athletic status in the largest group of elite athletes studied to date. Large collaborations and data sharing between researchers, as presented here, are strongly recommended to enhance the research in the field of exercise genomics.The  There is emerging evidence that elite athletes or former elite athletes are predisposed towards longer life expectancy, and lower risk of chronic diseases such as obesity and type 2 diabetes, than matched sedentary controls FTO) gene  is a strong candidate to explain how disease modifier polymorphisms may contribute to lower risk for obesity among trained individuals FTO A/T polymorphism has initially been identified as a risk factor for obesity by two independent genome-wide association studies (GWAS) Genetic factors may contribute to the low predisposition of elite athletes to the aforementioned disease conditions. Specifically, the A/T polymorphism (rs9939609) in the fat mass and obesity associated (FTO A/T polymorphism and obesity related-traits. The association between FTO A/T polymorphism and body mass index (BMI) is significantly weaker in individuals with higher exercise levels FTO A/T polymorphism might be a novel target to influence elite athletic status.Exercise may attenuate the association between FTO A/T polymorphism (rs9939609) between elite endurance athletes, elite sprint/power athletes, and ethnically-matched, non-athletic control participants in a large group of Europeans . We also examined the association of the FTO A/T polymorphism with respect to the level of achievement of the athletes , in both endurance and sprint/power athletes. We hypothesized that the frequency of the A-allele or the AA genotype will be lower among elite athletes compared with control participants.Therefore, the aim of the present study was to compare the frequency distribution of the Universidad Europea de Madrid, Spain, the Pomeranian Medical University, Poland, and the Kazan State Medical University, Russia.The study was conducted according to the Declaration of Helsinki. Written informed consent was obtained from all participants, and the study was approved by the ethics committees of A total of 551 athletes (266 endurance athletes and 285 power athletes) and 1416 control participants, from Poland, Russia and Spain, volunteered to participate in this study. All participants were unrelated European men (76%) or women (23%), and all of European descent (as self-reported) for ≥3 generations. The sample included elite athletes (57%) who had competed at an international level  and national-level athletes (43%) who participated in their chosen sport at a national level only. The competition level differentiation was made according to the athletes' best individual performances. The athletes were only included if they had never tested positive in anti-doping controls. Control participants were required to be free of any diagnosed cardiorespiratory disease and not participating regularly in any competitive or structured sport or physical activity .The Spanish cohort (n = 192) were all male and included 81 elite athletes (mean ± SD mass = 62.0±6.3 kg) and 60 control participants (71.9±8.3 kg):32 elite sprint/power athletes (mean age = 26±3 yr). Thirteen track and field athletes were Olympians during the period 2000–2008.49 elite endurance athletes (27±4 yr). This sample included 49 elite endurance runners .Universidad Europea de Madrid, Spain).60 healthy, non-athletic control participants (20±2 yr). All were undergraduate students from the same university (The Polish cohort (n = 844), were all male and included 214 athletes (mean ± SD mass = 71.3±6.2 kg) and 630 control participants (79.2±6.1 kg). Of the athletes, 132 were classified as elite and 82 were national-level athletes:101 power athletes (28±8 yr). This group included weightlifters (n = 42), sprinters , and track and field jumpers (n = 26). This group included 63 (62%) elite athletes.113 endurance athletes (26±6 yr). This group included rowers (n = 53), endurance road cyclists (n = 14), 5,000 m runners (n = 12), marathon runners (n = 12), 800–1,500 m swimmers (n = 11), 15–50 km cross-country skiers (n = 7), and triathletes (n = 4). This group included 69 (61%) elite athletes.630 healthy, non-athletic control participants (21±2 yr). All the control participants were students of the University of Szczecin.The Russian cohort  included 256 athletes  and 726 control participants . Of the athletes 105 were classified as elite and 151 were classified as national-level athletes:152 power athletes (24±8 yr). This group included: 100–200 m sprinters (n = 18), track and field jumpers (n = 47), short distance speed skaters , 50–100 m swimmers (n = 13), and weight lifters (n = 65). The group included 71 (47%) elite athletes.104 endurance athletes (20±2 yr). This group included rowers (n = 36), long distance runners , road cyclists (n = 12), long distance speed skaters , skiers (n = 15) and long distance swimmers .The group included 34 (33%) elite athletes.726 healthy, non-athletic control participants (21±5 yr). All the control participants were citizens of Moscow and Kazan.We followed recent recommendations for genotype-phenotype association studies provided by Chanock et al. Ariel University Centre, Israel. Polymerase chain reaction (PCR) was performed in order to amplify the sequence containing the mutation. A fragment of 105 bp was amplified with the following primers: FTO- F 5′- GGT TCC TTGCGA CTG CTG TGA AAT T '3 and FTO-R 5' GCT TTT ATGCTC TCC CAC TC '3. The PCR conditions were as follows: initial denaturing at 95°C 5 min; 35 cycles at 95°C 30 s, 60°C 30 s, 72°C 30 s and a final extension at 72°C 10 min. FTO genotypes were established by enzymatic digestion of amplicons with ApoI and by allelic discrimination assay on a Real-Time Polymerase Chain Reaction (PCR) instrument (Stratagene Mx3000D) with Taqman® probes (Genotyping ToughMix®). Following recent recommendations Genomic DNA was isolated from buccal epithelium or peripheral blood during the years 2004–2008 and genotyping was performed during 2012 in the Genetics Laboratory of Pomeranian Medical University using an allelic discrimination assay on a Rotor-Gene Real-Time Polymerase Chain Reaction (PCR) instrument  with Taqman® probes. For the discrimination of FTO A and T alleles (rs9939609), a TaqMan® Pre-Designed SNP Genotyping Assay was used  (assay ID: C__30090620_10), including primers and fluorescently labelled (FAM and VIC) MGB™ probes for the detection of both alleles.Genomic DNA was isolated from buccal epithelium using GenElute Mammalian Genomic DNA Miniprep Kit  during the years 2008–2010, according to the producer protocol. All samples were genotyped during 2012, in the FTO gene polymorphism was performed during 2012, at the Laboratory of Molecular Genetics, Kazan State Medical University by PCR on a multicanal amplificator Tercyk  and restriction enzyme digestion Genomic DNA was isolated from epithelial mouth cells using a DNK-sorb-A sorbent kit according to the manufacturer's instruction . Genotyping for the Following recent recommendations Chi squared tests were used to test for the presence of Hardy-Weinberg equilibrium (HWE). Genotype and allele frequencies were compared according to athletic status  using Fisher's exact test. Multinomial logistic regression analyses were conducted to assess the association between genotype and athletic status/competition level. In each case, gender and nationality were controlled for; and analyses were made comparing AA (reference group) vs. AT; AA vs. TT (co-dominant effect); AA vs. TT and TA combined (dominant effect); AA and TA combined (reference group) vs. TT (recessive effect). Significance was accepted when p≤0.05.FTO A/T polymorphism.Replication analysis with a different genotyping method yielded 100% agreement. There were no significant differences in age between cohorts. This added to the homogeneity of the study population and allowed us to pool the three cohorts to examine the association between physical performance level and p>0.1). In the Russian sample, no differences were observed in the proportion of men and women participating in endurance and power sports (p>0.05) and genotype and allele frequencies were similar according to gender . For these reasons, gender was considered as a covariate only in further analyses (see below).FTO A/T polymorphism (rs9939609) and elite athletic status in a large cohort of European athletes. No significant differences were observed in genotype/allele frequencies when comparing between the three groups  or when comparing between the groups with respect to the level of performance , suggesting that this polymorphic marker is not related to elite athletic performance.We have analysed, for the first time, the association between FTO A/T polymorphism and athletic performance in elite athletes from several cohorts. Taken individually, the results from our three cohorts are probably limited by relatively small sample size of the individual cohorts, and low statistical power. In an attempt to overcome the barrier of sample size, and the difficulty of gathering a homogenous cohort of elite athletes in each sporting discipline, we have recruited a total of 551 athletes (266 endurance athletes and 285 power/sprint athletes), all of European descent for ≥3 generations. Indeed, it has been estimated that testing a single variant using a case (athletes):control (non-athletes) design would require ∼250 cases to obtain a statistical power of 80% In the present study we explored the association between the FTO A/T polymorphism studied here are associated with increased BMI and energy intake FTO variants on obesity risk Genetic variants such as the PPARGC1A) Gly482Ser polymorphism, in which the 482Ser allele is associated with increased risk of obesity and type 2 diabetes PPARGC1A gene and fat oxidative metabolism suggest that this gene may influence athletic performance on one hand, and prevention of obesity on the other hand. Additional examples of polymorphisms that were found to be associated with both obesity and elite athletic performance are the ADRB2 Arg16Gly (rs1042713) ADRB3 Trp64Arg (rs4994) The duality of specific polymorphisms associated with both obesity and athletic performance has been well demonstrated. A good example is the peroxisome proliferator-activated receptor gamma coactivator1α (FTO A/T polymorphism (rs9939609) is located in the first intron of the FTO gene, which is expressed mainly in the brain, skeletal muscles and adipose tissue FTO gene, and significant reduction in adipose tissue and lean body mass FTO gene is functionally involved in energy homeostasis, mitochondrial coupling and substrate cycling by controlling energy expenditure FTO A/T polymorphism was shown to affect energy efficiency potentially by influencing mitochondrial coupling in human type I (oxidative) muscle fibres FTO mRNA expression in human skeletal muscle correlates with whole-body substrate oxidation rates FTO A/T polymorphism.The FTO gene in energy metabolism and muscle function, (ii) the fact that other gene polymorphisms have been shown to be associated with both obesity and athletic performance , (iii) the interaction between the FTO A/T polymorphism and physical activity levels, (iv) the low percentage of body fat characteristic of elite athletes excelling in both endurance and many sprint/power events (v) the lower risk of obesity in former elite athletes, and (vi) the suggestive role of the FTO gene in muscle performance, encouraged us to hypothesize that the FTO A/T polymorphism was associated with elite athletic status. However, no association was found between the FTO A/T polymorphism and athletic status in the largest group of elite athletes studied to date. Elite athletic status is a polygenic trait with several candidate gene variants (most of which likely remain unidentified) playing a certain role, either alone (which does not seem to be the case with the FTO A/T variation), or through complex, gene-gene and gene-environment interactions To summarize, (i) the potential involvement of the


CCL5), plays a key role in the inflammatory response by recruiting mononuclear cells during tuberculosis (TB) infection. Association studies of CCL5 -28 C>G (rs2280788) polymorphism and TB risk have shown inconsistent and contradictory results among different ethnic populations. The aim of this meta-analysis is to investigate the association between CCL5 -28 C>G polymorphism and TB susceptibility.The CC chemokine ligand 5 (CCL5 -28 C>G polymorphism and TB risk from PubMed (Medline), EMBASE web databases. The meta-analysis was performed and pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for all genetic models.We performed quantitative synthesis for published studies based upon association between A total of six studies including 1324 TB cases and 1407 controls were involved in this meta-analysis. Variant allele , heterozygous  and homozygous  carriers did not show increased risk compare with those individual with the CC genotype. Similarly, no associations were found in the dominant  and recessive  models.CCL5 is not associated with increased TB risk. However, future larger studies with group of populations will be needed to analyze the relationship between the CCL5 -28 C>G polymorphism and risk of TB.Overall findings of this meta-analysis suggest that genetic polymorphism -28 C>G in  Mycobacterium tuberculosis (M. tuberculosis), leading cause of death with an estimate of approximately 1.5 million deaths worldwide annually M. tuberculosis infection but only small fraction (5–15%) of population develops an active TB disease during their lifetime M. tuberculosis with environmental and host genetic differences may contribute to development of TB infection Tuberculosis (TB) is the most common chronic infectious disease caused by system confer strongly influence susceptibility to active TB at the individual level M. tuberculosis is mostly determined by the active recruitment and activation of immune cells to the site of infection. Migration of immune cells, like activated monocytes/macrophages to the site of granuloma formation, which is a characteristic histological structure in TB infection, is mainly facilitated by adhesion molecules known as cytokines or chemokines CCL5) gene is located on chromosome 17, a member of the beta (C-C) chemokine family and also known as ‘Regulated on Activation, Normal T cell Expressed and Secreted’ (RANTES). This chemokine plays an important role in the activation and proliferation of T-lymphocytes CCL5 in antimycobacterial immunity and warrants for further investigations dealing with relevance of CCL5 in mycobacterial infection.The immune response against CCL5 gene have been described earlier, among them cytosine (C) to guanine (G) substitution of nucleotide -28  found in the promoter region. The variant allele -28G was found to be associated with increased levels of mRNA and protein expression of CCL5 in-vitroCCL5 -28 C>G polymorphism with risk of human TB.Several functional polymorphisms in the CCL5 OR RANTES’ gene (polymorphism OR mutation OR variant) AND tuberculosis or TB (last updated on August 2013). We evaluated potentially relevant genetic association studies by examining their titles and abstracts, and all published studies matching with the eligible criteria were retrieved.We carried out a PubMed (Medline), EMBASE web database search covering all research articles published with a combination of the following key words: ‘In order to minimize heterogeneity and facilitate the proper interpretation of our study, published articles included in the current meta-analysis had to meet all the following criteria: a) must evaluated the association between -28 C>G and TB risk, b) use a case-control design based on unrelated individuals, c) recruited pathologically confirmed TB patients and TB free controls, d) have available genotype frequency in case and control, e) published in English language. In addition to above, when the case-control study was included by more than one research article using the same case series, we selected the study that included the largest number of individuals. The major reasons for study exclusion were, overlapping of data, case-only studies, review articles, and genotype frequencies or number not reported. The flow diagram information related to the selection of studies is appended as supporting For each retrieved publication, the methodological quality assessment and data extraction were independently abstracted in duplicate by two independent investigators using a standard protocol. Data-collection form was used to ensure the accuracy of the collected data by strictly following the inclusion criteria mentioned above. The major characteristic abstracted from the retrieved studies included the name of first author, publication year, the country of origin, the number of cases and controls, source of cases and controls, study type, and genotype frequencies. Cases related with disagreement on any item of the data from the collected studies were fully discussed with investigators to reach a final consensus.CCL5 -28 C>G polymorphism and TB risk, pooled ORs and their corresponding 95% CIs were calculated. Heterogeneity assumption was examined by the chi-square-based Q-test 2 statistics was employed to quantify inter-study variability and larger values indicated an increasing degree of heterogeneity http://www.meta-analysis.com/pages/comparisons.html. The Comprehensive Meta-Analysis (CMA) V2 software program  was selected and utilized to perform all statistical analysis involved in this meta-analysis.In order to estimate the relation between CCL5 polymorphism to predict survival in TB patients or considering CCL5 variants as an indicators for response to therapy were excluded straightaway. Similarly, studies investigating the levels of CCL5 mRNA or protein expression or relevant review articles were also excluded. We included only case-control or cohort design studies having frequency of all three genotype. Besides the database search, the references available in the retrieved articles were also checked for other potential articles  and EMBASE web databases. All retrieved articles were examined carefully by reading the titles and abstracts, and the full texts for the potentially relevant publications were further checked for their suitability for this meta-analysis. Studies either showing Begg's funnel plot and Egger's test were performed to appraise the publication bias among the selected studies for meta-analysis. The appearance of the shape of funnel plots was seemed symmetrical in all the genetic models. The Egger's test was performed to provide the statistical evidence of funnel plot. The findings showed lack of publication bias among all comparison models .2 statistics were employed. Heterogeneity was observed in all the models, i.e., allele (G vs. C), homozygous (GG vs. CC), heterozygous (CG vs. CC), dominant (GG+CG vs. CC) and recessive (GG vs. CC+CG) genotype model, which were included for this meta-analysis. Thus, random effects model was applied to synthesize the data , heterozygous  and homozygous  comparisons Click here for additional data file.Figure S2Sensitivity analysis for CCL5 -28 C>G polymorphism.(TIF)Click here for additional data file.Checklist S1PRISMA 2009 Checklist.(DOC)Click here for additional data file.


Measures of exploitativeness evidence problems with validity and reliability. The present set of studies assessed a new measure [the Interpersonal Exploitativeness Scale (IES)] that defines exploitativeness in terms of reciprocity. In Studies 1 and 2, 33 items were administered to participants. Exploratory and Confirmatory Factor Analysis demonstrated that a single factor consisting of six items adequately assess interpersonal exploitativeness. Study 3 results revealed that the IES was positively associated with “normal” narcissism, pathological narcissism, psychological entitlement, and negative reciprocity and negatively correlated with positive reciprocity. In Study 4, participants competed in a commons dilemma. Those who scored higher on the IES were more likely to harvest a greater share of resources over time, even while controlling for other relevant variables, such as entitlement. Together, these studies show the IES to be a valid and reliable measure of interpersonal exploitativeness. The authors discuss the implications of these studies. In addition, Sociology’s electronic library database, SocINDEX, contains more than 6,000 references related to exploitation; more than 900 of these records are from the past 5 years. The tendency to engage in exploitation – exploitativeness – has fewer citations, but nevertheless it is clear that social and behavioral scientists consider exploitation and exploitativeness important for theory, research and practice.The social and behavioral sciences have long shown an interest in the concepts of exploitation and exploitativeness, or unfairly using others for profit or advantage. A June 2012 check of PsycINFO (1967-Present) revealed more than 7,700 records containing the term Across several disciplines in the social and behavioral sciences, recent work on reciprocity in social exchange indirectly raises questions about exploitativeness. The norm of reciprocity states that people treat others as they have been treated, repaying kindness with kindness and retaliating against those who inflict harm  students, who were on average 19.37-years-old (SD = 3.11).Participants were 482 undergraduate students at a large Midwestern state university who completed the exploitativeness items as a part of mass testing in exchange for partial course credit. Nearly 90 percent of the students were Caucasian. Demographic and exploitativeness data were unavailable for 88 students, resulting in The intent was to create a pool of items which conveyed exploitativeness in the sense of violating the norm of reciprocity, that is, benefiting at the expense of others. We chose not to use items from the NPI or other existing measures that purportedly addressed exploitativeness. An initial pool of 33 items designed to measure interpersonal exploitativeness was independently generated by several of the authors and reviewed for clarity, vagueness, and redundancy by four subject matter experts whose specialties included clinical, social-personality, and quantitative psychology.strong disagreement and seven indicating strong agreement. Scores across the 33 items were averaged such that a higher score was indicative of greater exploitativeness. For the present sample, α = 0.94, M = 2.84, SD = 0.92.Following informed consent, participants completed the 33-item version of the IES. We used a 7-point Likert response scale, with one indicating M, and SD are displayed in Table We examined the factor structure of the 33 items through exploratory factor analysis in SAS, using PROMAX, an oblique factor rotation method, although a similar exploratory factor analysis with VARIMAX, an orthogonal factor rotation method, produced qualitatively similar results. Nevertheless, examination of the screen plot indicated that one-factor should be retained, which accounted for 79.8% of the variance. The items, as well as their This study yielded a potential one-factor measure of interpersonal exploitativeness. In Study 2, we sought to confirm the structure of the 6-item IES that we found in Study 1.M = 2.40, SD = 1.21.Participants were 535  undergraduates at a large state university in the Midwest who provided informed consent and completed the IES in exchange for partial course credit. Nearly 94 percent of the participants were Caucasian, and the mean age was 19 years (SD = 3.17). For the present sample, α = 0.89, 2 = 26.78, df = 9, p < 0.002). However, because the chi-square statistic is sensitive to sample size, we looked at other measures of fit as well  who participated in exchange for partial course credit. On average, participants were 19.35 years old (SD = 2.78). About 78.9% of the participants self-identified as Caucasian; another 11.4% self-identified as African-American.M = 2.53, SD = 1.38 for the IES). We selected several measures which theoretically should correlate with interpersonal exploitativeness. First, we chose Raskin and Terry’s . For our purposes, we report correlations with PNI scores, which were averaged across the 52 items, as well as the two most relevant subscales for our purposes: the 5-item Exploitative subscale  and the 8-item Entitlement Rage . It should be noted that the items assessing exploitativeness on the PNI are adapted from the exploitativeness subscale of the NPI. We expected that the IES would correlate positively with the PNI and its dimensions of exploitativeness and entitlement rage. For our sample, α = 0.94, M = 2.51, SD = 0.69 for PNI scores, α = 0.77, M = 2.61, SD = 1.02 for the PNI Exploitative subscale, and α = 0.85, M = 2.28, SD = 1.00 for the PNI Entitlement Rage subscale.Second, we selected the Pathological Narcissism Inventory . Given that we believe that exploitativeness and entitlement go hand in hand, we expected a positive correlation between these two dimensions. For our sample, α = 0.86, M = 3.32, SD = 1.20.Next we included the 9-item PES . For the present sample, α = 0.84, M = 3.35, SD = 0.65.We also included the 10-item Rosenberg Self-Esteem Scale . Most of the sample (78.8%) self-identified as Caucasian and 11.1% self-identified as African-American.Participants were 208  undergraduate students at a regional campus of a state university in the Midwest, who participated in exchange for partial course credit  and the 9-item PES . They then engaged in a competitive task in dyads, which was based on previous research about the tragedy of the commons  to answer two questions. First, they were asked to indicate their acquisitiveness by rating the extent to which they wanted to profit more than the other company . Second, participants were asked to indicate their apprehension by rating the extent to which they thought that the other company wanted to profit more than they did . After answering these two questions, participants began the bidding process. Each participant privately indicated the number of hectares that they wanted to harvest on a “bid sheet.” The researcher then (a) added together the total number of hectares harvested in the round, (b) subtracted that value from the amount of forest available (which started at 100 ha), (c) added 10% to this value, and (d) announced the total amount of hectares available for the next round. For example, if in the first round the combined harvest was 10 ha, the researcher would subtract 10 from 100, and then add in 10% (9 ha). The researcher would then announce that there was 99 ha of forest for the next round. This process was repeated up to 20 rounds  or until the harvest was completely exhausted. Participants were then debriefed and thanked for their time.Participants then used 7-point scales  but not with acquisitiveness  whereas the PES was correlated with acquisitiveness  but not apprehension . Acquisitiveness and apprehension were also positively correlated . When the IES was entered into a regression equation predicting acquisitiveness while controlling for apprehension, it significantly predicted acquisitiveness . However, when the PES was also added to the equation, the PES was significant  whereas the IES was not  = 1.19, p = 0.24). Next, the IES was entered into a regression equation predicting apprehension while controlling for acquisitiveness. The IES significantly predicted lower apprehension  = −3.38, p < 0.001), and remained significant , even while controlling for the PES  = −2.99, p < 0.01). When added to the models, gender was not a significant predictor of acquisitiveness  = 0.64, p = 0.52) or apprehension β = −0.06, t(201) = −0.99, p = 0.32). Thus, it appears that the PES was more strongly associated with acquisitiveness than was the IES. Both the PES and the IES were associated with lower apprehension, findings which are supported by previous research that found that narcissists experience less apprehension than non-narcissists when engaging in competitive tasks  = 0.55, p = 0.58, βGender = −4.64, t(101) = 1.44, p = 0.15) and the total number of rounds  = 0.22, p = 0.83, βGender = −0.36, t(101) = 0.62, p = 0.54).The mean amount harvested was 82.81 (SD = 22.17) hectares; the mean number of rounds the dyads completed was 13.18 (SD = 3.96) rounds. We investigated the influences of gender and exploitativeness on total harvested and on the total number of rounds using multiple regression. Because there was no difference in total harvested and total number of rounds within dyads, we constructed the regression models with dyads rather than individuals . We did not find a significant influence of the dyad’s gender or exploitativeness composition on the total amount harvested . Such a model allowed for the construction of an MLM version of an Actor-Partner Interdependence Model  were centered within the dyad, such that 0 represents the study midpoint for any given dyad . The variable Gender was a dichotomous variable with male = 0 and female = 1. As per the recommendation of Kashy et al.  = 2.08, p = 0.04. In particular, participants were more likely to allocate more for themselves in later rounds than in earlier rounds. In a related model we included a quadratic term for round number to test whether participants allocated more in early and later rounds than in middle rounds, the estimate of this parameter was non-significant, b = 0.004, p = 0.086. Consistent with the nature of the commons dilemma, dyads that played more rounds allocated less on average per round , b = −0.22, t(131) = −30.29, p < 0.0001.Results of the growth curve model indicate a significant effect of round number, the average b = 0.06, p = 0.51. In contrast, women appeared to allocate more in later rounds, compared to earlier rounds, than did men, b = 0.08, t(157) = 2.45, p = 0.02.We next investigated the role of gender differences in allocation behavior. Results indicated that women did not allocate significantly more than men at the midpoint of the study, i’s IES score on their own allocation behavior) and partner effects , we created variables ActIES and PartIES, as per the recommendations of Kashy et al.  = 2.26, p = 0.03, and the partner’s exploitativeness, b = 0.05, t(201) = 2.74, p = 0.007. That is, both the actor’s and their partner’s exploitativeness was positively related to increases in allocations in later rounds. As there was a null influence of exploitativeness on allocation decisions at the midpoint of the study, the significant interactions indicate that higher exploitativeness was associated with lower allocations  at the beginning of the study and higher allocations  at the end of the study. Testing an interaction of exploitativeness with round and gender  produced null results, p = 0.91 and p = 0.18, respectively.To investigate the role of actor effects  = 2.56, p = 0.01, and the PartIES × Round interaction remained significant, b = 0.05, t(205) = 1.94, p = 0.05. Taken together, the current results provide evidence in support of the predictive validity of the IES scale in terms of allocation behavior.One consideration is whether the observed effects are uniquely a product of exploitativeness, or whether they could be similarly predicted by a related construct. We tested this consideration by adding the PES to the MLM. When including both the IES and the PES  in the model, neither This study was designed to assess the role of interpersonal exploitativeness in a commons dilemma in which resources could be used irresponsibly or conserved. We hypothesized that those who scored higher on the IES would be less likely to conserve common resources. Results suggested that higher IES scores are related to cooperative behavior at the beginning of the study and less cooperative behavior  at the end of the study. Perhaps interpersonally exploitative people use this strategy to earn the partner’s trust early on and then defect later on to “win.” This pattern of findings remained significant even when controlling for other relevant constructs, such as psychological entitlement, which did not influence allocation behavior in the commons dilemma.The purpose of these studies was to develop and validate a new measure of interpersonal exploitativeness grounded in norms of reciprocity and exchange. In Study 1, the initial pool of 33 items was administered to a sample of undergraduate students who participated in mass testing. Exploratory factor analysis yielded one-factor that consisted of six items, with high internal reliability. Confirmatory factor analysis in Study 2 confirmed the fit of a one-factor solution consisting of the six items. The single factor solution evidenced satisfactory psychometric properties.In Study 3, the IES was correlated with other measures to determine the extent to which the IES was associated with narcissism and reciprocity. As predicted, the IES was positively associated with narcissism, narcissistic exploitativeness, entitlement, and negative reciprocity. Also as predicted, the IES was negatively associated with positive reciprocity. The associations between the IES and the validation measures were in the expected directions.Finally, in Study 4, we employed a commons dilemma to assess how interpersonally exploitative individuals behaved when confronted with a series of resource management decisions. Those who scored higher on the IES were initially cooperative but then became increasingly less cooperative over time in response to the partner’s behavior. This behavior led to greater resource destruction of the commons, which in turn prevented more exploitative people from harvesting more overall.Despite the widespread use of the NPI over the past 30 years, a number of social-personality psychologists have expressed dissatisfaction with it (Brown et al., We also think that the IES has uses outside the context of narcissism. For example, it has been argued that the personality traits that comprise the Dark Triad – Machiavellianism, narcissism, and psychopathy – share features including an exploitative interpersonal style (Palmen et al., Likewise, future research should examine how the IES corresponds to other personality measures that have facets that examine violations from the norm of reciprocity. For example, the HEXACO Personality Inventory (Lee and Ashton, modus operandi.There are a few of limitations of our studies to mention. First, in the present set of studies, we did not assess test-retest reliability, which future research should address. Also, as with any research that employs college student subjects with restricted demographic characteristics, our ability to infer to the general population might be limited. And although the findings from the commons dilemma suggest that those who score higher on the IES are more likely to exploit resources, it remains unclear how these individuals would behave in their daily lives outside a laboratory setting. Despite such limitations, the IES should serve as a useful measure for those interested in interpersonal exploitativeness as either a stable trait or a It is also important to note that the consequences of higher interpersonal exploitativeness might not always be negative. For example, in Study 4, participants were told that their individual goal was to harvest as much forest as possible. Those who scored higher on the IES cooperated early on and then defected at a later point in time, possibly to keep their opponents from outperforming them on this goal. In a “dog-eat-dog” world, a certain level of interpersonal exploitativeness might be beneficial to the individual striving for success, such as climbing the corporate ladder. Future research is needed to examine the beneficial and detrimental consequences of interpersonal exploitativeness.The IES was developed to provide scholars with a reliable and valid measure of interpersonal exploitativeness. Across four studies, the IES was demonstrated to be a reliable and valid measure of exploitativeness. We believe that the IES will be useful for examining the role of exploitativeness in understanding a wide range of social behaviors.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Objectives: Previous reports indicated that XRCC1 Arg280His polymorphism might be a possible risk factor for several cancers. Published studies on the association of XRCC1 Arg280His polymorphisms with glioma risk have yielded controversial results. The present study aimed to derive a more precise estimation of the relationship.Methodology: Meta-analyses assessing the association of XRCC1 Arg280His variation with glioma were conducted and subgroup analyses on ethnicity and source of controls were further performed. Eligible studies for the period up to May 2012 were identified.Results: A total of four case-control studies comprising 1439 cases and 2564 controls were selected for analysis. The overall data indicated no significant association of XRCC1 Arg280His polymorphism with glioma risk . Likewise, in the subgroup analysis regarding ethnicity and source of controls, no associations were observed.Conclusion: The results of the present study failed to suggest an association of XRCC1 Arg280His polymorphism with glioma risk. Further large and well-designed studies are needed to confirm this conclusion. The general prognosis for patients is very poor, particularly for the elderly patients. The mechanisms of carcinogenesis for glioma are still not fully understood. Evidence suggests that exposure to radiation might be an important risk factor for glioma, which could explain a small proportion of glioma because the exposure is generally rare.3 Generally, the repairing of various types of DNA damage is important for maintenance of genomic stability and cell survival. In this process, base excision repair pathways may play a predominant role in protecting both nuclear and mitochondrial DNA from radiation damages.4 X-ray repair cross-complementing gene 1 (XRCC1) is one of the most important DNA repair genes that play a key role in the process of base excision repair. The XRCC1 gene is located on chromosome 19q13.2-13.3 and is 33 kb in length, containing 17 exons and encoding a 70 kDa protein. A widely studied XRCC1 single nucleotide polymorphism at the codon 280, with a Arg to His change (rs25489), could have a diminished capacity to remove DNA adducts and oxidized DNA damage.5 Hence, Arg280His variation has been thought to associate with carcinoma risk.  Radiation exposure may cause DNA damage as well as cell injury. The consequences to the damaged cells can be disastrous, ranging from single gene mutations to massive chromosomal breakdown. The gene damage of the cells could result in severe human diseases including tumor. Published investigations on the association of XRCC1 Arg280His polymorphism with glioma have yielded inconclusive results. In the present study, we carried out a quantitative meta-analysis that increased statistical power to derive a more precise estimation of the relationship. 1: Literature search strategy: We carried out a search in the Medline, EMBASE, OVID, Sciencedirect, and Chinese National Knowledge Infrastructure (CNKI) without a language limitation, covering all papers published up to May 2012, with a combination of the following keywords: XRCC1, Arg280His, glioma, brain, neoplasm, cancer, variation and polymorphism. All searched studies were retrieved and the bibliographies were checked for other relevant publications. Review articles and bibliographies of other relevant studies identified were hand searched to find additional eligible studies. 2: Inclusion criteria: The following criteria were used for the literature selection: first, studies should concern the association of XRCC1 Arg280His polymorphism with glioma risk; second, studies must be observational studies (Case—control or cohort); third, papers must offer the size of the sample, odds ratios (ORs) and their 95% confidence intervals (CIs), the genetic distribution or the information that can help infer the results. After rigorous searching, we reviewed all papers in accordance with the criteria defined above for further analysis. 3: Data extraction: Data were carefully extracted from all eligible publications independently by two of the authors according to the inclusion criteria mentioned above. For conflicting evaluations, an agreement was reached following a discussion. If a consensus could not be reached, another author was consulted to resolve the dispute and then a final decision was made by the majority of the votes. Extracted information was entered into a database.4: Statistical analysis: The OR of XRCC1 Arg280His polymorphism and glioma risk was estimated for each study. The pooled ORs were assessed for the genetic comparisons of allelic contrast (His vs Arg), homozygote comparison (His/His vs Arg/Arg), dominant model (His/His+His/Arg vs Arg/Arg) and recessive model (His/His vs His/Arg+Arg/Arg), respectively. For detection of any possible sample size biases, the OR and its 95% confidence interval (CI) to each study was plotted against the number of participants respectively. A Chi-square based Q statistic test was performed to assess heterogeneity. If the result of the Q-test was P >0.1, ORs were pooled according to the fixed-effect model (Mantel-Haenszel); otherwise, the random-effect model (DerSimonian and Laird) was used. The significance of the pooled ORs was determined by Z-test. The Hardy-Weinberg equilibrium (HWE) was assessed by Fisher’s exact test. Publication bias was assessed by visual inspection of funnel plots6, in which the standard error of log (OR) of each study was plotted against its log (OR). An asymmetric plot indicates a possible publication bias. The symmetry of the funnel plot was further evaluated by Egger’s linear regression test.7 Statistical analysis was undertaken using the program STATA 11.0 software .1: Study characteristics: Relevant publications were retrieved and screened originally. As shown in 8 was discarded. Consequently, four case-control studies were included for data extraction and analysis.9-129,10 and two of Asians11,12 in the present meta-analysis.  All the selected publications were written in English. The relevant information was listed in 12 The distributions of XRCC1 Arg280His genotypes as well as the genotyping methods of the included studies were presented in 2: Test of heterogeneity: As shown in I-square value is another index for the heterogeneity test13, with value less than 25% indicating low, 25% to 50% indicating moderate, and greater than 50% indicating high heterogeneity. The I-square values were 36.8%, 0.0%, 0.0% and 0.0% for the overall data of the allelic contrast, homozygote comparison, dominant and recessive models, respectively, confirming the absence of the heterogeneities between the studies. Thus, the fixed-effect model was used in this model.3: Meta-analysis results: The main results of the meta-analysis are listed in  In subgroup analysis according to ethnicity, no association was presented in either the Asian subgroup or the Caucasian subgroup. Similarly, when the data were divided by source of controls, no associations were shown in either the population-based subgroup or the hospital-based subgroup .4: Sensitivity analysis: To test the stability of the overall results, we carried out the one-way sensitivity analysis.14 The statistical significance of the results was not changed when any single study was omitted (data not shown), indicating the robustness of the results.5: Bias diagnostics: Funnel plots were created for assessment of possible publication biases (n biases . Then, En biases , indicat For the overall data, XRCC1 Arg280His polymorphism has little association with glioma risk. Likewise, in the subgroups regarding ethnicity and source of controls, no associations could be observed.15 However, in the subgroup analysis according to ethnicity, significant associations were shown among neither Asians nor Caucasians, implying little effects of the ethnic variation of XRCC1 Arg280His polymorphism on glioma risk. Notably, the results should be interpreted with care because the limited number of the included studies containing small sample sizes might result in insufficient statistical power to evaluate a minor effect. Hence, future investigations regarding different ethnicities with large sample sizes are needed to address this issue.  Considering the possible effects of ethnic variation and source of controls on the results, we further conducted subgroup analyses. Evidence indicates the potential effects of ethnic-specific variation and different socioeconomic classes on glioma. In the subgroup analyses stratified by source of controls, significant increased glioma risk was not also observed in either the population-based subgroup or the hospital-based subgroup. Since hospital-based controls might not be always truly representative of the general population, any selection bias might exist. However, the data of the present study indicated that the influence of the possible selection bias on the overall results was not evident. Noticeably, use of proper control participants with rigorous matching criteria and large sample sizes in future studies is important for reducing such possible selection biases.  Several limitations might be included in the present meta-analysis. First, in this meta-analysis, the primary articles only provided data about Caucasians and Asians. Other ethnicities such as African should be noted in the future studies. Second, subgroup analyses regarding age, gender, histological types, radiation exposure and other factors have not been performed in the present study because relevant data were insufficient for further analysis. Third, only studies written in English were searched. Thus, some selection biases might exist. Therefore, the results should be interpreted with caution. However, the sensitivity analysis and publication bias analysis indicated the stability and credibility of the present meta-analysis.  In summary, the data of the present meta-analysis failed to suggest an association between XRCC1 Arg280His polymorphism and glioma risk. Further investigations with larger sample sizes and rigorous matching criteria in view of confounding factors are needed to confirm the associations.


XRCC3 gene might lead to altered protein structure or function which may change DSBR efficiency and result in cancer. The XRCC3 C18067T polymorphism has been reported to be associated with skin cancer susceptibility, yet the results of these previous results have been inconsistent or controversial. To derive a more precise estimation of the association, we conducted a meta-analysis.The X-ray repair cross-complementing group 3 (XRCC3) in homologous recombination repair (HRR) pathway plays a very important role in DNA double-strand break repair (DSBR). Variations in the XRCC3 C18067T polymorphism and skin cancer risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs).The quality of the studies was assessed according to a predefined scale. The association between the XRCC3 C18067T polymorphism and skin cancer risk in any genetic model. Stratified analyses according to tumor type, significant association was found in the relationship between XRCC3 C18067T polymorphism and nonmelanoma skin cancer risk . Furthermore, significant association was also observed in XRCC3 C18067T polymorphism with both basal cell carcinoma risk  and squamous cell carcinoma risk .Overall, no significant association was observed between XRCC3 C18067T polymorphism was not associated with risk of cutaneous melanoma but contributed a decreased risk to both basal cell carcinoma and squamous cell carcinoma.The present meta-analysis demonstrates that  Skin cancer is one of the most frequent malignant diseases in humans, especially in the Western world Extensive epidemiological, experimental, and molecular evidence indicates UV radiation as an important environmental carcinogen involved in the initiation and progression of skin cancer XRCC3 has been of great interest as a candidate gene for cancers, including skin cancer.The X-ray repair cross-complementing group 3 (XRCC3) protein, involved in the homologous recombination repair (HRR) pathway, is a member of an emerging family of Rad-51-related proteins participating in HRR to repair DNA damage and maintain genomic stability XRCC3 gene is located in human chromosomes 14q32.3 and various polymorphisms in this gene have been identified with susceptibility to cancers such as Thr241Met , 5-UTR (A4541G rs1799794) and IVERSUS 5–14 . In the past decade, the majority of molecular epidemiologic studies investigated XRCC3 C18067T polymorphism on skin cancer susceptibility. However, the results remain fairly conflicting rather than conclusive. To derive a more precise estimation of the relationship between XRCC3 C18067T polymorphism and skin cancer risk, we conducted a meta-analysis of all available case-control studies relating the XRCC3 C18067T polymorphism to the risk of developing skin cancer.The XRCC3 or DSBR” in combination with “polymorphism or variant or mutation” and in combination with “Skin cancer” updated on July 2013 for all publications on the association between XRCC3 C18067T polymorphism and skin cancer risk. There was no restriction on time period, sample size, population, language, or type of report. All eligible studies were retrieved, and their bibliographies were checked for other relevant publications. Additional studies were identified by a hand search of the references of original studies. The literature retrieval was performed in duplication by two independent reviewers (Xu Chen and Zhe Wang). When a study reported the results on different subpopulations, we treated it as separate studies in the meta-analysis.This study was conducted based on the predefined proposal of Meta-analysis of Observational Studies in Epidemiology group XRCC3 C18067T polymorphisms and skin cancer risk; (c) the papers had to provide the size of the samples, distribution of alleles, genotypes or other information that can help us infer the results; (d) Of the studies with overlapping data published by the same investigators, we chose the most recent or complete study was included. Accordingly, studies were excluded if one of the following existed: (a) studies that contained overlapping data; (b) Not offering the source of cases and controls or other essential information; (c) studies in which family members had been studied because their analysis are based on linkage considerations.The following inclusion criteria were used for the paper selection: (a) a case-control study; (b) information on the relationship between All the data were extracted by two investigators (Xu Chen and Zhe Wang) independently with the standard protocol and the result was reviewed by a third investigator (Yulan Yan). From each study, we extracted the name of first author, year of publication, country of origin, ethnicity of the population studied, the number of cases and controls, allele frequency, definition of cases, and genotype distribution in cases. Different ethnic descents were categorized as Caucasians, Asian, African or Mixed. For studies including subjects of different ethnic groups, data were extracted for ethnic group whenever possible. To ensure the accuracy of the extracted information, two investigators (Xu Chen and Zhe Wang) checked the data extraction results and reached consensus on all of the data extracted. If different results generated, they would check the data again and have a discussion to come to an agreement. A third reviewer (Yulan Yan) was invited to the discussion if disagreement still existed.Methodological quality of eligible studies was also independently assessed by the same two reviewers (Xu Chen and Zhe Wang) according to a set of predefined criteria  mainly bThe STATA Software  was used to analyze the data. For each study, odds ratio (OR) and its 95% confidence interval (95%CI) were calculated to assess the association strength. The pooled ORs were performed in different genetic comparison models, including homozygote comparison (TT versus CC), heterozygote comparison (TC versus CC) recessive model (TT versus TC/CC), and dominant model (TT/TC versus CC).2-test based Q-statistic. A significant Q-statistic (P<0.10) suggested heterogeneity among studies, thus the summary OR estimate of each study was computed by the random-effects model 2 = 100%* (Q – df)/Q, was applied to assess heterogeneity between studies The heterogeneity between the studies was assessed by the χ2>50%) or absence (P>0.10 and I2<50%) of heterogeneity, respectively. To better examine possible sources of between-study heterogeneity, meta-regression analysis was also used to both overall analyses and subgroup analyses when heterogeneity was observed. In addition, the Galbraith plot was applied to spot the outliers as the possible major sources of heterogeneity The overall estimate of risk (OR) was calculated by a fixed effects model or a random effects model according to the presence  in XRCC3 C18067T polymorphism in the overall population. In the stratified analysis by tumor type, the present meta-analysis showed that the C18067T polymorphism was associated with decreased nomelanoma risk . The detailed results of the present meta-analysis were shown in Forest plot of skin cancer risk associated with 2I = 47.3%); heterozygote comparison ; and dominant genetic model . To explore the sources of heterogeneity, we performed metaregression and subgroup analyses. Metaregression analysis of data showed that the tumor type was the major source which contributed substantially to heterogeneity. The Ethnicity (Caucasian or Mixed), Source of control , Genotyping methods (PCR-RFLP or TaqMan or PCR-SSP), Quality score (≥12 or <12) or Sample size (≤500 subjects or >500 subjects) were not effect modifiers. Subsequently, we performed subgroup analyses stratified by tumor type. The heterogeneity really reduced because there was no significant heterogeneity after subgroup analysis by tumor type under homozygote comparison (TT versus CC). However, heterogeneity still existed in heterozygote comparison (TC versus CC) and dominant genetic model (TT/TC versus CC) . The significance of the summary ORs for XRCC3 C18067T polymorphism in different comparison models in subgroup analyses were not influenced by omitting the two studies.There was significant heterogeneity for homozygote comparison  . To furtrsus CC) . All I2 Sensitivity analysis was also used to evaluate the stability of the overall results by sequential omission of individual studies. In this meta-analysis, the result of sensitive analysis shows that any single study could not influence the overall results qualitatively, indicating robustness and reliability of our results .XRCC3 C18067T polymorphism is shown in Begg funnel plot was created to assess the publication bias of literatures. Funnel plot of skin cancer risk associated with DNA injury and repair plays a critical role in carcinogenesis. DNA repair pathways are of great importance in the removal of damages, repair of base alterations caused by UV radiation, recombination of homologous or nonhomologous end joining, and other injuries caused by many carcinogenic agents XRCC3 in homologous recombination repair (HRR) pathway plays a very important role in DNA double-strand break repair (DSBR). Variations in the XRCC3 gene might lead to altered protein structure or function which may change DSBR efficiency and result in cancer. The functional SNP of XRCC3, rs861539 (C>T) which causes a substitution of corresponding amino acid (threonine to methionine) at codon 241, has been extensively investigated. Matullo et al have demonstrated that the XRCC3 C18067T polymorphism was associated with DNA repair capacity, which made it well-founded to hypothesize that XRCC3 C18067T polymorphism may be associated with cancer risk XRCC3 C18067T polymorphism and skin cancer risk. Unfortunately, the results of these previous studies have been inconsistent. Unfortunately, so far there has not yet a report which comprehensively and specially evaluates all of the previous literature to get a precious estimate of this association between XRCC3 C18067T polymorphism and skin cancer risk.The XRCC3 C18067T polymorphism and skin cancer risk has been performed, and the present meta-analysis is the first study on such an association. Consequently, fifteen individual case-control studies more than 10000 individuals (4329 cases and 7291 controls) were included in our meta-analysis.It is well recognized that small genetic association studies could inevitably add the risk that chance could be responsible for their conclusions because they have different study designs, diverse genotyping methods, insufficient statistical power, different population lifestyle and background. However, meta-analysis has the advantage of reducing random error and achieving precise estimates for potential genetic associations through pooling data. To the best of our knowledge, no meta-analysis specially evaluating on the association between the XRCC3 C18067T polymorphism with cancers risk, including colorectal, bladder, lung, breast, pancreatic cancer and so on. And a few meta-analyses have been conducted on XRCC3 C18067T polymorphism and cancers risk, including colorectal cancer, lung cancer, bladder cancer, and breast cancer. Our study was carried out to investigate the association between XRCC3 C18067T polymorphism and skin cancer risk. Different results derived from previous meta-analysis which focused on relationship between XRCC3 Thr241Met polymorphism with cancers risk. This phenomenon indicates that the XRCC3 C18067T polymorphism exerts different effect on various types of cancers. So that it is necessary to get a better understanding of XRCC3 C18067T polymorphism on skin cancer risk, especially when inclusive and controversial findings still exists. The present meta-analysis was carried out by critically reviewing 15 individual case-control studies on XRCC3 C18067T polymorphism and skin cancer risk. Our meta-analysis showed XRCC3 C18067T polymorphism was not associated with risk of skin cancer. Subgroup analysis based on tumor type indicated that XRCC3 C18067T polymorphism was not associated with risk of cutaneous melanomas but with decreased risk of nonmelanoma skin cancer. Both basal cell carcinoma and squamous cell carcinoma are two main tumor types of nonmelanoma skin cancer. Therefore, we divided them into two groups for further analysis. As a result, we found that XRCC3 C18067T polymorphism was associated with decreased risk of both basal cell carcinoma and squamous cell carcinoma.So far, plenty of studies have evaluated the XRCC3 C18067T polymorphism and cutaneous melanomas, which was consistent with our pooled conclusion. Moreover, deleting any study in sensitive analysis would not materially alter the corresponding pooled ORs, which reflects the reliability and stability of our study.In our study, the study of Figl et al accounted for more than 25% weight and its sample size was relatively large (1184 cases/1274 controls). Its conclusion showed no significant association between XRCC3 C18067T polymorphism among control populations disobeyed the law of HWE. It is widely accepted that deviation from HWE could be caused by genetic reasons including non-random mating, or the alleles which reflects recent mutations have not reached equilibrium and other methodological reasons HWE is an important law of genetic equilibrium. It seems that selection bias may occur if the genotype distribution of The heterogeneity plays an important role when performing meta-analysis and finding the source of heterogeneity is very important for the final result of meta-analysis. Because the inconsistent findings included in our meta-analysis among different studies were probably attributed to different genetic backgrounds, environmental exposures, genotyping methods and sample size. In the current study, obvious heterogeneity between-study was found in the overall population. Through conducting meta-regression, we found that the heterogeneity could not be explained by several possible source of heterogeneity such as Ethnicity, Source of control, Genotyping methods or Sample size. However, we found the tumor type was the major source of the high heterogeneity in our meta-analysis. Therefore, we perform subgroup according to tumor types. However, the tumor types did not explain all heterogeneity in this meta-analysis and other sources need further investigating. It is possible that other limitations of recruited studies may partially contribute to the observed heterogeneity. For this reason, we conducted analyses using the random effects model. Another important aspect which may have a negative effect on our meta-analysis is the publication bias. In our meta-analysis, Funnel plot and Egger's test were used to test the publication bias of the included studies. Both the shape of funnel plot and statistical results show no obvious publication bias, this suggests that the publication bias have little effect on the results in our study and the results of our meta-analysis are relatively stable and reliable.XRCC3 C18067T polymorphism and risk of skin cancer, there are still some limitations should be pointed out. Firstly, the primary studies in the present meta-analysis mainly provided data towards Caucasians. Given that the race-specific association probably exists, other ethnicities including Asians, mixed and Africans should be investigated in future studies. Secondly, only four of eleven eligible studies used controls that were population-based Although comprehensive analysis was conducted to show the association between XRCC3 C18067T polymorphism on skin cancer risk is statistically more powerful than any other single study. Second, strict searching strategy which combination computer-assisted with manual search make the eligible studies included as much as possible. Third, the quality of case-control studies included in the meta-analysis was met our inclusion criteria and was satisfactory, and the sensitivity analysis and publication bias analysis indicated the stability and credibility of the meta-analysis, which leads to a more convincing result. More important, the process of literature selection, data extraction and data analysis in the meta-analysis was well designed and conducted.In spite of the shortages above, our meta-analysis had also several advantages as follows: First, a meta-analysis of the association of XRCC3 C18067T polymorphism and the risk of skin cancer. The pooled results suggest that the XRCC3 C18067T polymorphism was not associated with risk of cutaneous melanoma but contributed a decreased risk to nonmelanoma skin cancer including basal cell carcinoma and squamous cell carcinoma. Considering the limited sample size and ethnicities included in the meta-analysis, further large scaled and well-designed studies are needed to confirm our results.In summary, this meta-analysis systematically analyzed the association between Checklist S1PRISMA checklist.(DOC)Click here for additional data file.