To determine the association between HLA-DRB1 haplotypes and risk of cervical cancer in unselected and samples from Chinese ethnicities.A comprehensive search for articles from their inception to April 1st, 2013 was conducted from PubMed, Medline, Elsevier Science, Springer Link, Cochrane Library database, China biology medical literature database (CBM),China National Knowledge Infrastructure (CNKI),VIP,and Chinese literature database(Wang fang). A total of 1596 patients with cervical cancer and 2048 controls from the 12 studies on the relationship between gene polymorphism of HLA-DRB l and cervical cancer were performed and data were analyzed and processed using Review Manager 5.0 and Stata 11.0.Among the 13 family alleles, two (DRB1*03 and DRB1*08) were found to be negatively associated with cervical cancer in all studies or in Uighur subgroups, and two (DRB1*10 and DRB1*15) were positively associated with in all studies or in Uighur subgroups. Among the 25 specific alleles, six  were associated with an increased risk cervical cancer in all studies. No significant association was established for other HLA-DRB1 family alleles and specific alleles. Ethnicity partially explained the race influence of DRB1*12, DRB1*14, DRB1*0301, DRB1*0403, DRB1*0404, DRB1*0803, DRB1*1312 and DRB1*1502 phenotypes.Our results support the hypothesis that the HLA-DRB1 family alleles and specific alleles might influence the susceptibility or resistance to cervical cancer, suggesting that immune regulation may play a key role in this disease, although further investigations are still needed. Cervical cancer is one of the leading causes of cancer-related death among women worldwide, with 88% of cases occurring in less developed countries Human leukocyte antigens (HLA) comprises a family of Class I and Class II genes within the major histocompatibility complex, which is located on the short arm of chromosome 6 (6p) in humans The etiology of cervical cancers might be related to risk factors, and HLA-DRB1 gene polymorphism was initially proposed in the late 1990s and has created considerable interest Studies published in English and Chinese were considered in this study. Studies in English were identified through PubMed, Medline, Elsevier Science, Springer Link and Cochrane Library database from their earliest available date to April 1st, 2013. Reports in Chinese were found through China National Knowledge Infrastructure (CNKI) , Database of Chinese Scientific and Technical Periodicals (VIP) , Chinese literature database(Wan fang)  and China biology medical literature database (CBM) . Key words  and (“HLA-DRB1” or “human leukocyte antigen” or “HLA antigen”) were used in combination to retrieve the relevant literatures in all these databases. Moreover, we reviewed the reference lists from retrieved articles to search for further relevant studies. This Meta-analysis was planned, conducted, and reported in accord with standards of quality for reporting meta-analyses The inclusion criteria were: (1) studies presented original data and the number of genotype of HLA-DRB1 in cases and controls; (2) the articles provided raw data including odds ratio (OR) with 95% confidence interval (CI) and respective variance, or the relevant information could be calculated; (3) analytical study (case -control study or cohort study) or experimental study; (4) the diagnosis of CC was based on at least one of the following criteria: typical histological characteristics or colposcopy biopsies.The exclusion criteria were: (1) raw data not available for retrieval; (2) repetitive reports ; (3) the study did not fit the diagnosis criteria.The frequency of HLA-DRB1 alleles varies according to ethnic and racial background, with some alleles being extremely rare. Therefore, articles were not required to identify all alleles for inclusion.To decide inclusively or exclusively, articles were identified by two independent reviewers using a standardized data extraction form designed by our group. Data with discrepancies in identification were discussed. If consensus was not achieved, the decision was made by a third reviewer. The following data were extracted from each study: the first author’s name, publication year, area where the study was performed, study period, range of age, number of cases and controls, HLA-DRB1 type alleles, diagnostic method, control sample description . The main features of the trials included in the meta-analysis are shown in 2 test. Meta analysis was carried out by using random-effects or fixed effects model based on the pooled effect estimates in the presence (p≤0.1 or I2≥50%) or absence (p>0.1 or I2<50%) of heterogeneity (1) The pooled OR and 95% CI were determined by Z test with P<0.05 considered statistically significant; (2) Heterogeneity across studies was estimated using the Cochran’s Q statistic and IAfter carefully reading each article, 12 studies were eligible for the meta-analysis (including 5 in English and 7 in Chinese). A flow diagram of the study selection process is shown in A summary of the meta-analysis findings between HLA-DRB1 genetic polymorphisms and susceptibility to cervical cancer worldwide was provided in 2<50%). On the other hand, there was a significant difference between different studies in control groups in the following alleles: DRB1*04, DRB1*11, DRB1*13, DRB1*15 (P≤0.1 and I2>50%). These analyses were based on the data from 12 studies irrespective of the ethnicity of the study populations. Publication bias in the studies was assessed by Begg’s and Egger’s tests, results showed that there were no evidence of publication bias  conferred a significantly increased risk and four allele family  conferred a significant protective effect for cervical cancer. Their combined OR value, 95% CI and Begg’s and Egger’s tests are listed in ion bias  .2<50%). However, there was a significant difference between different studies in control groups in the following alleles: DRB1*0301, DRB1*0406, DRB1*0802, DRB1*0901, DRB1*1101, DRB1*1201, DRB1*1202, DRB1*1302, DRB1*1401, DRB1*1405, DRB1*1501, DRB1*1602 (P≤0.1 and I2>50%).  were significantly associated with an increased risk, However, there are no specific alleles with a decreased risk . We founI2>50%). . Begg’s 2>50%), so a random effect was used. Begg’ s and Egger’s tests revealed no significant publication bias for any of the allele families  were significantly associated with an decreased risk and two allele families (DRB1*10 and *15) were significantly associated with a increased risk for cervical cancer. Only DRB1*04 and DRB1*15 had heterogeneous . On the other hand, DRB1*1202 and *1401 played a major protective role in patients with cervical cancer . Furthermore, DRB1*15 was associated with susceptibility to cervical cancer in Swedish However, recent studies on the association between HLA-DRB1 allele polymorphisms and cervical cancer have been inconclusive and controversial. Climent Meta-analysis is a powerful method to increase the sample size from individual studies to enhance the statistical power of the analysis, which may reduce the probability that random error of producing false-positive or false-negative associations A subgroup analysis was performed to evaluate the effects of ethnicity on the meta-analysis. When the six studies in Uighurs were analyzed separately , 5 of 13Although the correlation of cervical cancer with HLA-DRB1 genes has been demonstrated by various studies, the mechanisms underlying the effect have yet to be elucidated. Human tumor cells express diverse types of antigens, depending on the etiology and pathogenesis of the disease This study also has its own limitations. First, since little literature including DRB1 genotype was available for inclusion in our meta-analysis, not all alleles were not reported in each Uighur study. This might can not reach a conclusion that whether special alleles have a difference in the different groups. Since only published studies written in English and Chinese were included in the meta-analysis, publication bias may occur. Secondly, although people in control groups were mainly healthy adults, there may be specific genetic effects among these controls and we could not entirely rule out the possibility of the incidence of cervical cancer in the future. It is necessary to use standardized unbiased methods on homogeneous cervical cancer patients and well matched controls. Third, our results were based on unadjusted estimates. A more precise analysis should be conducted with individual data, which would allow the adjustment by other co-varieties including age, ethnicity, family history, environmental factors and lifestyle. Finally, five studies used PCR-sequence specific primer for HLA, while others used PCR- sequence-based typing or PCR-sequence specific oligonucleotide for HLA at the time of the studies. The different typing methods were not identical between different laboratories, which might lead to a heterogeneity in current meta – analysis.In summary, in the present study we performed a meta- analysis on the association of cervical cancer with the HLA-DRB1 alleles. Our results indicated the difference of HLA-DRB1 genetic susceptibility of cervical cancer in Chinese population. For the HLA-DRB1 family alleles polymorphism, a significantly association with cervical cancer was found in Chinese Uighur group, indicating that HLA-DRB1*03 and DRB1*08 alleles may be the protective factors for cervical cancer and HLA-DRB1*10 and DRB1*15 alleles may be the risk factors for cervical cancer, but not data found in other ethnic groups. Overall, ethnicity may play an key role in cervical cancer outcome. A major limitation of this pooled analysis of previously published data relies on the fact that several studies included limited sample size, so we can not get information of special alleles in Uighur group. More studies on individuals from various ethnic groups and large-scale and well designed case-control studies are needed to determine the role of HLA-DRB1 polymorphisms in the outcome of cervical cancer.Checklist S1PRISMA checklist.(DOC)Click here for additional data file.


Previous reports have indicated that the X-ray repair cross-complementing gene 1 (XRCC1) Arg194Trp polymorphism may be a risk factor for several types of cancer. Published studies on the association of XRCC1 Arg194Trp polymorphisms with glioma risk have yeilded conflicting results. The present study aimed to obtain a more precise estimation of this association. Meta-analyses assessing the association of the XRCC1 Arg194Trp variation with glioma were conducted and subgroup analyses based on ethnicity and source of controls were also performed. Eligible studies were identified during the period before May 2012. A total of four case-control studies comprising 1,440 cases and 2,562 controls were finally selected for analysis. The overall data failed to indicate a significant association of the XRCC1 Arg194Trp polymorphism with glioma risk . Similarly, in the subgroup analysis based on ethnicity and source of controls, no associations were observed. In conclusion, the results of the present study failed to suggest an association between the XRCC1 Arg194Trp polymorphism and glioma risk. Further large and well-designed studies are required to confirm this conclusion. Glioma is the most common type of primary brain tumor in adults. The general outcomes for patients are poor, particularly for older patients. The etiology of glioma is unclear. Evidence suggests that exposure to radiation may be a significant risk factor for glioma, which may explain a small proportion of glioma since this exposure is generally rare . HoweverRadiation exposure may cause DNA damage and cell injury. The consequences to the cells may be disastrous, ranging from single gene mutations to massive chromosomal breakdown and rearrangements. The instabilities may result in severe human disorders, including cancer . The repPublished data on the association of the XRCC1 Arg194Trp polymorphism with glioma have yielded controversial results. In the present study, we carried out a quantitative meta-analysis that increased statistical power to derive a more precise estimation of this association.We performed a search of the Medline, Embase, Ovid, Sciencedirect and Chinese National Knowledge Infrastructure (CNKI) databases without a language limitation, including all studies published until May 2012, with a combination of the following keywords: XRCC1, Arg194Trp, glioma, brain, neoplasm, cancer, variation and polymorphism. All searched studies were retrieved and the bibliographies were reviewed for other relevant publications. Review articles and bibliographies of other relevant studies identified were searched manually to identify additional eligible studies.The following criteria were used for the literature selection: i) studies should report the association of the XRCC1 Arg194Trp polymorphism with glioma risk; ii) studies are observational studies (case-control or cohort); iii) studies should provide the sample size, odds ratios (ORs) and 95% confidence intervals (CIs), the genetic distribution or the information to infer the results. After rigorous searching, we reviewed all studies in accordance with the criteria defined above for further analysis.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 a majority of the votes. Extracted information was entered into a database.The OR of the XRCC1 Arg194Trp polymorphism and glioma risk was estimated for each study. The pooled ORs were assessed for the genetic comparisons of allelic contrast (Trp vs. Arg), homozygote comparison (Trp/Trp vs. Arg/Arg), dominant model (Trp/Trp + Trp/Arg vs. Arg/Arg) and recessive model (Trp/Trp vs. Trp/Arg + Arg/Arg). For the detection of any possible sample size biases, the OR and 95% CI for each study was plotted against the number of participants. A Chi-square based Q statistic test was performed to assess heterogeneity. If the result of the heterogeneity test was P>0.1, ORs were pooled according to the fixed-effects model (Mantel-Haenszel); otherwise, the random-effects model (DerSimonian and Laird) was used. The significance of the pooled ORs was determined by the Z-test. The Hardy-Weinberg equilibrium (HWE) was assessed by Fisher’s exact test.Publication bias was assessed by visual inspection of funnel plots , in whicet al (Relevant publications were retrieved and screened. As shown in et al  was exclet al ,12,14,15All the selected publications were written in English. The relevant information is listed in The distributions of the XRCC1 Arg194Trp genotypes as well as the genotyping methods of the included studies are presented in As shown in Notably, when the overall data were divided for subgroup analysis, we observed a loss of heterogeneity in the subgroups in the allelic contrast and dominant models.The main results of the meta-analysis are listed in Considering the possible effects of ethnic variation and selection of controls on the results , we condTo test the stability of the overall results, we carried out one-way sensitivity analysis . The staFunnel plots were created for assessment of possible publication biases . Then, EThe overall data obtained failed to show a significant association between the XRCC1 Arg194Trp polymorphism and glioma risk. Similar results were demonstrated in the subgroup analysis based on ethnicity and source of controls.Previous meta-analyses have focused on the association between the XRCC1 Arg194Trp polymorphism and several cancer risks and have generated conflicting results. The XRCC1 Arg194Trp variation has been demonstrated to increase risk of lung and gastric cancer ,19. HoweIn the subgroup analysis based on ethnicity, no significant associations could be observed in the Asian or Caucasian subgroup. Evidence indicates that ethnic-specific variation, different health care and socioeconomic class might exert an effect on the incidence of glioma . The resWhen the data were stratified based on the source of controls, no association was observed in either the population-based or hospital-based subgroup. Since hospital-based controls may not be representative of the general population, a selection bias may exist. However, the data of the present meta-analysis suggest that the potential influence of the selection bias on the overall results was not evident. However, use of proper control participants with rigorous matching criteria and large sample sizes in future studies is important to reduce such possible selection bias.In the present meta-analysis, evident between-study heterogeneities for overall data were observed in the allelic contrast and dominant models. However, when the subgroup analyses were conducted, we found that the heterogeneities were removed in the subgroups regarding Caucasian, Asian and population-based controls. However, the heterogeneity was still present in the hospital-based subgroup. Therefore, the heterogeneities might be multifactorial. In addition to ethnicity and source of controls, other factors including age, pathology grade and life styles may also contribute to the heterogeneity.Several limitations should be addressed. First, in this meta-analysis, the primary articles only provided data regarding Caucasians, Asians and mixed races. Other ethnicities such as African should be investigated in future studies. Second, subgroup analyses based on age, gender, histological types, radiation exposure and other factors have not been performed in the present study since sufficient relevant data were not available in the primary literature. Third, only studies written in English and several other languages indexed by the common databases were searched. Thus, a selection bias 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 conclusion, the results of the present meta-analysis failed to suggest an association of the XRCC1 Arg194Trp polymorphism with glioma risk. Further investigations with larger sample sizes and rigorous matching criteria in view of confounding factors are required to confirm the associations.


Demographic and social changes in the last decades have resulted in improvements in health and longevity. The survival of elderly people has improved significantly and thus centenarians are becoming the fastest growing population group. Environmental, genetic, and accidental factors have influenced the human life span. Researchers have gained substantial evidence that advanced glycation end products may play an important role in the processes of physiological aging. The aim of the present study was to investigate any differences in the frequencies of –374T/A polymorphism in subjects aged >90 years and in middle-aged individuals. We observed association between the A allele and genotype homozygous for this allele (AA) with a longer life expectancy in the male population. In particular, there was a prevalence of AA genotype and A allele in long-living subjects and a prevalence of the allele T in middle-aged subjects, indicating a possible protective role of the allele A to aging. In conclusion, our results support the hypothesis that longevity is the result of a good functioning of the immune system and a presumable hyper-expression of variants of anti-inflammatory genes of immunity. The differences in the genetic regulation of inflammatory processes may influence the presence of age-related disorders. The survival of elderly people has improved significantly and thus centenarians are becoming the fastest growing population group . EnvironResearchers have gained substantial belief that advanced glycation end products (AGEs) may play an important role in the processes of physiological aging . AGEs coThe –374T/A RAGE promoter polymorphism leads to reduced binding of a nuclear factor to a regulatory element of the RAGE gene promoter. Transcription factor binding assays revealed that the introduction of the –374 A allele cause the abolition of a nuclear protein binding site, supporting the role of these polymorphisms in affecting RAGE transcriptional repression .The aim of the present study was to investigate any differences in the frequencies of –374T/A polymorphism in subjects aged ≥90 years and in middle-aged individuals.2.n = 119) and subject aged 18 to <80 years were used as Control Group (n = 135). The age of long-living subjects group ranged between 90 and 106 (mean ± standard deviation: 93 ± 3). The mean age of the control group was 62 ± 10.The characteristics of subjects included in the study were listed in p = 0.0029 and p = 0.01 respectively). HDL cholesterol and triglycerides levels were not significantly different between cases and controls. As regards the cardiovascular risk factor, we found no differences in hypertension frequencies but we found that subjects having ever smoked was significantly lower in people more than 90 years old compared to controls .Levels of total cholesterol and glucose were significantly higher in subject aged ≥90 years . There was a significant reduction in frequency of heterozygous AT genotype in subjects aged ≥90 years compared to subjects aged <90 (p = 0.023). No differences were found as regards the TT genotype. Concerning allelic frequencies, we observed a greater frequency of A allele in the long-living group and a greater frequencies of T allele in middle-aged individuals, although it did not reach a statistical significance  with a longer life expectancy. In particular, there was a prevalence of AA genotype and A allele in long-living subjects and a prevalence of the allele T in subjects with middle-age, indicating a possible protective role of the allele A to aging.et al., documented the gender-independent differences in the expression profiling of aged skin between young and elderly European Caucasian adults when circulating hormones reach their maximum levels in blood and after the onset of hormone decline, accordingly [et al. explored the association between oxidative stress and gender-specific aging in C57BL6 mice, in which females are the shorter-lived gender. They demonstrated that differences in ROS homeostasis contribute to gender divergence in survival, but also suggest that mitochondrial superoxide production may not be primarily responsible for gender differences in lifespan [Some new studies showing that the aging process in both genders is gender-specific. Recently, Makrantonaki E, ordingly . Previoulifespan .et al. demonstrated that skin autofluorescence and pulse wave velocity as non-invasive parameters significantly correlate with the AGE contained in graft material and therefore are strong predictors of vessel AGE modifications in patients with coronary heart disease. Whether the analysis of the skin autofluorescence leads to an improvement of the risk stratification in patients suffering from cardiovascular disease has to be further tested [Hofmann B, r tested .In our previous study, we found that the AA genotype seemed to correlate with the age of onset of myocardial infarction: patients with this genotype showed a 5 years higher mean age of onset than patients with at least one T allele, indicating that homozygosis for the A allele could play a protective role in the pathogenesis of the disease . Our resWomen live longer than men and make up a large proportion of the older population. Whether genetic factors play more or less of a role in men or in women is a matter open to debate. Estrogens and phyto-estrogens up-regulate expression of antioxidant enzymes through estrogen receptor and MAPK activation, which activate the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathway, resulting in the up-regulation of expression of longevity-related genes . The asset al. [The current study is a candidate-gene association study that compared long-living subjects with middle-aged subjects with no possible prediction of their future longevity. The mechanisms underlying the association between the studied polymorphism and longevity cannot be directly inferred from the present study but it can be assumed that the reduction of transcription of RAGE gene associated with AA genotype generate a decreased expression of the receptor on the cell surface and consequently a decrease in the pro-inflammatory signal in male subjects. The correct trigger axis RAGE-ligand results in a cell phenotype in which the activation of transcriptional factor NF-κB leads to the overproduction of pro-inflammatory mediators . Cytokinet al.  found thThe aging process is a universal, intrinsic, progressive accumulation of deleterious changes in cells and tissues that increases morbidity and leads to death. The immune system seems to be involved in the chronic oxidative and inflammatory stress conditions of aging, according to the recent theory of oxidation-inflammation to explain the aging process . Thus, h4.4.1.n = 135). Subject aged ≥90 years who had MMSE  score in the top 75th percentile [n = 119). This MMSE cut-off has previously been used to characterize individuals as having “intact cognition” [The population in this study consists of 254 Caucasian subjects (170 women and 84 men). Subject aged 18 to <80 years, no personal history of coronary artery disease, no diabetes mellitus, no high alcohol consumption, professional athleticism and any chronic disease were used as control group , tobacco smoke, hyperlipidemia, and diabetes mellitus. With regard to cigarette smoking, subjects were grouped under the headings “always” or “never”: in the former group were included subjects who had smoked daily for at least 1 year. We considered dyslipidemic patients with cholesterol levels above 200 mg/dL or in treatment with lipid-lowering drugs. The diagnosis of diabetes mellitus has been placed in patients previously treated with dietary treatments, who had received oral antidiabetic agents or insulin or had a fasting plasma glucose value higher than 126 mg/dL.All subjects signed informed consent before study. The study was conducted in accordance with the guidelines of the Declaration of Helsinki for human research and the guidelines of our local ethics committee.4.2.Genomic DNA was extracted from ethylenediaminetetraacetic acid (EDTA)-treated blood using the Maxwell 16 Blood DNA purification kit . The –374T/A polymorphism of the RAGE promoter was analyzed by polymerase chain reaction (PCR) restriction fragment length polymorphisms (RFLPs). In brief, a section of the RAGE promoter that contains the –374T/A variant was amplified by PCR. The sequences were 5′-CCTGGGTTTAGTTGAGATTTTTT-3′ for upstream and 5′-GAAGGCACTTCCTCGGGTTCT-3′ for downstream primers. The conditions of amplification were: 94 °C for 2 min; 30 cycles at 94 °C for 30 s, 58 °C for 30 s, 72 °C for 1 min; and finally 10 min at 72 °C. The PCR product (671 bp) was then subjected to Tsp509 I  digestion for 4 h at 65 °C, whereas the PCR product was resolved by electrophoresis on 3% agarose gels. Genotypes were scored according to the patterns of DNA bands. Treatment of the T allele with Tsp509 I gave rise to five fragments of 284 bp, 217 bp, 110 bp, 44 bp, and 16 bp. In the case of the A allele, digestion resulted in four fragments of 327 bp, 284 bp, 44 bp, and 16 bp. To reduce the possibility of genotyping errors, all results were scored by two independent investigators blinded to clinical status of subjects. All ambiguous samples were analyzed a second time.4.3.n) and relative (%) frequencies. The associations between the categorical variables were evaluated using the chi-square test. Statistical significance was defined as p < 0.05.The hypothesis of normal distribution for continuous variables was tested according to Kolmogorov-Smirnov statistics. Continuous variables are expressed as mean ± standard deviation in the case of Gaussian distribution and as median in the case of variables with non-normal distribution. The data were analyzed using the Student t test for paired. All categorical variables are reported as absolute (5.Our research showed a higher prevalence of the AA genotype in male population of subjects aged ≥90 years who have reached that age in good state of health. These results confirm the hypothesis that longevity is the result of a good functioning of the immune system and a presumable hyper-expression of variants of anti-inflammatory genes of immunity. The differences in the genetic regulation of inflammatory processes may influence the presence of age-related disorders. Surprisingly, the prevalence of the AA genotype is lower in the long-living female population than in the male one, in which this genotype would appear to have a more protective role.Thus, AA genotype would not seem to have a role in determining a better aging in the female gender. In the general population, women are more long-living than men, so one wonders if the endocrine system cannot have a protective role even in those subjects without this genotype. Further research is needed to identify other agents involved in healthy aging.


N = 258) finds both domain-general and numerical factors contribute independently to explaining variation in 3 significant arithmetic skills: basic calculation fluency, written multidigit computation, and arithmetic word problems. Estimation accuracy and number system knowledge show the strongest associations with every skill, and their contributions are independent of both each other and other factors. Different domain-general factors independently account for variation in each skill. Numeral comparison, a single digit processing skill, uniquely accounts for variation in basic calculation. Subsamples of children with MLD  are compared with low achievement  and typical achievement . Examination of these and subsets with persistent difficulties supports a multiple deficits view of number difficulties: Most children with number difficulties exhibit deficits in both domain-general and numerical factors. The only factor deficit common to all persistent MLD children is in multidigit skills. These findings indicate that many factors matter but multidigit skills matter most in 3rd grade mathematical achievement.Explanations of the marked individual differences in elementary school mathematical achievement and mathematical learning disability  have involved domain-general factors  and numerical factors that include single-digit processing efficiency and multidigit skills such as number system knowledge and estimation. This study of 3rd graders ( Educational psychologists have long sought to understand the variation in arithmetical skills in the normal range . A more Another perspective seeks to explain variation in arithmetic by identifying numerical factors that underpin the development and execution of many arithmetical skills. Single digit processing, number system knowledge, and number line estimation are candidate numerical factors. Single digit processing is assessed by magnitude comparison and quantity enumeration in tasks involving up to 10 items. The efficiency of single digit processing, a combination of speed and accuracy, develops with age and is associated with variation in the normal range and number difficulties . Single Number system knowledge concerns how numbers are related, and number line estimation is the ability to approximate numerical magnitudes . Both shNumerical factors such as number system knowledge and number line estimation develop with experience and instruction. As domain-general factors influence learning from experience and instruction, it follows that individual differences in the acquisition of numerical factors will to some extent reflect individual differences in domain-general factors .The purposes of the present study are to assess the contributions made by domain-general and numerical factors to three significant arithmetic skills in third grade  and to examine their role in mathematical learning disability (MLD) and lesser number difficulty.Conceptions of general factors have developed from psychometric research and theory. Omnibus intelligence tests e.g.,  include Working memory is the ability to maintain and process goal-relevant information. Second, using numerical activities in working memory tasks, such as counting span  may confDespite these issues and concerns about the underlying construct , most reg, the general factor common to different mental tests . Place value understanding is important for understanding written arithmetic procedures. As estimation skill supports computational estimation then it should support successful monitoring of the execution of procedures in written arithmetic.On the basis of previous work, we anticipate that across the three outcomes the domain-general factors will vary in their contributions. In contrast, we hypothesize that both number system knowledge and estimation will contribute to all three arithmetical outcomes. The theory behind number system knowledge  posits aDiagnostic and Statistical Manual of Mental Disorders, 4th ed.; DSM–IV; Mathematical learning disability MLD,  is acknoComparisons of groups varying in number difficulties have indicated both domain-general and numerical factors are relevant . This coThe findings from behavioral-genetic studies have been interpreted as consistent with numerical factors as responsible for number difficulties . AlthougMLD has been identified on the basis of arithmetic below the 16th percentile e.g.,  but somePrevious studies differ in the type of arithmetic test used to identify number difficulties, the IQ cutoff score, and the persistence of number difficulties . WhetherUsing an IQ cut off is consistent with the clinical diagnosis of MLD , but it Persistence can be determined from consistency across two consecutive academic years . RequiriIn this study, we examine the occurrence of domain-general and numerical deficits in MLD, LA, and TA groups. First, we construct the groups on the basis of a standardized untimed test administered in third grade. Secondly, we examine the subset of these children with persistent difficulties and exclude those with IQs below 85.The main aim of this study is to assess the relationships of domain general and domain specific factors to variation in mathematical achievement. We use measures of general factors that do not involve numbers so as to eliminate the contribution of number knowledge and skills from domain-general assessments. As domain-general functioning affects assessment of numerical factors, fixed order regressions are used to ascertain the contributions of each type of factor independently of the other.The second aim of this study is to assess the contribution of deficits in domain-general and numerical factors to MLD, LA, and TA group membership and differentiation. We examine groups defined by single point assessment and subsets with persistent difficulties to enhance comparability with other studies and prevent conclusions that are specific to the method of group construction.M = 7 years 11 months, SD = 5 months), and at the third grade assessments, their ages ranged from 8 years 0 months to 10 years 5 months . The large range in age results from assessments taking place throughout the school year and a child who was 8 months older than the others.The sample comprised 258  participants in a longitudinal math project. They were drawn from nine state school classes in the same English administrative district. When assessed in second grade, their ages ranged from 7 years 0 months to 9 years 5 months  with teachers’ assessments of children’s number skills using a national scheme. In these single point assessment groups there were 29 MLD , 42 LA , and 187 TA  children. The numbers of children qualifying for additional support through statements or being identified for school action were as follows: 17 in the MLD group, 9 in the LA group, and 22 in the TA group.Groups varying in number difficulties were first constructed from third grade mathematical composite scores of the WIAT-II UK : MLD forThe persistent groups were the subsets of the single point assessment groups that scored in the same percentile range on a basic calculation fluency test administered in second grade and had a standard score of 85 or more on the CPM . For exan = 212, r = .76), and its predictive relations with the third grade mathematical composite score  and third grade teachers’ ratings . The additional requirements for persistent group membership resulted in 67 children being excluded: 14 due to low CPM scores, 44 because of inconsistency between second grade and third grade, and 9 due to both low CPM and inconsistency. In the persistent and specific groups there were 11 MLD , 14 LA , and 166 TA  children. The frequencies of children qualifying for additional support were as follows: 6 in the MLD group, 6 in the LA group, and 17 in the TA group.The validity of the second grade assessment is indicated by its concurrent correlation with teachers’ assessments of a subset of children in second grade , relative magnitude , and numerical distance . All these were derived from the Number Knowledge Test . One child had an interval of 14 months. Testing was conducted by a female researcher during the school day.The aims of the study are addressed in two sets of analyses. The first set assesses the contributions of domain-general and numerical factors to explaining variation in the three arithmetical skills. The second examines which factors discriminate between MLD and LA and between LA and TA.r = .39). The processing speed constituent measures correlated substantially (r = .53), as did the oral language constituents (r = .54). Single digit efficiency scores and RAN were transformed into speed measures so that higher scores meant faster performance. Measures were transformed to deal with deviations in normality as suggested by r < .50, r > .50) with every arithmetic skill and with each other. By contrast single digit processing skills were less related to general factors and arithmetic skills with quantity enumeration showing weaker relationships than numeral comparison.As children were drawn from different school classes we ran one-way analyses of variance with school class as a fixed factor for each factor variable to determine the extent of clustering. The intraclass correlations (ICC) were calculated from these in accordance with We conducted sets of fixed-order regression analyses to assess the contributions of domain-general factors, multidigit number skills, and single digit processing. All factors were included in these analyses because comparing their contributions both within and across arithmetical skills is the purpose of this study rather than identifying the most parsimonious set of variables.t = 5.01, p < .001), oral language , and RAN . When domain-general factors were entered last, only processing speed still uniquely accounted for variance .t = 10.89, p < .001) and estimation . Both still made unique contributions when entered last (Model A-3); number system knowledge  and estimation .Multidigit skills accounted for much of the variance in basic calculation fluency (54%) when they were entered first (Model D-1), and although there was much shared variance, both factors made unique contributions; number system knowledge  and quantity enumeration ; Model A-2, numeral comparison  and quantity enumeration ; Model D-2, numeral comparison  and quantity enumeration : Model B-3, numeral comparison  and quantity enumeration .The single digit processing factors differed: numeral comparison was a significant unique predictor whatever other factors were in the model but quantity enumeration never was: Model C-1, numeral comparison , central executive , reasoning , RAN , and oral language . As with basic calculation fluency the shared variance is considerable. When entered last, the only significant predictors are visuo-spatial sketchpad , reasoning , and oral language , and they account for 1% of variance each.The contributions of domain-general and domain-specific factors are summarized in t = 7.13, p < .001) and estimation, ; Model A-3, number system knowledge  and estimation . Again much of the variance is shared between predictors.Both multidigit skills factors uniquely contribute to variance in written arithmetic whether entered first or last: Model D-1, number system knowledge  and quantity enumeration ; Model A-2, numeral comparison  and quantity enumeration ; Model D-2, numeral comparison  and quantity enumeration : Model B-3, numeral comparison  and quantity enumeration .Quantity enumeration never uniquely accounts for variance. Numeral comparison only makes a unique contribution to written arithmetic when multidigit skills are not included: Model C-1, numeral comparison , reasoning , processing speed , and oral language , but the amounts of variance they account for are small (2%–4%). When entered last, the only significant predictors are central executive , reasoning , and oral language .The results of the fixed-order regressions are summarized in t = 8.57, p < .001) and estimation ; Model A-3, number system knowledge  and estimation .Both number system knowledge and estimation uniquely account for variance in arithmetic word problems whether entered first or last: Model D-1, number system knowledge  and quantity enumeration ; Model A-2, numeral comparison  and quantity enumeration ; Model D-2, numeral comparison  and quantity enumeration : Model B-3, numeral comparison  and quantity enumeration speed .Similar to written arithmetic, neither single digit processing skill makes a unique contribution when multidigit skills are included. Unlike the other arithmetic skills, quantity enumeration does make a contribution independently of numeral comparison but only when no other factors are included: Model C-1, numeral comparison  and mathematics achievement (WIAT-II UK Mathematics Composite) are shown in F ≥ 11.37, p < .001; persistent, F ≥ 6.13, p < .005. All factors showed overall group differences: single point, Another way of considering the contribution of domain-general and numerical factors is through examining the incidence of deficits in the groups. We categorized children as having deficits if their score on one or more of the constituent factors was more than 1SD below the mean. 2 = 5.91, p = .015, persistent χ2 = 4.66, p = .031; multidigit skills, single point χ2 = 5.67, p = .017, persistent χ2 = 5.36, p = .021; domain-general, single point χ2 = 3.08, p = .079, persistent χ2 = 0.02, p = .895.In both single point and persistent classifications, the MLD groups had higher proportions of single digit processing and multidigit skills deficits than the LA groups, but the frequency of domain-general deficits did not differ: single digit processing, single point χ2 = 5.08, p = .024, persistent χ2 = 0.10, p = .755; multidigit skills, single point χ2 = 42.48, p < .001, persistent χ2 = 24.279, p < .001; domain-general, single point χ2 = 18.69, p < .001, persistent χ2 = 7.82, p = .005.The LA groups had more multidigit skills deficits and domain-general deficits than the TA groups in both classifications, but single digit processing deficits were more common only in the single point groups: single digit processing, single point χMost children in the MLD and LA groups had more than one type of deficit. In the single point groups, 86% (25/29) MLD and 55% (23/42) LA children had multiple deficits. This pattern was repeated in the persistent subset: 91% (10/11) of the MLD group and 50% (7/14) of the LA group had combinations of deficits. No MLD children just had single digit processing deficits. There was one MLD child who only had deficits in multidigit skills, and she was in the persistent subset. In the LA groups there were two cases of single digit processing deficits in isolation, but neither were in the persistent subset. There were three children in the single point LA group whose only deficits were in multidigit skills, and one of these was also in the persistent subset.In summary, multidigit skills differentiated most clearly between number difficulty groups. In our sample, the overwhelming majority of low achievement and mathematical learning disability groups had both domain-general and numerical factor deficits. No children in the persistent subsets of MLD and LA groups had single digit processing deficits in isolation.This study contributes to knowledge about arithmetical skills and children with low mathematical achievement in several ways. First, it establishes that domain-general factors are directly important in determining variation in arithmetical skills. This broadly endorses the conclusions drawn by others e.g.,  but addsBefore we discuss the interpretations of the results further, we must acknowledge the limitations of our study. The foremost of these is that we have studied a single cohort of children drawn from one grade for 1 year. It is quite possible that the findings might vary with year of schooling. Another limitation is that the sample sizes for our persistent number difficulty groups are small. This reduces the power to detect relationships. Another constraint is that the conclusions about the importance of factors do depend on the quality of the measures used to assess them. Finally although the factors we include do broadly represent the factors identified as salient in previous research, it is possible that further research will identify numerical factors that explain the variance we attribute to domain-general factors or domain-general factors that account for the variance attributed to numerical factors.The use of domain-general measures that do not feature numerical stimuli or activities and the inclusion of multidigit skills and single digit processing in models strengthen the support that this study offers for the role of domain-general factors in arithmetic skills and in discriminating between groups. Attributing importance to one domain-general factor rather than another is complicated by the ways in which tasks ostensibly assessing one factor draw on skills implicated in others.Central executive measures such as listening recall and backward digit span consist of a phonological loop task and extra processing . This reConversely, measures of other general factors make demands on working memory. The processing speed tasks we used require children to remember symbol combinations while searching for duplicates. The reasoning and oral language tasks require children to identify the best solution from a set of choices. These give grounds for expecting correlations between measures of domain-general factors. They also suggest caution in interpreting findings from studies like ours that feature several general factor measures in addition to working memory as contradicting those that have concentrated on working memory.These considerations suggest that it may be difficult to disentangle domain-general factors in correlational studies. The zero-order correlations show all domain–general factors are related to each other as well as to all the arithmetical skills. They are also related to every numerical factor: this challenges the notion that numerical factors are independent of domain-general factors. Unique contributions in the regressions suggest direct relationships. The factors identified as making direct relationships varied with arithmetical skill in broadly explicable ways. Basic calculation fluency does depend on speed of response, so a direct relationship with processing speed is plausible. Similarly the importance of visuo-spatial sketchpad for written arithmetic involving multidigit numbers is consistent with the role it is expected to play in keeping place when reading . The impDomain-general factors are more important for variation in written arithmetic and word problems than basic calculation fluency. This suggests that solving written arithmetic and word problems is more than just the execution of routine arithmetic skills and procedures. This might well change with school year as a result of practice. With increasing practice, domain-general factors may make less of a contribution to written arithmetic. Future research will determine whether this decline occurs and whether it applies to word problems too.The importance of domain-general functioning was also indicated by the analyses of number difficulty groups. Domain-general deficits in isolation did not prevent typical achievement, as Understanding the natural number system as expressed in number words and numerals is hypothesized to be a crucial component of number development e.g., . Case etNumber system knowledge and estimation accounted for variance independently of each other despite both being regarded as assessing the quality of an internal mental number line. There are several possible explanations for this to be explored in further research. One possibility derives from considering the arithmetical competences underlying successful performance on the measures. The number system knowledge test involves no more than addition and subtraction. To make accurate estimates may require understanding ratios and division.Another possibility is that the difference reflects the approximate nature of estimation. Some of the variation in estimation skill may reflect differences in acuity of the approximate number system (ANS) that has been found to discriminate MLD from LA groups . AlthougNumeral comparison and quantity enumeration are suggested to measure a system that is a cognitive precursor for the development of more advanced number skills . It is dIn our study, numeral comparison is only directly related to one arithmetical skill, basic calculation fluency. Direct relations with every skill would be expected if numeral comparison efficiency reflected a characteristic of general importance for number development. The small and specific contribution of numeral comparison in our study might reflect the age of our sample: single digit processing in first grade predicts second grade math , but sinThe relation between numeral comparison efficiency and basic calculation fluency might result from both being affected by calculation experience. Calculation experience is a major driver of the development of calculation fluency . CalculaSingle digit processing deficits were more common in MLD than LA but did not discriminate persistent LA from TA. No child in the MLD groups or persistent LA subset had an isolated deficit in single digit processing. These groups have small sample sizes, and so this finding must be interpreted with caution, but it is the only study so far to include a range of domain-general factors as well as single digit processing measures. It does not support the idea that most children with MLD have isolated deficits in single digit processing and shows that IQ cutoffs do not rule out general factor deficits.This study finds that both domain-general and numerical factors make important contributions to arithmetic skills and to number difficulties. Although this study used measures in 1 year to predict differences a year later, it does not escape the limitations of a correlational design. The case for the causal significance of factors can be strengthened by the success of interventions that focus on them in producing general gains in mathematical achievement.All domain-general factors are modifiable, but the evidence of the benefits for mathematical development is limited and controversial . Both nu


PAI-1 -675 4G/5G polymorphism and susceptibility to diabetes mellitus (DM), diabetic nephropathy (DN), diabetic retinopathy (DR) and diabetic coronary artery disease (CAD). A literature-based search was conducted to identify all relevant studies. The fixed or random effect pooled measure was calculated mainly at the allele level to determine heterogeneity bias among studies. Further stratified analyses and sensitivity analyses were also performed. Publication bias was examined by the modified Begg’s and Egger’s test. Twenty published articles with twenty-seven outcomes were included in the meta-analysis: 6 studies with a total of 1,333 cases and 3,011 controls were analyzed for the PAI-1 -675 4G/5G polymorphism with diabetes risk, 7 studies with 1,060 cases and 1,139 controls for DN risk, 10 studies with 1,327 cases and 1,557 controls for DR and 4 studies with 610 cases and 1,042 controls for diabetic CAD risk respectively. Using allelic comparison (4G vs. 5G), the PAI-1 -675 4G/5G polymorphism was observed to have no significant association with diabetes , DN , DR  or diabetic CAD risk , and similar results were obtained in the dominant, recessive and co-dominant models. Our meta-analyses suggest that the PAI-1 -675 4G/5G polymorphism might not be a risk factor for DM, DN, DR or diabetic CAD risk in the populations investigated. This conclusion warrants confirmation by further studies.A meta-analysis was performed to assess the association between the  PAI-1 gene. Some increase the t½ of PAI-1 while others inactivate it or slow down its secretion into the plasma. It has been found that the most-studied 4G/5G polymorphism (rs1799889), characterized by a single guanosine nucleotide insertion/deletion variation at -675 bp of the PAI-1 promoter, increases PAI-1 concentration or its activity in the plasma of humans without changing its t½ [PAI-1 level in 4G/4G allele carriers suggesting that the PAI-1 4G/5G polymorphism is a genetic risk factor for diabetes [PAI-1 gene and the risk of diabetes and diabetic complications [Numerous single nucleotide polymorphisms (SNPs) have been observed in the phism rs199889, chications , mainly PAI-1 -675 4G/5G polymorphism and susceptibility to DM, DN, DR and diabetic CAD, which would have a much greater possibility of reaching reasonably strong conclusions. Considering a single study may lack the power to provide a reliable conclusion, we performed a meta-analysis on these eligible case-control studies, to investigate the precise relationship between the This meta-analysis is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement .  PAI-1 -675 4G/5G polymorphism was investigated by combinations of the following search terms: ‘plasminogen activator inhibitor-1 or PAI-1’, ‘polymorphism, variant or mutation’ and ‘diabetes or diabetic complications’. We used the PubMed option ‘Related Articles’ for each study to retrieve additional potentially relevant articles, and also hand-searched the included articles to identify any other relevant citations. No restriction was set on the source of control participants . The comprehensive literature searches were carried out independently by two investigators (Kuanfeng Xu and Xiaoyun Liu) using the electronic data-bases PubMed, Embase and ScienceDirect without language restrictions, and updated on July 11, 2013. The etc. The inclusion and exclusion criteria were as follows: (1) each case-control study were published as an original study designed to evaluate the association; (2) numbers in case and control groups were reported for each allele or genotype; (3) case-control studies had sufficient published data to estimate an odds ratio (OR) with 95% confidence intervals (CI) or provide raw data that allowed us to calculate them; (4) only the most recent or complete study was used if the data were duplicated and had been published in several publications; (5) studies were excluded if the genotype distribution of the controls deviated from Hardy-Weinberg equilibrium (HWE); (6) the following were excluded: animal studies, review articles, abstracts, editorials, reports with incomplete data, studies based on pedigree data or prospective studies, Data were independently extracted by two investigators who discussed disagreements and reached a consensus on all of the items. Information extracted from each study was considered as follows: name of first author, year of publication, ethnic origin of the studied population, available number of participants in case and control groups, genotype and allele frequency by case/control status, and OR (95% CI). Not all papers reported the necessary statistics directly, so in some instances we transformed and estimated an OR from the reported data . We did PAI-1 -675 4G/5G polymorphism with diabetes and diabetic complications was estimated by calculating the pooled OR and 95% CI in the allelic and genotypic  comparisions respectively. The significance of the OR was determined by the Z test . HWE of the genotype distribution of controls was tested by a goodness-of-fit χ2 analysis. The distribution was considered to be deviated from HWE at P < 0.05.The association of the I2) statistic. The I2 statistic is defined as the percentage of the observed between-study variability that is due to heterogeneity rather than chance, with high values suggesting more possible existence of heterogeneity. Potential heterogeneity between results of individual studies or in subgroups respectively by ethnicity, study design, source of controls, genotyping method, diagnostic criterion, and sample size was explored using χ2 test. Sensitivity analysis was conducted to evaluate the key studies with a substantial impact on between-study heterogeneity. Influence analysis was performed to assess the stability of the results, with a single study in the meta-analysis being deleted each time to reflect the influence of the individual data set on the pooled OR. We employed the DerSimonian and Laird random effect model (REM) to bring the individual effect size estimates together, and quantified between-study heterogeneity by inconsistency index  & STATA 11.0 . All tests were two-sided.Publication bias was assessed by the modified Begg’s and Egger’s test . The sigPAI-1 -675 4G/5G polymorphism with diabetes risk [The trial flow is summarised in tes risk ,22,24,27tes risk ,23,26,, tes risk ,18-21,25tes risk ,17,20 rePAI-1 -675 4G/5G polymorphism and diabetes risk, either by allelic comparision , dominant , recessive  or co-dominant  models. When the study from De Cosmo S et al on type 1 diabetes (T1D) was excluded [Our meta-analysis revealed no association between the excluded , the resOur meta-analysis also showed this polymorphism had no significant association with DN risk using all genetic models . Further, no significant association was revealed using an allelic comparision on both T1D  and T2D risk , and the results were consistent in the dominant, recessive and co-dominant models stratified by ethnicity. Results of pooled analyses are summarised in detail in On the association with DR risk, the 4G allele was not associated with an increased DR risk using the allelic comparision  or dominant model , the recessive  or co-dominant  model, not using model. Moreover, after stratified by ethnicity, a weak association was revealed by recessive model , but not in an allelic comparision dominant or co-dominant model in populations of European descent, and after Bonferroni correction, the P value in the recessive model were 0.06, which indicated no significant association existed in Europeans. Also our results indicated that no significant association was observed in those of Asian descent in all genetic models. Results of pooled analyses are summarised in detail in PAI-1 -675 4G/5G polymorphism and diabetic CAD in all genetic models , which were all from European descent. Results of pooled analyses are summarised in detail in In addition, our meta-analysis showed no significant association between the As shown in To assess the degree to which each individual study affected the overall OR estimates, influence analysis was conducted by repeating the meta-analysis sequentially excluding one study at a time. No single study excessively influenced the analyses (data not shown).Funnel plots and Egger’s test were performed to assess the publication bias of the literature. As expected, symmetrical funnel plots were obtained in diabetes and its complications tested in all genetic models. And Egger’s test further confirmed no publication bias for any of the polymorphisms examined, indicating that our results are statistically robust, as shown in PAI-1 have been observed consistently in blood from patients with T2D or insulin resistance [PAI-1 -675 4G/5G polymorphism, a single guanosine insertion/deletion, has been identified to contain an additional binding site for a DNA binding protein that may play a pivotal role as a repressor during transcription and exert the greatest impact on plasma PAI-1 concentration [PAI-1 -675 4G/5G polymorphism had no association with T2D in all genetic models. Further studies also indicated that the elevation of PAI-1 concentration correlates with complications of diabetes, including DN, DR and diabetic CAD risk [PAI-1 -675 4G/5G polymorphism with the risk of diabetic complications were reported, which showed significant between-study variations and were inconclusive. Unfortunately, in our results of meta-analysis this polymorphism had no association with risk of diabetic complications in overall populations in all genetic models, given that the underlying studies were carried out in different populations, we also performed by random effects model, in which the results indicated no association in either European or Asian descendent.Elevated concentrations of sistance . The PAIntration . The infCAD risk -34. Also2-based Q test. Our meta-analysis showed no significant between-study heterogeneity except for diabetic CAD risk in all genetic models and DN risk in the recessive model. Many of the variables that varied between the various studies might be responsible for this observed heterogeneity, including the source of the controls, sex bias, ethnicity, etc. Initial inspection of the data did not immediately identify any likely candidate variable or study that was significantly impacting on our overall results. Then we conducted sensitivity analyses by repeating the meta-analysis with one study excluded at each time [Heterogeneity is potentially a significant problem when interpreting the results of any meta-analysis of genetic association studies . To deteach time . The resThe results of the present meta-analysis should also be interpreted within the context of its limitations. First, other potential environment-gene interactions or gene-gene interactions may well be contributors to the observed disease-effect unconformity except for ethnicity, but we had insufficient data to perform an evaluation of such interactions. Second, our meta-analysis is based on unadjusted estimates because of a lack of original data. Third, though the Egger’s test gave no publication bias, sample size is still a limitation of our meta-analysis , especiaIn conclusion, our results indicate that the PAI-1 -675 4G/5G polymorphism might not be a risk factor for DM, DN, DR or diabetic CAD risk in the populations investigated. Maybe this association is not robust and could be due to chance, and additional larger studies that allow stratification for other gene-gene and gene-environment should also be conducted in future analyses.Checklist S1PRISMA Checklist.(DOC)Click here for additional data file.Figure S1Systematic review flow diagram n, number of studies.(TIF)Click here for additional data file.Table S1Egger's publication bias test for the PAI-1 -675 4G/5G polymorphisms in DM, DN, DR and diabetic CAD.(DOC)Click here for additional data file.


MLL rearrangements (MLL-r). The aim of this case-controlled study was to investigate whether single nucleotide polymorphisms (SNPs) of IKZF1, ARID5B, and CEBPE could be related to the onset of EAL cases (<24 months-old at diagnosis).Acute leukemia in early age (EAL) is characterized by acquired genetic alterations such as IKZF1 rs11978267, ARID5B rs10821936 and rs10994982, CEBPE rs2239633) were genotyped in 265 cases [169 acute lymphoblastic leukemia (ALL) and 96 acute myeloid leukaemia (AML)] and 505 controls by Taqman allelic discrimination assay. Logistic regression was used to evaluate the association between SNPs of cases and controls, adjusted on skin color and/or age. The risk was determined by calculating odds ratios (ORs) with 95% confidence interval (CI).The SNPs . The heterozygous genotype in ARID5B rs10821936 increased the risk for MLL-r leukemia in both white and non-white . Furthermore, ARID5B rs10821936 conferred increased risk for MLL-MLLT3 positive cases . Our data do not show evidence that CEBPE rs2239633 confers increased genetic susceptibility to EAL.Children with the IKZF1 and CEBPE variants seem to play a minor role in genetic susceptibility to EAL, while ARID5B rs10821936 increased the risk of MLL-MLLT3. This result shows that genetic susceptibility could be associated with the differences regarding MLL breakpoints and partner genes. Acute leukemia (AL) is one of the most common malignancies of early childhood. Leukemias in infants ≤12 months) (IL), even being rare, are recurrently studied because they are associated with a high frequency of early death during the first months of life. Despite advances in most other age groups, the prognosis of infants remains poor . All statistical analyses were performed using the Statistical Product and Services Solutions statistical package, version 18.0 .The expected gene polymorphism frequency was calculated using the Hardy-Weinberg law based on the allele frequency in the control group. To compare the distribution of genotypes between cases and controls the IKZF1, ARID5B rs10821936 and rs10994982, and CEBPE was respectively 247 of 265 (93.2%), 244 of 265 (92.1%), 246 of 265 (92.8%), and 251 of 265 (94.7%) in the investigated cases. The call rate for each SNP was ≥94% in the control groups. Control genotypes for all four SNPs loci were in Hardy-Weinberg equilibrium (P > 0.05).The call rate for MLL status was established for 149 ALL and 86 AML patients. The analysis of genomic breakpoints by LDI-PCR within the MLL breakpoint cluster region was performed in a subset of 55 MLL-r with available biological material and successfully determined in 41 cases.The demographic characteristics of cases and controls are shown in Additional file ARID5B rs10821936 . Increased risks of developing c-ALL (CD10 positive) have been observed for patients with variant alleles of ARID5B rs10821936  and rs10994982 . Among patients with AML, an increased risk has been observed for those patients with the homozygous variant of ARID5B rs10821936 .The distribution of allele frequencies among controls and cases within the major acute leukemia subtypes has been evaluated and the results are shown in Additional file MLL status are displayed in Additional file ARID5B rs10821936 increased the risk for MLL-r leukemia in both white and non-white . The mutant genotype in ARID5B SNP rs10821936 significantly increased the risk for MLL-germline leukemia in white and non-white children . The heterozygous/mutant genotype in the other ARID5B rs10994982 also significantly increased the risk for MLL-germline leukemia in white and non-white children .The distributions of allele frequencies in controls and cases and the risk association between genetic variants and acute leukemia further stratified by skin color and by versus children aged between 13 and 24 months), white children with ALL of both age groups presented with an increased risk for MLL-germline leukemia associated with the heterozygous/mutant genotypes IKZF1 . The heterozygous genotype in ARID5B rs10821936 increased the risk for MLL-r ALL in both white and non-white infants , while for children aged between 13–24 months the mutant genotype significantly increased the risk for ALL in white children, regardless the MLL status  , while the CEBPE variant allele was negatively associated with MLL-germline AML   and even higher odds of MLL-MLLT3 positive leukemia . Moreover, this increased risk magnitude was also observed for individuals with MLL breakpoints non-located in MLL intron 11 . A multivariate analysis has been performed to address whether the MLLT3 TPG and the MLL breakpoint region (exon 9-intron 10) were variables dependent on each other. The results showed that the susceptibility risk of having the MLL breakpoint localized outside of MLL intron 11  and the MLLT3 as the TPG  is cross-dependent.Because the variant IKZF1, ARID5B and CEBPE in the risk susceptibility to EAL . However, we could not observe a trend for increasing ORs as the number of risk alleles increased.We further tested the effect of cumulative variant alleles of in utero[in utero-acquired somatic alterations frequently found in EAL must be explored.The molecular epidemiological approach in several genetic studies has raised the concept that most, if not all, childhood leukemia cases originate in utero. Previouin utero. MoreoveIKZF1, ARID5B, and CEBPE) in a series of children enrolled in the BCSGIAL. We observed an increased magnitude of ALL risk for children with SNPs in IKZF1 and ARID5B. This is expected from the previous genome wide association studies (GWAS) that have been performed in childhood ALL (peak incidence 2–5 years-old) [CEBPE rs2239633 confers increased genetic susceptibility to EAL, in agreement with previous data in IL [CEBPE SNPs were strongly related to ALL risk in European Americans, with variable effects in non-European populations [In this case–control study, we genotyped known susceptibility loci (ars-old) ,19. Our ta in IL . In a reulations . This reIKZF1 rs11978267 was associated with the increased risk of MLL-germline ALL in both infants and older children consistent with results found in previous settings of childhood ALL. Different from ours, the only previous study that has also addressed involvement of IKZF1 polymorphism in AML has found a contribution of rs11978267 to susceptibility in infant AML overall, irrespective of MLL-r [IKZF1 susceptibility role in EAL. As this is an extremely rare disease, pooling studies would be of great interest.of MLL-r . HoweverARID5B gene variants have been systematically shown to increase the risk of childhood ALL in various populations [ARID5B gene variants were strongly associated with the risk of EAL in this Brazilian series. This gene encodes a member of the AT-rich interaction domain (ARID) family of DNA binding proteins. The encoded protein forms a histone H3K9me2 demethylase complex together with PHD finger protein 2 to regulate the transcription of target genes involved in adipogenesis and liver development [ARID5B variants in AML had not been reported previously. The gene expression level of ARID5B is up-regulated in two different AML subtypes (acute megakaryoblastic and promyelocytic leukemia) [ARID5B contributes to susceptibly to EAL AML, and an ongoing case–control study is currently underway to answer this question [ulations ,18-23. Mulations ,24. Thisulations . Overallelopment . An increukemia) ,28. Acuteukemia) ,30. Therquestion .ARID5B rs10994982 has only significantly increased the risk in MLL germline children, in agreement with observations in childhood [ARID5B rs10821936. This is consistent with previously mentioned studies, as this specific SNP has been strongly associated with risk across several populations and leukemia subgroups. In our study, the rs10821936 increased the risk for both MLL wild-type and MLL-r ALL and MLL-r AML patients. One of the most significant findings from this study is that ARID5B rs10821936 not only differed between EAL and control groups but also distinguished MLL-MLLT3 positive leukemias from other MLL-r. Interestingly, a strong association could be observed both by analyzing the TPG (MLLT3) and the breakpoint location of MLL (mainly intron 9), and the multivariate model confirmed that these parameters were dependent on each other. Recently, the MLL recombinome analysis pointed out different tendencies concerning the breakpoints localization when it was analyzed breakpoint distributions together with TPGs [MLL breakpoint cluster region was subdivided into 3 sub regions . The observed ‘mean breakpoint frequencies’ for these 3 regions in South America (dataset includes our Brazilian samples) was A = 31.9%, B = 21.7%, and C = 43.5%. However, when separating by MLLT3 TPG and restricted to the infants subgroup, the MBPF was A = 41.8%, B = 13.3%, and C = 42.9%, while in pediatric and adults these ‘mean breakpoint frequencies’ were: 35.7%, 18.8%, 43.8% and 34.2%, 7.59%, 57.0%, respectively. Therefore, recombination affecting MLLT3 displayed a tendency for MLL intron 9 breaks in IL. Together, all these data are concordant with our finding that increased risk susceptibility in infants is associated with MLL-MLLT3 rearrangement. Although future studies will be necessary to confirm this finding and to understand the specific role of this SNP in the pathogenesis, the availability of such rare epidemiological set of cases prompted us to suggest an association between inherited gene variants and specific somatic aberrations in the pathogenesis of MLL-r EAL.The hildhood ,19 and Ihildhood . We obseith TPGs . For thaThere are limitations in this present analysis. First, the small number of cases after some subsets stratification raises concern with regards to statistical power. However, given the rarity of this disease, one should consider that the consistency of the associations observed, and the concordance with previously published data indicate good validity and sensitivity of our study. Second, we had missing genotyping calls in some cases and controls that precluded us to have all samples screened uniformly. However, an acceptable call rate has been achieved in either cases or controls and the frequencies obtained did not present any deviation.ARID5B genomic region has been requested in order to reveal the exact nature of the differences previously observed. Moreover, this report focus on EAL and particularly those harboring MLL-r, and in this context, this study is innovative.We can also mention some study strengths. As replication of GWAS is highly desirable, this is an important contribution of the present Brazilian work, especially because the studies have been so far concentrated to European and American populations. For example, validation sequencing of this IKZF1 and CEBPE studied genetic variants seem to play a minor role in susceptibility to EAL, while ARID5B seems to contribute to the multifactorial causes of this disease, even increasing the risk of specific acquired somatic abnormalities such as the MLL-r recurrently seen in IL. This knowledge sheds new light onto the complex interactions that exist between environmental factors, inherited polymorphisms, and somatic alterations in leukemogenesis. While improvements on successful therapy have being hard to achieve within very young children, prevention is a major need and, therefore, the clarification of etiology should be tirelessly pursued.In summary, we have shown that The authors declare that they have no competing interests.MLL rearrangements. AF performed infant leukaemia cases diagnosis and collected their clinical-demographic data. CM has performed molecular analysis to determine the MLL breakpoints. RM provided the conditions to MLL breakpoint analysis and contributed with revision of the manuscript. ME and MSPO contributed to the conception of the study, writings and critical analysis of the data. All co-authors of the Brazilian Collaborative Study Group of Infant Acute Leukaemia contributed with clinical and demographical data. All authors read and approved the final manuscript.ME wrote the manuscript. ME and TCB performed genotyping assays. BAL contributed significantly with controls’ data collection and DNA samples preparation. CBB and CA performed cytogenetic-molecular studies to characterize The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/14/127/prepubDemographic and biological characteristics of controls and cases according to age at diagnosis.Click here for fileThe distribution of allele frequencies among controls and cases within the major acute leukemia subtypes, Brazil, 2003-2013.Click here for fileMLL gene status, Brazil, 2003-2013.The distribution of allele frequencies among controls and cases within the two major acute leukemia subtypes by skin colour and by Click here for fileMLL status in overall and specific subtypes of acute leukemia, Brazil, 2003-2013.The risk associations between genetic variants and Click here for fileIKZF1, ARID5B and CEBPE genetic variants according to leukemia subtype and MLL status, Brazil, 2003-2013.Cumulative risk effects of Click here for file


The association between obesity and Barrett’s esophagus (BE) in the Japanese population remains unclear. The prevalence of BE and its associated risk factors was examined.2) and waist circumference (WC) . Because endoscopic diagnosis of ultra-short ESBE (<1 cm in extent) is difficult and highly unreliable, this type of ESBE was excluded from the study.A cross-sectional study of 1581 consecutive individuals who underwent upper gastrointestinal endoscopy was conducted. The prevalence of endoscopically suspected BE (ESBE) was evaluated. Obesity was evaluated by body mass index  non-users, the prevalence of ESBE ≥ 1 cm was 5.6%. In univariate analysis, male sex and reflux esophagitis (RE) were significantly associated with BE, but BMI, WC, and reflux symptoms were not. In multivariate logistic regression analysis, only RE  was an independent risk factor for BE; obesity and the other factors were not. In contrast, RE  and large WC  were significant risk factors for ESBE ≥ 1 cm in PPI users. Only male sex, but not obesity or the other risk factors, was associated with an increased risk of RE in patients not taking PPIs.RE, but not obesity, may have an independent association with the risk of ESBE in the Japanese population. Furthermore, obesity measures were not independent risks for RE. Interestingly, PPI-refractory RE and large WC were risk factors for ESBE ≥1 cm in patients taking PPIs. The main risk for Barrett’s esophagus (BE) is considered to be gastroesophageal reflux disease (GERD) -4. El-SeThere is strong evidence from epidemiological studies conducted among Western populations that total obesity, as measured by body mass index (BMI), is associated with GERD symptoms, reflux esophagitis (RE) and esophageal adenocarcinoma ,8. FurthIn contrast, few studies have investigated the association between obesity and BE in a Japanese population. RE studies conducted in Japan have found a positive association between high BMI and RE ,12, and In most of the BE cases identified in Japan, the lesions were very short, i.e., < 1 cm in length. Such cases are classified as ultra-short BE, although the diagnosis of this disease entity is difficult and highly unreliable -18. One A recent study by Kramer et al. found no associations between BMI, WHR and short-segment BE, but a strong and statistically significant association between WHR and long-segment BE in the US . In the A hospital/clinic-based, cross-sectional, pilot study assessing the association between obesity and the development of BE was performed. Between November 2011 and June 2012, 1581 consecutive patients who underwent upper endoscopy at the Gastroenterology Division of Hyogo College of Medicine Hospital (n = 1114), one affiliated hospital (n = 327), and one clinic (n = 140) were enrolled in this study. Most patients were outpatients, and patients who had previously undergone upper gastrointestinal tract surgery, who had previously undergone endoscopy during this period, and those who were followed in the surveillance registry of BE in our department were excluded. At the affiliated hospital and the clinic, transnasal endoscopy with an ultrathin endoscope was performed only for medical check-up, while at our college hospital endoscopy was performed for various reasons, such as GERD symptoms , detailed examination of gastric cancer or neoplasms , follow-up study after endoscopic treatment for dysplasia and/or cancer , and other reasons, including screening, follow-up for peptic ulcers, and so on. A standardized questionnaire was used to obtain a history from each subject regarding GERD symptoms, smoking and alcohol habits prior to endoscopy. Whether or not subjects were taking PPIs was determined by self-report and a review of the medical prescriptions in our database. The Ethics Committee of Hyogo College of Medicine and the affiliated hospital and clinic approved this study. Written, informed consent was obtained from all patients prior to this study.In Japan, the GEJ is defined as the distal limit of the lower esophageal palisade vessels , but in 2). “Obesity” was defined as BMI ≥ 25.0 kg/m2, based on the criteria of the Japanese Society of Obesity [Prior to endoscopy, we performed the following body measurements of the subjects. BMI was calculated as weight divided by the square of height  or cigarette (active smoking of any number of cigarettes) habit was determined by interview prior to the study. A PPI user was regarded as a patient who had continuously taken a PPI such as omeprazole (20 mg/day), lansoprazole (15 or 30 mg/day), rabeprazole (10 or 20 mg/day), or esomeprazole (20 mg/day) once a day beginning at least 2 months before this study.U-test for patients’ age and adiposity measures, and the chi-square test or Fisher’s exact test for the other variables between the two groups. Statistical significance was defined as a p value < 0.05. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) for risk factors for ESBE and RE were calculated using StatView Version 5.0 for Macintosh . We included all factors with p < 0.10 in unadjusted models in the multiple logistic regression model. Those factors with p > 0.05 in backwards stepwise regression were dropped from the final model.The data were assessed by the Mann–Whitney A total of 1581 individuals  were enrolled in this study. Their mean age was 58.9 ± 14.7 years (range: 18 to 92 years). Of these, 1214 patients (76.8%) were not taking PPIs and, of these, 840 (69.2%) showed no evidence of ESBE on endoscopy and thus constituted our control group. On the other hand, the remaining 367 patients were regular PPI users, of whom 256 (69.8%) did not show ESBE and the remaining 111 (30.2%) had ESBE.Among patients who were not taking PPIs (n = 1214), the prevalence of ESBE was 30.8% (374 cases): 25.2% (n = 306) for ultra-short ESBE, 5.4% (n = 65) for ESBE of ≥1 cm but <3 cm, and only 0.2% (n = 3) for long-segment ESBE . On the other hand, that of ESBE among patients taking PPIs (367 cases) was 30.3%: 24.0% (n = 88) for ultra-short-segment ESBE, 5.2% (n = 19) for ESBE of ≥1 cm but <3 cm, and 1.1% (n = 4) for long-segment ESBE.Because endoscopic diagnosis of ultra-short ESBE is difficult and highly unreliable, as mentioned above, patients with ultra-short ESBE were excluded from this evaluation.As shown in Table Among both patients taking and those not taking PPIs, all adiposity measures including BMI, WC, and WHR in patients with ESBE ≥ 1 cm were not significantly different from those among controls Table . HoweverWhen analyzing the strength of the association between obesity and ESBE development on multivariate logistic regression analysis, RE was an independent risk factor for ESBE ≥ 1 cm in both patients who were not taking PPIs  and those who were regularly taking PPIs   and alcohol drinking p = 0.049) were significantly associated with the development of RE (data not shown), whereas gastric atrophy significantly reduced the development (p = 0.02). In keeping with the findings from previous studies in the West ,8 and Ja9 were siA recent study in the US reported that high WHR, but not BMI, was associated with a significant increase in the risk of LSBE but not short-segment BE in white men . The preThe natural history of GERD, including RE, is incompletely understood because very few well-designed prospective studies and endoscopic studies in general populations have been performed . In the In the current study, all adiposity measures were significantly associated with RE, whereas obesity was not a risk factor for increased BE. Observational studies from Asia have reported a consistent association between WC or VAT and RE ,33. Two Male sex was not a significant risk factor for ESBE with or without PPIs  in this study, although it was associated with an increased risk of RE development. Male sex has been reported to be an important predictive factor for BE ,37. GeneThere was no significant difference in the prevalence of ESBE, including ultra-short ESBE, between patients taking PPIs  and those not taking PPIs . The prevalence rates of endoscopically suspected LSBE were only 1.1% and 0.2% in patients taking PPIs and those not taking PPIs, respectively; therefore, the remaining cases were mostly short-segment ESBE, especially ultra-short ESBE < 1 cm. These findings are consistent with reports from Japan and Asia, in which SSBE was shown to be more common and LSBE more rare than in Western countries ,42. It rThe frequency of SIM increased with longer BE, a finding that is consistent with recent reports ,45. In oH. pylori infection, which appears to have an inverse association with BE, was not evaluated [H. pylori infection, was not related to BE development, a finding that is consistent with the previous study [The present study had several potential limitations. A possible weakness is that only ESBE without histological confirmation of SIM was evaluated, in contrast with the American criteria . Althougvaluated ,51. Howeus study . Additious study .In conclusion, simple and visceral obesity were not risk factors for ESBE in the present study. In fact, RE was the only one of the parameters studied that was a significant risk factor for ESBE independent of obesity. Interestingly, PPI-refractory RE and large WC in regular PPI users were strongly associated with increasing risk of ESBE ≥ 1 cm. Further studies with a larger sample size will be needed to clarify the reason for this lack of association between obesity and ESBE in the Japanese population.BE: Barrett’s esophagus; ESBE: Endoscopically suspected BE; BMI: Body mass index; WC: Waist circumference; WHR: Waist-to-hip ratio; VAT: Visceral adipose tissue; PPI: Proton pump inhibitor; RE: Reflux esophagitis; GERD: Gastroesophageal reflux disease; GEJ: Gastroesophageal junction; SIM: Specialized intestinal metaplasia; OR: Odds ratio; CI: Confidence interval.The authors declare that they have no competing interests.JW provided major input into the conceptual development of the study, analyzed the dataset, wrote the manuscript and supervised all investigations. All authors performed esophagogastroduodenoscopy according to our endoscopy protocol and measured adiposity measures in the patients. NK input all the data to a database. JW and HM had full access to all of the data  in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. 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/13/143/prepub