The recent International Symposium on Molecular epidemiology in Embryonal Tumours and Paediatric Leukaemia was held on 4–6 March 2008 in Rio de Janeiro, Brazil. It proved a very productive meeting in which studies relating to genetics, therapeutical trials, identification of risk factors in acute leukaemia neuroblastoma and Wilms’ tumours were presented. Over 120 participants gathered for three days of fruitful discussions, including representatives of paediatrics, haematology, laboratory, epidemiology and pathology. Debates were held about strategies of applications of important biomarkers for clinical trials. Highlights of each of the scientific presentations are summarized below. The First Symposium on Molecular Epidemiology in Childhood Leukaemia was held in June 2006 to gather colleagues to discuss and work together on molecular epidemiology in childhood acute leukaemia. During this meeting, the preliminary results of the Brazilian Collaborative Study Group of Infant Acute Leukaemia (BCSGIAL) were discussed, and the commitment of several institutions was consolidated. Since then a centralized biological reservoir of material in INCA has allowed studies on environmental factors and biomarkers in childhood leukaemia to start. A second symposium was organized for the results of previous studies, and to start a new programme for the study of molecular epidemiology in paediatric embryonic tumours. The content of the programme predominantly includes acute leukaemia Wilms’ tumour (WT) and neuroblastoma.This second symposium was opened by Marisa Breitenbach, the coordinator of the Instituto Nacional do Câncer Rio de Janeiro. Paulo de Biase (Director INCA Rio de Janeiro) welcomed all the participants from abroad and from other parts of Brazil. He acknowledged the importance of international meetings for the exchange of knowledge in order to improve the understanding and treatment of childhood cancer. Marisa Breitenback emphasized the dedication of the participants of the Haematology-Oncology Paediatric Program carrying out multidisciplinary research as an exemplary approach to the challenges of cancer research. As the official spokeswoman for the institute, she discussed the development of the Instituto Nacional de Câncer in promoting the interaction between basic scientific researchers and members of the medical society, reinforcing the link between education, research and clinical innovations. Increased research funding and the establishment of advanced translational research infrastructures were also discussed.TEL-AML1) occurring prenatally are important, but not exclusive markers for clinical phenotype. The biologic pathway of TEL-AML1 leukaemia was further discussed and candidates for the second post-natal hit were outlined. This second hit could be related to infectious disease, pesticide exposure and the deletion of p arm of chromosome 12. The biological evidence of Ras mutations occurring post-natally was also presented (from Guthrie card data). Loss of heterozygosity in a common region of chromosome 14 was also disclosed as an important factor in the scenario of ALL pathogenesis. In summary, the two-hit model for the development of c-ALL was proposed; the challenge is now to understand the role of delayed infections, exposure to pesticides and the impact of gene promoter methylation signature in its pathogenesis.The two-hit model, as a paradigm explanation for the etiopathology of childhood common acute lymphoblastic leukaemia (c-ALL), was reviewed by Joseph Wiemels . Sustained by the molecular epidemiological data, he demonstrated that specific gene fusions  the Northern California Childhood Leukaemia Study by Catherine Metayer  and (2) from BCSGIAL by Sergio Koifman , addressing parental exposure and environmental factors, were the subject of a roundtable discussion.The epidemiological studies conducted in Berkeley focused on exposure to home and agricultural pesticides, the timing of exposure and carcinogenesis. On the basis of the two-hit model hypothesis, the design of these studies analysed the questionnaires compiled by mothers of children with leukaemia, taking into account geographic distribution and biological markers. Preliminary data demonstrated that the use of paint at home during the post-natal period presented an OR of 1.37 95%CI (1.05–1.79) for ALL in the offspring, whereas the risk of AML was OR 2.54 95%CI (1.19–5.42) for petroleum solvents. The data were analysed according to cytogenetic status. Although based on small numbers, the association found with paint and solvent exposures diverged markedly, depending on the abnormal karyotype, suggesting that a role for subtype-specific pathways and genetic susceptibility. Additionally, increased risks of childhood ALL was associated with increased dust levels of herbicide combustion sources and organochlorine compounds.Sergio Koifman presented a hospital-based case-control study in which the participants were enrolled between 1999 and 2006 with ALL, AML and a control group. Moderate increased risk for acute leukaemia was associated with a birth weight of 3500 gm or more (OR 1.88 95% CI 1.29–2.15). Increased ORs were observed comparatively to quartile of birthweight distribution: OR = 1.46 95% CI 0.79–2.71 in the second quartile OR = 3.18 95% CI 1.83–5.53 in the third quartile and OR = 3.57 95% CI 2.07–6.18 in the fourth quartile. Similar trends were observed according to birthweight strata for ALL and AML. Some hypotheses for the biological mechanisms relating birthweight to the development of infant acute leukaemia (IAL) were proposed. One of them being hormonal intake during pregnancy, which in a previous analysis showed a high association with IAL with an OR 8.76 95% CI 2.85–26.93 (Pombo-de-Oliveira MS 2006).n=3618) compared to 1990–9 (n=1003). Increasing expectations of these improvements was hampered by the complexity of the overlap from local infectious diseases. Differential diagnosis of local parasitic disease is under evaluation. Kala-zar, an infectious disease caused by Leishmania chagasi, an important medical problem mainly in the Northeast and Central plateau regions , is either treated with glucantine or amphotericin B. A particular topic under exploration is whether Kala-zar, or its treatment could represent the second hit for the development of childhood c-ALL. A proposal to start an exploratory epidemiological study combined with genomic signature was positively accepted. Other questions were raised, such as previous exposure to medications leading to bone marrow abnormalities and the standardisation of protocols to identify minimal residual disease in ALL.Cellular and immunomolecular profiling of childhood leukaemia in Brazil was described by Maria S Pombo-de-Oliveira as a consequence of the Brazilian immunomolecular study group. The results according to immunophenotyping and genotyping profiles demonstrated the same frequencies of biomarkers as described worldwide. There was a positive change in the process of identification of childhood leukaemia and an improvement in diagnosis. The amount of biological samples sent for diagnosis increased threefold in 2000–07 , was described by Catherine Metayer and Beatriz de Camargo . Catherine Metayer reviewed the history of Childhood Leukaemia International Consortium (CLIC), established in collaboration with UC Berkeley and IARC to overcome the limitations of childhood leukaemia studies, due to limited number of samples especially for rare subtypes. The objective is to combine existing data from several comparable case-control studies conducted in Northern Europe, Southern America and Asia to increase the numbers to approximately 8000 childhood leukaemia and 13,000 controls. Because of the participation from New Zealand, Seoul, Australia, United Kingdom, Quebec, Montreal, Italy, France, Germany, Brazil and California (USA), 8106 cases and 13,303 controls have been collected since 1989. Fifty per cent of these have DNA specimens available.Following on, Beatriz de Camargo presented the new proposal from the IARC on an International Study of non-CNS Embryonal Tumours (ISET). The rational for this proposal is the lack of large-scale aetiological studies on solid embryonal tumours. The study will be started with a pilot project on WTs and neuroblastoma. The objective of the full scale study is to understand the aetiology of embryonal tumours, focusing on genetic susceptibility prenatal factors and neonatal exposures as well as aspects of molecular epidemiology, including epigenetic profiles, DNA repair capacity and mutation patterns.NFAT transcription factors in regulation of apoptosis cell proliferation and transformation of T and B cells was presented by João Viola (CPq-INCA). The functional role of NFAT1 and 2, demonstrated in knockout mice for the first time, indicated a dichotomous role of NFAT family members in cell cycle control. This should be evaluated in human models as NFAT1 suppresses cell transformation of the neoplastic cells may act as a tumour suppressor.Dual role for CYP2D6, CYP3A5, EPHX1, MPO, NQO1, NAT2, TS, XRCC1 and XPD polymorphisms were studied in a group of children with acute lymphoblastic leukaemia and CYP2D6 (del A and G/A), CYP3A5 (*3) and XPD (A/C) may have an important role in increasing the risk of ALL in children. EPHX1 (T/C and A/G), TS (tandem repeat), NQO1 (C/T) and MPO (G/A) polymorphisms may have a role in protection against ALL.Genetic polymorphisms and susceptibility to childhood acute lymphoblastic leukaemia was discussed by Carlos Scrideli . TP53 R337H mutation in paediatric ALL, which was tested in a group of 208 children treated at the Centro de Investigações Infantil D Boldrini Campinas, São Paulo, during the period 2001–07. Although this alteration is already known to be associated with adrenocortical tumours in Brazilian children, no association of the TP53 R337H mutation was found in ALL.Juliana Godoy Assumpção discussed a study on the role of A large review of the literature in case-control studies in AML was carried out by Maria Lucia de Martino Lee (Instituto de Oncologia Pediatrica/UNIFESP São Paulo). Risk factors such as alcohol during pregnancy, parental exposures to pesticides and drugs exposure were mentioned. Comparison of the incidence of chromosomal abnormalities in different regions of the world was also reviewed. The proportion of promyelocytic leukaemia in Hispanic children varies with the series of cases considered, ranging from 13.0% to 37.5%. The same can be observed in the Brazilian series of AML cases. A proposal for a new multi-institutional study of chromosomal abnormalities in AML was disclosed by Maria Luiza Macedo Silva (CEMO-INCA).FLT3 in AML was presented by Ilana Zalcberg (CEMO-INCA). This study used an innovative approach that searches for unidentified activating FLT3 mutations and NPM1 abnormalities.The integration of flow cytometry into AML protocols, to assess levels of minimal residual disease, was presented by Mihoko Yamamoto (UNIFESP São Paulo). The detection and clinical significance of aberrant phenotypes associated with molecular detection of fusion gene was reviewed. The mutation analysis of Childhood cancers originate from embryonal cells during prenatal and post-natal development. Defects in any of the pathways that control development, tissue growth and differentiation can promote transformation, making these cells particularly prone to carcinogenesis. These pathways were elegantly discussed by Rogier Versteeg  specifically in neuroblastoma. Embryonal tumours have clinical and epidemiological common features that suggest common pathways. Features such as age of onset, birthweight and association with congenital abnormalities were reviewed by Beatriz de Camargo. It is well known that children with cancer have a high incidence of malformation syndromes. WT has been reported in association with more than 50 different clinical conditions and several abnormal constitutional karyotypes. High-risk syndromes (>20%) associated with WT include Denys-Drash syndrome, Perlman syndrome, Familial WT and WAGR syndrome. Beckwith-Wiedman syndrome and Simpson-Golabai-Behmel syndrome are associated with a moderate risk of 5–20%. Isolated hemi-hypertrophy and several other syndromes have been described in association with WT. High birthweight has been identified as a possible risk factor for WT in several population-based studies, but results are not consistent outside the context of overgrowth disorder association. Low birthweight is associated with hepatoblastoma in several reports. For rhabdomyosarcoma, the histological alveolar subtype is associated with heavier birthweight, suggesting that this should be analysed separately. Costello syndrome and type 1 neurofibromatosis is associated with embryonal rhabdomyosarcoma. All embryonal tumours are associated with Beckwith-Wiedman and some other overgrowth syndromes. Birthweight and congenital anomalies suggest that there are critical time points during the gestation and common risk factors.An overview of the recommendations for genetic counselling in children with embryonic tumours was presented by Fernando Vargas (INCA-Brazil). Although the percentage of childhood cancers with a clearly inherited predisposition is low, sentinel karyotyping should be beneficial in children with a genetic abnormality. Structural chromosomal aberrations such as del (1p36), del (8q24.1), del (9p24), del (11p13) and del (13q14) are strongly associated with neuroblastoma, osteosarcoma, gonadoblastomam WT and retinoblastoma. The criteria for genetic testing and genetic counselling were presented.GATA1 gene are present in AML blasts of DS children. In order to test whether specificity of GATA1 mutations would be a helpful tool to distinguish different haematopoietic disorders in children with DS, samples from a cohort of DS children were analysed. GATA1 mutations in haematological clonal disorders were found in 75% of AMLs. Although inherent mutation leading to the production of the short isoform of GATA1 is associated with impaired megakaryopoiesis and erythropoises, it does not lead to leukaemia in the absence of trisomy 21. Therefore, trisomy is essential for the leukemogenesis with additional changes characterized by a third hit.Down’s syndrome (DS) offers a natural genetic model for cancer protection. A review of the association of DS with paediatric neoplasm was presented by Isis Magalhães . A study of 17,897 Americans with DS confirmed the higher incidence of leukaemia and testicular cancer and a lower incidence of breast cancer. A study of 3581 persons with DS in Finland has also reported a higher risk of leukaemia and testicular cancer, and a lower risk for solid tumours than in the general population. Aneuploidy of chromosome 21 has been linked to leukemogenesis, as trisomy or tetrasomy of chromosome 21 is common in childhood ALL. In recent years, it has been reported that somatic mutations in the X-linked WT1 mutations are associated with intralobar nephrogenic rests and rhabdomyomatous differentiation. Gene fusions such as PAX3-FKHR and PAX-7-FKHR are associated with alveolar rhabdomyosarcoma, while other abnormalities are present in embryonal rhabdomyosarcomas. The Ewing’s sarcoma family of tumours has several histology features, but all share a common molecular pathogenesis . Recognition of morphological and molecular features is important for determining biological behaviour. Classifications of paediatric neoplasms should include morphology immunohistochemical and molecular biologic aspects. The importance of the cancer biobanking was highlighted.The correlation between histology and molecular features was reviewed by Paulo Faria (INCA-Brazil). Chromosomal abnormalities including reciprocal translocations, deletions, mutations and amplifications have a specific histopathology type. As embryonal tumours differ from adult tumours, it is important to study them under the perspective of organ development, taking into consideration histological differentiation. WT morphology is similar to specific development phases of kidney morphogenesis.In a study, Dirce Carraro  demonstrated that the blastema component preferentially presented gene expression patterns similar to the earliest stage of kidney development, suggesting that morphological aspects acquired by WT are dependent on the temporal and spatial occurrence of the mutation in embryonic blastema during kidney development.WT1 at 11p13 is well established as the genetic basis for WAGR , while germ line mis-sense mutations in WT1 are responsible for WT occurring as part of Denys-Drash syndrome. Several candidate genes at the second WT locus WT2 have been described. WT1 is altered in only approximately 20% of WT. Beta-catenin mutations have been described as present in 15%, and Wnt signalling pathway is probably implicated in this neoplasm. Recently, a novel gene WTX at Xq11.1 was reported to be mutated in WT. Genetic abnormalities are known in about 75% of tumours: 15% WT; 30% WT2; 30% WTX. Much progress has been made in understanding the biology of WT.The evolving story of WT biology was reviewed by Jeff Dome . WT, whose pathogenesis was once thought to follow the same single-gene, two-hit model as retinoblastoma, has instead become a paradigm for genetic heterogeneity and complexity. Several genes have been implicated in its development, most of which are associated with familial disease or malformation syndromes that affect only a small fraction of cases. Constitutional deletions of N-myc was higher than that reported by other studies. In a series of patients from Parana, Southern Brazil, all the male patients with amplified N-myc and unfavourable histology who died were of an older age and a more advanced stage of disease, which suggested late diagnosis.An 11-year study carried out in Southern Brazil  emphasized that there was a significant delay in diagnosis, resulting in less successful treatment and poorer survival in children less than two years of age. The frequency of amplified N-myc in tumours was reported by Arissa Ikeda . Twenty-nine tumour samples, 14 fresh and 21 paraffin embedded were analysed. Nine had amplifications and this was correlated with the outcome. N-myc evaluation is routinely recommended to all patients for risk classification and appropriate treatment strategy. However, cost–benefit effectiveness in our country was discussed, and this type of evaluation was recommended mainly in children with neuroblastoma, with localized disease stage INSS 2A/2B/3, stage 4S and INSS stage 4, at less than one year old .A study carried out in INCA on the amplification of n-MYC amplification. A wait-and-see strategy in localized disease and children less than one year old is recommended. Induction surgery, megatherapy, radiotherapy and consolidation therapy are given to high-risk patients. In conclusion, risk adapted treatment is necessary for children with neuroblastoma. Data from an experience with a dendritic-cell tumour, in which cell hybrid vaccination was given every six weeks in advanced relapse neuroblastoma  indicated that immune function, recovery and time to tumours progression was delayed.A presentation of treatment strategies was given by Jeff Dome for WT and Barbara Hero  for neuroblastoma. There are two major approaches in WT, one with pre-chemotherapy and the other with surgery first. Both approaches have similar overall survival. Modern approaches to WT treatment include both reduction of therapy and augmentation of therapy. Reduction strategies are being tested by SIOP (Europe and Brazil) and COG (USA), and these propose the omission of doxorubicin in stage II/III, omission of chemotherapy in stage I small tumours and omission of lung irradiation for rapid responders. Augmentation therapies are being tested in patients with tumours presenting LOH 1p/16q, patients with tumours histology after chemotherapy blastema-predominant stage IV, patients with anaplasia. New agents are becoming available; the most promising are the microtubule inhibitors ixabepilone and ABT-751. An international relapse protocol will be started with ICE (ifosfamide carboplatin vincristine)-topotecan as an induction phase, followed by randomization to BMT (autologous bone marrow transplant) or maintenance. The treatment approach for neuroblastoma goes from minimal intervention in stages 1, 2, 4S and stage 3 less than two years, to maximal treatment in stage 4 patients over one year old and tumours with The survival rate of childhood cancer has exceeded 80% and classification of prognostic risk is essential for treatment strategies. Current prognostic factors for WT neuroblastoma and acute lymphoblastic leukaemia were reviewed by Jeff Dome, Barbara Hero, Silvia R Brandalise,  and Marco Borato Vianna , respectively.In WT, the most important negative prognostic factor is histological findings of anaplasia. Recent research has focused on identification of possible molecular genetic markers. In the study of NWTS-3–4, loss of heterozygosity for markers on chromosome 16q and 1p was associated with poorer two-year relapse-free and overall survival rates. This observation was tested on NWTS-5 and confirmed in tumours with loss of heterozygosity jointly for both chromosomes 1p and 16q. The level of telomerase expression in tumours has been correlated with risk of tumour recurrence. Gain of chromosome 1q is associated with loss of 1p and 16q and is under evaluation as a risk factor. Gene expression arrays were of limited value until now. Tumours are heterogeneous with regard to their relapse signatures.N-myc amplification status, tumours cell ploidy, 1p deletions and tumours pathology. The most important independent factor is still N-myc amplification.The major prognostic variables in neuroblastoma are age at diagnosis stage, in vitro drug sensitivity. This knowledge is useful for stratifying patients into low, moderate and high-risk groups.Prognostic values in ALL are age, white blood count at diagnosis, early response to treatment, cytogenetics, immunophenotyping, molecular biology and The Brazilian Cooperative Study Groups (GBTLI) were reviewed by Silvia R Brandalise. The GBTLI-93 stratified children with ALL into three groups: very low risk , low risk  and high risk . Overall survival was 84%, 81% and 57%, respectively. In a following study, GBTLI-99 patients were classified as high risk (age Ə year or > 9 years white blood count < 50000) and low risk (age between one and 10 years white blood count < 50000). Although immunomolecular results were not considered for risk definition, immuno-phenotyping, DNA index and molecular biology were performed in 92%, 64% and 51% of the cases, respectively. Event-free survival was 59% for high-risk and 78% for low-risk patients. Socio-economic factors were discussed by Marco Borato Vianna. Overall survival for children with ALL living in underdeveloped or developing countries is clearly inferior to those in developed countries. Environmental factors such as nutritional status, total income of the family, height for age and ethnicity have been published as prognostic factors. Compliance, treatment, intensity and genetic polymorphisms are also important in predicting outcome. Additional efforts should be undertaken to clarify mechanisms of socioeconomic influence that are clearly multifactorial.Rede de Atenção Oncológica, has been improving the research and outcome in paediatric oncology . The aim of this enterprise is mainly to reduce mortality and improve quality of life of cancer patients in Brazil. There is a strong commitment and participation from government and non-government organisations. The epidemiological and immunomolecular study (sponsored by INCA FAF/Swiss Bridge Foundation) is currently working very well. Cases are notified, samples are sent by courier overnight to be analysed and their results promptly available online. The establishment of this network represents a potential contribution to assist the demands of clinicians and researchers.The visibility of the Brazilian network, so-called Discussion was stimulated by the organizing committee  with colleagues from all over Brazil having the opportunity to exchange experiences. The meeting provided an outstanding overview on molecular epidemiology in paediatric leukaemia and embryonal tumours. International scientific collaboration provided direction for future research, which has been, or will be, implemented.


We investigated the association between polymorphisms of the angiotensin converting enzyme-1 (ACE-1) and angiotensin II type one receptor (AT1RA1166C) genes and the causation of renal disease in 76 advanced chronic kidney disease (CKD) pediatric patients undergoing maintenance hemodialysis (MHD) or conservative treatment (CT). Serum ACE activity and creatine kinase-MB fraction (CK-MB) were measured in all groups. Left ventricular mass index (LVMI) was calculated according to echocardiographic measurements. Seventy healthy controls were also genotyped.The differences of D allele and DI genotype of ACE were found significant between MHD group and the controls (p = 0.0001). ACE-activity and LVMI were higher in MHD, while CK-MB was higher in CT patients than in all other groups. The combined genotype DD v/s ID+II comparison validated that DD genotype was a high risk genotype for hypertension .~89% of the DD CKD patients were found hypertensive in comparison to ~ 61% of patients of non DD genotype(p = 0.02). The MHD group showed an increased frequency of the C allele and CC genotype of the AT1RA1166C polymorphism (P = 0.0001). On multiple linear regression analysis, C-allele was independently associated with hypertension (P = 0.04).ACE DD and AT1R A/C genotypes implicated possible roles in the hypertensive state and in renal damage among children with ESRD. This result might be useful in planning therapeutic strategies for individual patients. Chronic kidney disease (CKD) is a complex disorder encompassing a large variety of phenotypes. Each phenotype is a result of an underline kidney disease and superimposing environmental and genetic factors. The complexity of the phenotypic makeup of renal diseases makes it difficult to diagnose and predict their progression and to decide on the optimal treatment for each patient. End stage renal disease (ESRD) is an advanced form of chronic renal failure where renal function has declined to approximately 10% of normal prior to initiation of dialysis or transplantation ,3. PathoThe Renin-angiotensin system (RAS) is a key regulator of both blood pressure and kidney functions and may play a role in their interaction. Its role in the pathogenesis of hypertension is well documented, but its contribution to chronic renal failure, progression of kidney nephropathy is still debated . It has The gene coding for ACE is subjected to an insertion/deletion (I/D) polymorphism that is a main determinant of plasma and tissue ACE levels . The D aSeveral polymorphisms were identified in the AT1RA1166C gene which was linked to essential hypertension . It has The aim of the present study was to investigate the association between polymorphisms of the ACE and AT1RA1166C genes and the occurrence of renal disease in 76 advanced CKD (stages 4 and 5) pediatric patients undergoing MHD or CT. In addition, we evaluated the prevalence and the severity of left ventricular hypertrophy (LVH) and its association with these genetic polymorphisms.α-adrenoceptor antagonists in one MHD and two CT, ß-blockers in nine MHD, ACE inhibitors in seventeen MHD and six CT, and Ca channel blockers in twenty-nine MHD and ten CT. Subjects were taking their medication when ACE activity was measured and no influence of medication on the measurement. In 1967, Ng and Vane -L-phenylalanylglycylglycine) method. . The ACE presented in the serum catalyzes the hydrolysis of the FAGG; forming furyl acryloyl phenylalanine (FAP). The decrease of the absorbance in the unit time at 340 nm is proportional to the activity of the ACE in the serum .DNA was extracted from whole blood using a QIAamp Blood mini-prep Kit . ACE I/D genotype was determined according to the method of losiro et al. . Each DD3-[LVEDD]3)]+ 0.6 g, where LVEDD is left ventricular diameter in end diastole, PWT is posterior wall thickness in diastole, and IVST is inter-ventricular septum thickness in end diastole. The calculated mass correlated well with necropsy values for LVM [2.7. Correcting LVM for height2.7 minimizes the effect of gender, age, and obesity [2.7, which has been shown to be at four- fold greater risk of cardiovascular morbid outcome in adult patients with hypertension [th percentile for LVMI in normal children and adolescents [-Echocardiographic imaging was performed using the Vivid 3 Pro machine (Norway) equipped with 3 and 7 MHz transducers. Two dimensional (2D) guided M-mode measurements were made in supine position. Left ventricular mass (LVM) was calculated using measurements made according to the recommendations of the American Society of Echocardiography: LVM = 0.8 [1.04  test. A 2 × 2 contingency table was used for test of the differences of allele frequencies between cases and controls. Odds ratios (OR) with 95% confidence intervals (CI) were estimated for the effects of high risk alleles. Clinical characteristics of CKD patients with different ACE and AT1R genotypes were compared using independent t test. Pearson's analysis was performed to correlate LVMI with the individual variables. Multiple regression analysis was performed to assess the combined influence of variables on hypertension and LVMI values. A p value of < 0.05 was considered statistically significant.Statistical package for social science (SPSS) program version 11.0 was used for analysis of data. Data were summarized as mean ± SD, range or percentage. Histograms and normality plots were used for evaluating the normality of data. For those data with skewed distribution, log transformation was performed before a t-test. Power analysis was used to calculate the minimum sample size required to accept the outcome of a statistical test with a particular level of confidence. A sample size of 20 will give us approximately 80% power  to reject the null hypothesis of zero correlation. We used power calculations performed by the Power and Precision program (Biostat) to determine the number of chromosomes required to detect a significant difference between the polymorphism frequency in the reference population and the expected frequency. Power commonly sets at 80%; however, at that level, a polymorphism would be missed 20% of the time. Data were valuated between the experimental groups by One-Way Analysis of Variance (ANOVA) followed by Tukey's multiple comparison test. Allele and genotypic frequencies for ACE and AT1R alleles were calculated with the gene counting method. Hardy-Weinberg equilibrium was tested by using the Pearson Chi-square Anthropometric, clinical and biochemical parameters in controls and CKD subjects are shown in Table Independent segregation of alleles for these studied polymorphisms was kept in HWE. Genetic association analyses with Pearson Chi-square test was performed and data are summarized in Table 2 X= 36.97, P = 0.0001). This may suggest that patients with DD genotype are at high risk of developing renal disease . Further, we have analyzed the data by pooling the II genotype with DD genotype. The genotypic level was also visible at the allelic level as D allele was found in a higher frequency in MHD patients than in the controls. . The MHD group showed an increased frequency of the C allele and the homozygous genotype CC of the AT1RA1166C polymorphism compared to the controls 2 .No significant differences were observed between CT patients and the controls as regards to ACE or AT1RA1166C genotypes or alleles.There was a significant difference between the MHD group and the controls as regard to DD genotype  Table .When we compared the number of hypertensive patients between the two sub groups it was noticeably evident that ~89% of the DD genotype patients were hypertensive as compared to the 61% of II+ID genotype group (P = 0.02). The results further confirmed the association of DD genotype with the hypertensive state and implicate a strong possible role in renal damage.We pooled patients homo- and heterozygous for the C allele for comparison with the AA homozygotes. When serum creatinine and urea levels were compared between the two sub groups, the difference was found to be significant as regards to urea level P = 0.04). Patients that carry C- allele had the highest ACE activity, while those carrying A-allele had the lowest (P = 0.04) . A positive correlation was found between serum CK-MB level and serum urea level . DBP was found to be positively correlated with serum hs-CRP level .LVMI was positively correlated with indexed SBP , indexed DBP  and CK-MB levels  , serum hs-CRP level  and CK-MB level . C-allele was independently associated with hypertension . On correlating LVMI to other variables, serum CK-MB level , serum TG concentration , serum urea level , serum creatinine concentration  and indexed DBP  were independently associated with LVMI. No significant interaction was observed between D- allele and C-allele in relation to LVMI  .The current data demonstrated an association between the ACE, and AT1R gene polymorphisms and advanced CKD in children undergoing MHD compared with conservative treatment. The I/D polymorphism of the ACE gene and plasma concentration were studied as a cluster of cardiovascular risk factors that could contribute to excess metabolic cardiovascular and renal risks in MHD patients compared with patients undergoing CT. Several reports linked this polymorphism to the development and progression of chronic renal diseases of different etiologies -33.Our study revealed highly significant differences in the presence of DD genotype and D allele of ACE gene in MHD patients than in normal controls. These differences might validate that the ACE gene polymorphism is an important genetic determinant of non-diabetic nephropathies. D allele of ACE gene might confer a high risk of developing renal diseases and this association was highly compounded when D allele was present in homozygous state. Even inclusion of the heterozygous ID state known to have intermediate levels of ACE production along with the DD genotype depicted a high risk of renal failures. Therefore, the finding that ACE DD genotype and D allele was associated with renal ESRD is likely to be true for pediatric populations . There wOur results were free of genotyping errors/mistakes in data manipulation  and were in accordance with results of others as Settin et al.  with hisWe postulated that DD genotype confered a greater role in hypertensive state as ~89% of DD genotype patients were hypertensive and this phenomenon might have been the major factor behind the association of ACE genotypes and ESRD pediatric patients.Hypertension being a complex polygenic disorder is often regarded as a physiological state affected by, "Genetic Predisposition" which highlights the presence of heritable allelic differences in the genes coding/associated with different components of RAS. Such differences result into differential transcript and protein expression accounting for different rates of progression of hypertension and other related diseases mainly, renal failures .The DD genotype had unanimously been shown to have increased serum ACE production and activity while II and ID genotypes produced low and intermediate levels of proteins respectively . In thisAssociation between hypertension and ACE gene polymorphism had not been found in the general population, in some particular conditions, such as malignant hypertension, the D allele had been shown to be a significant risk factor . In dialThe interesting finding of our study was the association of the AT1RA1166C genotype with the development of renal disease and progression to end-stage renal failure. This confirmed a previous result . We obseThe present study revealed that patients carrying C- allele had the highest ACE activity, while those carrying A-allele had the lowest. Inhibition of the RAS, either through reducing the production of angiotensin II with ACEI or by blocking the action of angiotensin II at the AT1R receptor level with A II-type 1 receptor blockers (ARBs), is particularly effective at preventing renal injury .On correlating indexed SBP to different cardiovascular risk markers by multiple linear regression analysis, we found that C-allele, serum urea, hs-CRP and CK-MB were variables that were independently associated with indexed SBP. In hypertensive patients it is suggested that the combination of DD polymorphism type and AC/CC for AT1R gene, could contribute in a synergistic way to organ damage. The AT1R mediates the more deleterious effects of angiotensin II--that is, cardiac and vessel hypertrophy including extracellular matrix production. In addition to the conversion of angiotensin I to angiotensin II, ACE inactivates the vasodilator peptide bradykinin . StudiesThe relationships between the ACE gene polymorphism and LV mass and remodeling were extensively investigated in different populations ,43. TheoIn the present study LVMI was not associated with any of the polymorphisms examined. The absence of a gene dosage effect on LVMI may be because (1) tissue ACE activity may be more important and may be influenced by gene polymorphism differently from serum ACE activity and (2) there may be no mechanistic relationship between the ACE polymorphism and LVMI.Some reports indicated a high prevalence of LVH in children on dialysis, as identified in adults. However, the mean LVMI was higher in our patients than in the patients in other pediatric studies ,47. Two There were some limitations in this study. The small sample size of the patients and this leads to low statistical power and insignificant difference between CT patients and the controls as regards to ACE and AT1RA1166C gene polymorphisms. Also, only one centre is included in the study. Further large study on the pediatric Egyptian population from different renal centres will be done for better interpretation for the role of ACE gene polymorphism on the progression of renal failure.ACE gene polymorphism appeared to be an important genetic determinant in causation and progression of renal diseases and DD genotype was found to be significantly associated with advanced ESRD in children. Our results suggested that the CC/AC genotype might serve as a predictor of an early pediatric ESRD and could in the future become an important part of the clinical process of renal risk identification. Further studies in this regard will open a plethora of options like timing, type and doses of anti-hypertensive therapy. Incorporation of such approaches will allow an advance anticipation of the clinical outcome and can lead to a shift from "One treatment fits all" approach.The authors declare that they have no competing interests.MFE, SMS and HMB carried out all samples collection and patients work up. MFE has interpretated the data, performed the statistical analysis and has written the manuscript. HMK was involved in the patients work up. EAE, NAK, EHT and DAH have performed the immunoassay and the gene polymorphism determination. All authors read and approved the final manuscript.


To investigate the risk factors of scrub typhus infection in Beijing, China, a case-control study was carried out. Cases (n = 56) were defined as persons who were diagnosed by PCR and serological method within three years. Three neighborhood control subjects were selected by matching for age and occupation. Living at the edge of the village, living in the houses near grassland, vegetable field or ditch, house yard without cement floor, piling weeds in the house or yard, all of these were risk factors for scrub typhus infection. Working in vegetable fields and hilly areas, and harvesting in autumn posed the highest risks, with odds ratios (ORs) and 95% confidence intervals (CIs) of 3.7 (1.1–11.9), 8.2 (1.4–49.5), and 17.2 (5.1–57.9), respectively. These results would be useful for the establishment of a detail control strategy for scrub typhus infection in Beijing, China. Scrub typhus, also known as tsutsugamushi disease, is an acute, febrile infectious illness. It is caused by Orientia tsutsugamushi (formerly named as Rickettsia tsutsugamushi), a gram-negative obligate intracellular bacterium. Scrub typhus can be transmitted to human and other vertebrates by the bite of an infected larval trombiculid mite (chigger), which belongs to the family Trombiculidae and primarily consisting of the genus Leptortrombidium Most cases in disease-endemic areas occur through agricultural exposure such as working in rice fields in South Korea, Thailand, and Japan, and in oil palm and rubber plantations in Malaysia Factors that may contribute to the increase of scrub typhus include: increase outdoor activities performed by urban inhabitants, rapid urbanization of societies, aging populations, changes in ecological environment, development of ecotourism, significant evolution of diagnostic techniques and public surveillance systems Although some studies of scrub typhus have been performed in disease endemic areas, little attention has been given to the living environment, living habits and behavioral risk factors of the disease. Scrub typhus is not transmitted directly from person to person; it is only transmitted by the bites of vectors. Therefore, the human living habits and health behaviors during outdoor activities are meaningful factors for strategies to control scrub typhus. To identify the kinds of living and behavioral risk factors associated with the incidence of scrub typhus, we undertook a case-control study in Beijing.The Institutional Review Board (IRB) of Beijing Center for Diseases Prevention and Control reviewed and approved all protocols to conduct the Scrub typhus study entitled “A Case-control Study of Risk Factors Associated with Scrub Typhus Infection in Beijing, China”. Written and informed consent was obtained from all patients involved in this study.2 area and a population of 500,000. This district has shown a high incidence of scrub typhus in recent years. The prevalence rate of scrub typhus in this area was 0.029‰ in 2009 and 0.109‰ in 2010 according to the report of China Information System for Diseases Control and Prevention.The study area consists of 15 villages and towns that are located in the northeast of Beijing, situated at the junction of Beijing, Tianjin and Hebei province, with 1075 kmThe case inclusion criteria were scrub typhus cases reported in the China Information System for Diseases Control and Prevention within the past three years. The case exclusion criteria were the reported cases that lacked laboratory confirmation  were controlled by matching. A standardized questionnaire was used by trained interviewers to collect detailed information of cases and controls. Three main categories of variables were considered in the questionnaire: socioeconomic status , living habits and outdoor activities .We obtained verbal informed consent from all study subjects. This study was reviewed and approved by the Beijing Centers of Disease Control and Prevention (BJCDC), the governmental agency in charge of communicable disease control in Beijing.P value of <0.05 was considered statistically significant.EpiData software was used to develop the data set. Statistical analyses were performed with SPSS 13.0 software . The multivariate logistic regression model was used to investigate the potential correlative factors that were associated with scrub typhus infection. The significance level for entering the multivariate logistic regression model was set as 0.10, and the level for staying in the model was 0.05. A We recruited 56 scrub typhus cases and 168 matched controls. For cases and controls, respectively, 48.2% and 66.1% were female, 67.9% and 78.6% were farmers. The greatest age class in the age distribution was the 40∼ years group, and this was similar between the two groups. There were no significant differences in some demographic characteristics, such as occupation, age and education years between case group and control group . When maFor cases and controls, respectively, 98.2% and 92.9% lived in houses, others lived in apartments, 69.6% and 82.1% lived in houses with yard of cement floor, 51.8% and 17.3% live in houses near grassland, vegetable field or ditch, 14.3% and 1.8% piled weeds in the room, and 60.7% and 9.6% piled weeds in the yard. There were significant differences in most factors of living environment, except housing type between cases and controls .2 = 0.636. The results showed that gender, education≤ 6 years, working in vegetable fields, hilly area, harvesting in autumn, living in a house without cement floor, piling weeds in the house and yard, living in houses near grassland, vegetable field or ditch were positively associated with scrub typhus infection. The details are showed in Backward selection logistic regression analysis showed that when using gender, residential location, housing type, working places, activity type and living habits etc. as independent variables, and scrub typhus infection as a dependent variable, the model had significance, p<0.001, RSince the emergence of the first scrub typhus infection case in 2008 in northeast district of Beijing, an increasing number of cases were reported from 2009 to 2011 in Beijing The results showed that comparing with living in town or in the center of the village, living at the edge of the village, living in the houses near grassland, vegetable field or ditch, were positively associated with scrub typhus infection. The house at the edge of the village is more likely near the farmland or grassland, where the chigger mite grows, and this makes resident contact with transmission vectors of scrub typhus easily. Our results also showed that living in a house that has a yard without cement floor, or piling weeds in the house or yard was a high risk factor of scrub typhus infection. The lack of the cement floor in the house yard allows grass or weeds to grow easily, and these weeds in the house and yard area can increase the risk for people to come into contact with the transmission vector. All these factors increase the exposure and resident contact with transmission vectors of scrub typhus.Although farmers are considered to be a high-risk group for scrub typhus Farm and forest workers are well known to be high-risk groups for scrub typhus. We found strong positive associations with working in the vegetable field, woodland and hilly area; persons who had harvested crops or had gathered wood or weeds in the field within the previous month also showed a high risk for scrub typhus infection.Our results suggest that people who tend to expose their skin during outdoor activities are vulnerable to scrub typhus infection. As the proportion of people raising animals was low, the possession of pets or domestic animals was not associated with the disease. In our study, we found that only 2.3% and 3.3% of the participants (cases and control respectively) had received health education for scrub typhus during their lifetimes. Therefore, the efficacy of these measures for preventing scrub typhus was not clearly evaluated. Beijing Center for Disease Prevention and Control should begin to perform an intensive health education program in disease-endemic areas. And a prospective study is required in these regions to investigate the efficacy of the prevention measures.According to the report of the of China Information System for Diseases Control and Prevention, the difference in ratio of male and female scrub typhus patients is not significant, but the multivariate logistic regression analysis showed that male has a higher risk of catching the disease than female. Typically, men are more involved in the farm work and field work than women in north China, and this offers more chance for male to get the chigger bite than female, and thus a higher risk to catch the scrub typhus.The multivariate logistic regression analysis also showed that lower education level (education ≤ 6 years) is a risk factor for scrub typhus infection in this area. Higher education provided individuals with more knowledge about this disease and allowed easier access to get health education about this disease through various channels. Individuals with higher education may also possess better personal hygienic habits, such as changing clothes or taking bath after field work. All these behaviors can help to protect a man from the chigger bite. Since these contents were not included in the questionnaire, we need to carry out further study to confirm the hypothesis in the future.Our study has specific strengths. First, the study was representative of the Beijing population and specifically designed according to the rural conditions of Beijing area. Second, the results have definite implications for public health because the study targeted modifiable behaviors.There were also limitations to our study. First, the sample size was relatively small considering the heterogeneity of the study participants. Second, there were some potential for recall bias because of using cases that had the infection in 2008 and 2009, which involved a longer time from the onset to be interviewed.Despite these limitations, our study presents worthy results that can contribute to the establishment of an evidence-based intervention strategy to reduce the incidence of scrub typhus. Outdoor activities and living habits can make a person vulnerable to scrub typhus infection. Conducting health education constantly and increasing public awareness, such as changing living habits of not piling weeds in the house and yard, improving living conditions to the best of one’s ability, cementing the ground of the house and yard to reduce the weed growth, taking preventive behaviors that reduce exposure to infected mites, e.g., wearing a long-sleeve shirt, not resting on the bare field or grass may have significant effects in preventing scrub typhus infection in Beijing.In conclusion, our findings will be helpful in the establishment of a detailed intervention program to control scrub typhus in Beijing area or other similar disease-endemic area in China.


TYMP S471L (rs11479) and early dose modifications and/or severe adverse events . There was also a significant association between these phenotypes and a signature of DPYD mutations . We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers.The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between  Folate-dependent one-carbon metabolism is a target for drug groups that are widely used in the treatment of cancer and inflammatory diseases. Two of the drugs, 5-fluorouracil (5-FU) and capecitabine, are central to the medical management of colorectal cancer in both advanced and adjuvant settings; they are used as monotherapies or in combination with other chemotherapeutic and biological agents. Both folate metabolism and the catabolism of 5-FU and capecitabine depend on a number of enzymes that are functionally polymorphic . 5-FU isThe fluoropyrimidine, capecitabine , has been designed for oral administration and to be more specific than 5-FU, thus leading to potential differences in the safety profile -5.The use of 5-FU/leucovorin in randomized controlled trials of adjuvant chemotherapy for colorectal cancer has been shown to improve both disease-free and overall survival as compared to surgery alone ,7. SubseTYMS and methylenetetrahydrofolate reductase (MTHFR) , p=0.023, and OR of 2.15 , p=0.020 in the dominant model (2). An association for severe toxicity and or SHMT1 (rs1979277) heterozygotes; an adjusted OR of 0.40 , p=0.023 compared to CC homozygotes, and OR of 0.47 [0.23-0.97], p=0.041 in the dominant model. No other adjusted results were significant.Adjusted results that we do not emphasise  were (1) an association for dose modification and DPYD and TYMP genotypes) and clinical phenotype data for the 44 participants who had severe adverse events. Nineteen of the 44 participants with severe adverse events carried at least one of the candidate predictive markers. If detection of the combined SNP signature was used as a diagnostic procedure to identify those who would subsequently suffer severe adverse events, the sensitivity would be 45.5 %, with a positive predictive value of 33.9 %. The potential impact of testing for the combined SNP signature and then changing to a different chemotherapy regimen in affected individuals can be estimated in a hypothetical clinical population of 1000 patients. If those patients had similar characteristics to those within our cohort, 233 of them would be combined SNP signature positive. The impact of changing the regimen in these 233 patients would be 79 fewer severe adverse events. Here, 95 patients would still have severe adverse events . However, 156 patients with the combined SNP signature would have had their regimen changed for no specific benefit because they would not have gone on to develop severe adverse events.We present an analysis of functionally important genetic variants in the pharmacokinetic and pharmacodynamic pathways that influence response to fluoropyrimidines. The phenotypes examined were adverse events that were identified by a dose delay or dose modification within 12 weeks due to toxicity, and by CTCAE grade 3, 4 or 5 scores. Each of the pharmacokinetic variants that we consider are compelling candidates as predictive markers because they have a known or putative functional impact on the enzymes needed for drug catabolism or their metabolism to an active form.DPYD variants analysed lead to enzyme deficiency or absence and their functional effects can be observed in heterozygous carriers. However, each DPYD SNP is rare, which reduces their potential clinical utility as predictive markers. In this study therefore we have also considered these DPYD variants as a signature of alternative polymorphisms, and found a strong association with early adverse events  mixed cohort of breast and colorectal cancer patients treated with capecitabine [TYMP SNP, rs470119 [citabine . We pres1479 see  and S2, citabine . In anotrs470119 . UMPS (rs1801019) and CDA (rs2072671). Genetic variants for these loci have previously been associated with severe neutropenia and diarrhoea in patients treated with 5-FU [We found no significant associations or trends for early dose modifications or severe adverse events with the candidate variants of ith 5-FU , and witith 5-FU .MTHFR, DHFR, MTHFD1, and SHMT in addition to TYMS. These are non-synonymous SNPs or variants that affect untranslated control regions; each polymorphism has a demonstrated or putative influence on gene expression or function. Inhibition of thimydylate synthase is an important pharmacodynamic mechanism for fluoropyrimidines but the balance of folate species within the biochemical pathway may depend on the enzyme variants at key branch points . We haveTYMS genotypes, it has been suggested that haplotype rather than genotype analysis may improve the sensitivity and specificity of pharmacogenetic testing. The G>C polymorphism in nucleotide 12 of the TYMS 28 bp VNTR repeat elements has been proposed to affect both expression of TYMS in vitro and levels of 2’-deoxyuridine in vivo. However, the published data are inconclusive, the majority of the possible genotypes have not been examined in relation to 5-FU sensitivity; different methods have been used to test gene expression; and conclusions about the putative functional effects have not been congruent [TYMS variants, rs45445694 and rs16430  for which there is linkage disequilibrium [No significant associations or trends were found for individual polymorphisms that have been classified as low activity thymidylate synthase variants and toxicity within 12 weeks . In the ongruent -45. Anotongruent  compriseilibrium ,32,47. DHFR, SHMT or MTHFD1 genotypes. Associations with an increased risk of dose modification were identified for particular DHFR genotypes and decreased risk of severe adverse events with particular SHMT genotypes in this study. But we do not emphasise these results because they derive from the adjusted dominant model only and there was no concordance between the 2 phenotypes considered . The observational nature of this study means that potential bias cannot be excluded. There are a number of factors that could bias towards the null. This may stem from incomplete recording of adverse events, missing data, or patients having early dose modifications and/or prophylactic interventions before higher grade events occurred. Small effect sizes, coupled with low allele frequency in some instances would have reduced the power of the study to detect any significant association. Conversely, type I error may also occur in erroneously reporting a significant finding when there is actually no true association. This can stem from multiple testing of a diverse range of genetic markers  and is a problem that may be ameliorated through a Bonferroni correction. However, Perneger highlights a number of methodological weaknesses with Bonferroni corrections , and he recommends that Bonferroni correction ‘should not be used when assessing evidence about specific hypotheses’. This poIn conclusion, these data identify and confirm markers that predict toxicity but our analysis of their clinical validity indicates limited utility. This has important implications for helping clinicians and patients arrive at evidence-based decisions on the pros and cons of investing in commercially available genotyping tests for predicting 5-FU toxicity during treatment of colorectal cancer. Only a few pharmacogenetic studies of the genotypes described have considered the role of epistasis but some interactions have been identified that warrant further analysis ,46,49,50Table S1The genotypes at the loci DPYD and TYMP for 44 participants who had grade 3, 4 or 5 adverse events within 12 weeks of starting the chemotherapeutic protocol.Treatment regimes; 1 = 5-FU as monotherapy; 2 = 5FU in combination chemotherapy; 3 = capecitabine as monotherapy; 4 = capecitabine in combination chemotherapy.For the genotype data; 0 = homozygous for the minor allele; 1 = heterozygous; 2 = homozygous for the major (wild type) allele. The genotypes 1236G>A and c1129-5923C>G are in linkage disequilibrium. LFT; liver function tests.(DOC)Click here for additional data file.Table S2Analyses of associations between fluoropyrimidine toxicity and genotype.The results from the test for trend and from dominant and recessive genetic models are shown. (a) Main effect of polymorphisms on fluoropyrimidine dose modification: markers of pharmacodynamics.† Adjusted for age, sex, previous chemotherapy and treatment regime using logistic regression ‡Fisher’s exact estimate used *Test for trend could not be calculated because of 0 observations in one or both phenotype groups for homozygotes in the minor allele.(b) Main effect of polymorphisms on fluoropyrimidine dose modification: markers of pharmacokinetics.† Adjusted for age, sex, previous chemotherapy and treatment regime using logistic regression ‡Fisher’s exact estimate used.(c) Main effect of polymorphisms on grade 3, 4 or 5 toxicity events: markers of pharmacodynamics.† Adjusted for age, sex, previous chemotherapy and treatment regime using logistic regression ‡Fisher’s exact estimate used.(d) Main effect of polymorphisms on grade 3, 4 or 5 toxicity events: markers of pharmacokinetics.† Adjusted for age, sex, previous chemotherapy and treatment regime using logistic regression ‡Fisher’s exact estimate used *Test for trend could not be calculated because of 0 observations in one or both phenotype groups for homozygotes in the minor allele.(DOCX)Click here for additional data file.Table S3Individualised data for each toxicity phenotype.(XLS)Click here for additional data file.


Premature ejaculation (PE) has been reported as the most common male sexual dysfunction with global prevalence rates estimated at approximately 30%. The neurobiogenesis of ejaculation is very complex and involves the serotoninergic  system. Recently, genetic polymorphisms located on SLC6A4 gene codifying for 5-HT transporter (5-HTT), the major regulator of serotonic neurotransmission, have been linked with the pathogenesis and risk of PE. Apparently studies of this type of polymorphism in PE have show conflicting results.5-HTTLPR) polymorphism and the risk of lifelong PE (LPE) in men to clarify this relationship. We searched Pubmed and Embase (last search updated on Aug 2012) using ‘premature ejaculation’, ‘polymorphism or variant’, ‘genotype’, ‘ejaculatory function’, and ‘rapid ejaculation’ as keywords and reference lists of studies corresponded to the inclusion criteria for meta-analysis. These studies involved the total number of 481 LPE men and 466 health control men subjects. Odds ratio (OR) and 95% confidence intervals (CIs) were used to evaluate this relationship.A meta-analysis was performed that are available in relation with 5-HTT gene-linked promoter region . Moreover, in subgroup analysis based on ethnicity, similar significant associations were detected. The Egger’s test did not reveal presence of a publication bias.In the overall analysis, significant associations between LPE risk and 5-HTTLPR polymorphism were found  polymorphism might protect men against LPE risk. Further studies based on larger sample size and gene-environment interactions should be conducted the role of 5-HTTLPR polymorphism and LPE risk.Our investigations demonstrate that  Premature ejaculation (PE) is one of the most common male sexual complaints Lifelong PE (LPE) is defined as a male sexual dysfunction characterized by ejaculation that always or nearly always occurs prior to or within about 1 minute of vaginal penetration, the inability to delay ejaculation on all or nearly all vaginal penetrations, and with negative personal consequences, such as distress, bother, frustration, and/or the avoidance of sexual intimacy The complete etiology of PE is largely unknown. PE has historically been considered a psychological disorder. However, besides psychological, environmental, and contextual aspects, several published articles have focused on neurobiological, endocrine, and genetic causative factors The successful use of selective serotonin reuptake inhibitors (SSRIs) in the treatment of PE indicates that the classical psychological view of PE is no longer tenable as the only possible pathogenetic theory behind PE, and that serotonin  plays a role in the ejaculation process 5-HTTLPR gene has two variant alleles: a short (S) and a long (L) allele. The short allele has 44 base pairs (bps) less than the L allele The 5-HTT functioning is moderated by a polymorphism in the 5-HTT promoter region of the serotonin transporter (SERT) gene (SCL6A4), which encodes for the SERT (5-hydroxytryptamine transporter-linked promoter region [5-HTTLPR]) 5-HTTLPR gene polymorphism with potential functional significance and risk of LPE 5-HTTLPR gene polymorphism and risk of LPE in larger samples by meta-analysis.Several epidemiologic studies have examined associations between 5-HTTLPR gene polymorphism and LPE risk up to Aug, 2012. The medical subject headings and key words used for search were ‘premature ejaculation’, ‘polymorphism or variant’, ‘genotype’, ‘ejaculatory function’, and ‘rapid ejaculation’. The electronic searching was supplemented by checking reference lists from the identified articles and reviews for additional original reports.We searched the Pubmed and Embase databases for all articles on the association between 5-HTTLPR gene polymorphism and LPE risk was explored; (3) LPE was operationally defined as the lifelong presence of an intravaginal ejaculation latency time (IELT) of 1 minute or less after vaginal penetration occurring an more than 90% of occasions of sexual intercourse with complaints of inability to delay ejaculation and feelings of frustration about it. The major exclusion criteria were: (1) duplicate data, (2) abstract, comment, review and editorial, (3) no sufficient data were reported and (4) The patients with erectile dysfunction and other sexual problems, such as decreased libido, a history of sexual abuse, chronic prostatitis and infravesical obstruction.Eligible studies had to meet the following criteria: (1) study was designed using the methodology of a case-control study; (2) the association between The following items were collected: first author’s last name, year of publication, country of origin, ethnicity, source of control  and Hardy–Weinberg equilibrium (HWE) of control group, total number and genotype distributions in cases/controls and the L-allele frequency of control groups.5-HTTLPR gene polymorphism and LPE risk was measured by odds ratios (ORs) with 95% confidence intervals (CIs). Pooled ORs were obtained from combination of single studies by allelic contrast , homozygote comparison (LL vs. SS), heterozygote comparison (LS vs. SS), and dominant model (LL+LS vs. SS), respectively. The heterogeneity among the studies was checked by using the chisquare based Q statistic and considered statistically significant at P<0.05 P>0.05, the pooled OR of each study was calculated by using the fixed-effects model ; otherwise, the random-effects model (the DerSimonian and Laird method) was used Z-test, and P<0.05 was considered statistically significant. The departure of frequencies of 5-HTTLPR gene polymorphism from expectation under HWE was assessed by the chi-square test in controls and a P<0.05 was considered as significant disequilibrium. Publication bias was diagnosed with Egger’s linear regression method and funnel plot. The P-value less than 0.05 in Egger’s linear regression indicated the presence of potential publication bias The strength of the association between the A and LG variants. In our study, we combined these two variants together as L-allele. Finally, six studies with 481 LPE cases and 466 health controls were retrieved based on the search criteria. Characteristics of studies in this meta-analysis are included in A total of 23 articles were achieved by literature search from the Pubmed and Embase, using different combinations of key terms. As shown in 5-HTTLPR gene polymorphism in different genetic models: allelic contrast , homozygote comparison , heterozygote comparison , and dominant genetic model  , homozygote comparison , and dominant genetic model , which are reported to be effective for treating PE 5-HTTLPR gene polymorphism and PE/LPE, but the results were inconclusive. Janssen et al. 5-HTTLPR gene polymorphism in LPE patients vs. controls. In contrast, two studies P<0.01), however, the LS genotype was more prevalent in the control group (P<0.01). Our study showed partly similar conclusions with above two studies. However, two included studies Several epidemiological studies have investigated the association between 5-HTTLPR gene polymorphism and LPE: LL genotype or L-allele was a protect factor for LPE. Because of the coupled and complementary association between L-allele and S-allele, in contrast, SS genotype and/or S-allele were risk factors of LPE. Then, we analyzed the association stratified analysis by ethnicity, the similar conclusion was found in Asians not Caucasians, which can be explained that the prevalence of PE is different in distinct geographic locations and ethnicities. The Global Study of Sexual Attitudes and Behaviors (GSSAB) reported a PE prevalence ranging from 12% in the Middle East to 30% in Southeast Asia among men 40–80 years of age [44]. In a separate study of men between the ages of 18 and 59 years in the United States, the overall prevalence of PE was 21%, which comprised 19% of Caucasian men, 27% of Hispanic men, and 34% of African-American men [45]. Finally, in case-control studies whose controls were from PB, significant association was also found. Our study may help scientists to detect this SNP in 5-HTTLPR gene in healthy men and to find high-risk group of PE in the future.We first analyzed the overall association between 5-HTTLPR gene polymorphism and LPE risk, there are still some limitations inherited from the published studies. First, although we collected all the eligible studies, the sample size of the included studies was not large enough, which could increase the likehood of type I and type II errors. Second, gene-gene and gene-environment interactions were not analyzed. It is possible that specific environmental and lifestyle factors may alter those associations between gene polymorphism and LPE. Third, the distribution of genotypes in the controls of two studies Although, we have put considerable efforts and resources into testing possible association between 5-HTTLPR gene polymorphism was associated with significantly decreased risk for LPE risk in Caucasians. Therefore, further well designed large studies, particularly referring to gene–gene and gene–environment interactions are warranted. These future studies should lead to better and comprehensive understanding of the association between the 5-HTTLPR gene polymorphism and development of LPE.In summary, in the present, our meta-analysis showed the evidence that


Studies on adults treated in adolescence surgically or with braces for idiopathic scoliosis, and on untreated subjects, indicate that both the condition and interventions can lead to psychological stress, poorer body image and self-esteem and can reduce quality of life -4. CompaWe aimed to discuss the design of our ongoing case-control study on adults treated in adolescence for scoliosis with specific exercises in the Centre of Corrective and Compensatory Gymnastics in Bielsko–Biala, Poland, and to indicate tendencies shown in a pilot analysis.Medical records of 3009 subjects who attended the Centre between 1984 and 1995 and 2158 age–matched individuals, are accessible. A pilot case-control study on 12 treated subjects and 10 controls, aged 31.4 (27 – 37) years, Cobb 35.4 (10 - 54°), was conducted. Total lung capacity and spirometry, physical activity, back pain, self-functioning, quality of life and patients’ attitudes towards treatment were measured. One-way ANOVA or a non-parametric U-test were performed.Individual results differed, but their relation to curve angle was observed. Differences between treated and untreated individuals were ambiguous. However, inter-group analyses showed nonsignificant differences between all variables (p<0.05).Preliminary results differ from findings of the studies on braced patients: the Ste-Justine Adolescent Idiopathic Scoliosis Cohort Study, studies of Danielson and Nachemson, and continuing observations of Weinstein and coauthors. However, low power of the pilot study does not allow concluding.This paper is a part of a research project DS.136, University School of Physical Education, Warsaw, Poland.


TG6, a brain expressed transglutaminase, is implicated in the neurological manifestations of celiac disease (CD). We hypothesized that earlier brain injury due to head trauma may be more common in patients with CD, potentially through trauma-induced TG6 leading to interaction with TG2.Through biopsy reports from all 28 pathology departments in Sweden we identified 29,096 individuals with CD (in this study defined as villous atrophy). We then examined the risk of earlier head trauma in CD compared to the risk in 144,522 controls matched for age, sex, county and calendar year. Odds ratios (ORs) were calculated using conditional logistic regression.981 (3.4%) individuals with CD and 4,449 (3.1%) controls had a record of earlier head trauma. Individuals with head trauma were hence at a 1.10-fold increased risk of future CD (95% CI = 1.02-1.17). ORs were independent of sex or age at CD. The highest risk of future CD was seen during the first year after trauma. There was no association between severity of trauma and risk of developing CD.This study found a very small excess risk for future CD in individuals with an earlier head trauma. Celiac disease (CD) occurs in about 1% of the population in Western Europe  peripherOur research has shown that a large proportion of individuals with gluten ataxia show increased levels of tissue transglutaminase 6 (TG6) ,9. AlthoCD is a lifelong small intestinal immune-mediated enteropathy characterised by inflammation and villous atrophy (VA). It occurs in about 1% of the Western population, and requires lifelong treatment with gluten-free diet. The overwhelming majority of individuals with CD are DQ2+ or DQ8+, but even if genetic studies have shown a high concordance rate of CD in monozygotic twins , geneticThe aim of this study was to examine if individuals with head trauma leading to brain injury were at increased risk of developing CD. We hypothesized that head trauma and secondary cerebral and cerebellar insult may trigger autoimmunity against TG6 which in turn may lead, in genetically susceptible individuals, to the development of CD.We used data from small intestinal biopsy reports obtained from all 28 pathology departments in Sweden to identify individuals with CD. Biopsy data were then linked to inpatient and hospital-based outpatient data on head trauma through the unique Personal Identity Number assigned to all Swedish residents .ICD7: 800–4 and 851–55; ICD8: 800–4 and 850–54; ICD9: 800–4 and 850–54; and ICD10: S02 (minus S02.5) and S06). A recent validation found that the most common criteria for assigning an ICD code for head trauma in Sweden are loss of consciousness (76%) and posttraumatic amnesia (38%) [We defined head trauma  as having a relevant international classification of disease (ICD) code in the Swedish Patient Register (ia (38%) .The data source for head trauma, the Swedish Patient Register began in 1964 (then exclusively inpatient care) . The covWe collected data on VA (histopathology stage Marsh 3)  from comEach individual with CD was matched with up to 5 controls for age, sex, county, and calendar year. Controls were sampled from individuals without a previous small intestine biopsy, and identified through the Swedish Total population register. Control matching was carried out by the government agency Statistics Sweden. After removal of duplicates and other data irregularities, our data-set was identical to that of our previous paper on mortality in CD . The maiConditional logistic regression was used to calculate odds ratios (ORs) for later CD in individuals with head trauma. We used a conditional approach; meaning that each individual with CD was first compared only to his/her matched controls within the same stratum. This eliminated the effect of age, sex, county and calendar year on our risk estimate. We then summarized stratum-specific data and calculated an overall OR for future CD.A priori sub-analyses were carried out and included ORs according to sex, age and calendar period at CD diagnosis. We also examined the risk of CD according to time since head trauma .In a sub-analysis we adjusted for country of birth (Nordic vs. not Nordic) and education according to four priori-defined categories . Some 4%In another analysis we examined head traumas occurring in adults (>19 years of age) and risk of future CD. We did so hypothesizing that non-nutritional risk factors may be especially important for adulthood CD.severe head trauma and CD. We defined severe head trauma as requiring either a) inpatient care in a neurosurgery department or b) ≥3 days of inpatient care. To increase the specificity of our exposure variable we also calculated the OR for CD in individuals with at least two prior records of head trauma .We performed three sensitivity analyses. In two of these we examined the association between We used SPSS 18  for all analyses. ORs with 95% confidence intervals that did not include one were regarded as statistically significant.The current study was approved by the Ethics Review board of Stockholm, Sweden, which deemed that no individual informed consent was required since data were strictly register-based.The majority of the study participants were female Table . The medOf 29,096 individuals with CD, 981 (3.4%) had a record of earlier head trauma compared to 4,449/144,522 (3.1%) controls. The OR for future CD in individuals with head trauma was 1.10 (95% CI = 1.02-1.17). Adjustment for education and country of birth did not affect the risk estimates (data not shown).The highest risk for future CD was seen in the first year after head trauma , with decreasing ORs thereafter . No association was seen between head trauma and future CD ≥5 years after the trauma .The OR for future CD was similar in males and females, but only in females did the association reach statistical significance (OR = 1.13) Table . Head trRestricting our analysis to head traumas occurring in adults we found a small excess risk of later CD .We found no statistically significant associations between CD and head trauma, when we restricted our exposure to severe head trauma defined as either requiring inpatient care in a neurosurgery department , or ≥3 days of any inpatient care  . Data from stratified analyses are given in Table In this nationwide case–control study we examined the association between head trauma and CD. Given the role of TG6 in the pathophysiology of gluten ataxia and its abundance in brain tissue, we hypothesized that head trauma resulting in cerebral and cerebellar insults may trigger autoimmunity against TG6 which in turn may lead in some genetically susceptible individuals, to the development of CD. This study found a slight but significantly increased risk of CD in individuals with previous head trauma.TG6, TG2 (the autoantigen in CD) and TG3 (the autoantigen in dermatitis herpetiformis) share genetic, structural and enzymatic properties. It has been shown that patients with gluten ataxia have an immunological response primarily directed against TG6 even in the absence of enteropathy . The intDuring brain injury self epitopes (e.g. TG6), which are normally shielded from the systemic immune system, may become exposed to adaptive immunity. This may result in the immune system reacting to self-antigens in the central nervous system ultimately leading to autoimmunity. One study has demonstrated the presence of intrathecal antibodies against transglutaminases in the cerebrospinal fluid of patients with neurological dysfunction . After bWe are not aware of any earlier study that has examined if head trauma could trigger CD. In CD diagnosed in early childhood, nutritional factors are likely to play an important role in the CD pathogenesis, while less is known with regards to adulthood CD. Risk factors may exert different degrees of influence depending on the age of the individual. Due to the large statistical power of our study we were able to perform age-stratified analyses, but also specifically analyze the impact of head trauma in adulthood. Odds ratios were similar in all these analyses except for a lack of association among individuals aged ≥60 years at CD diagnosis. The lack of association between head trauma and CD in this age stratum could be due to limitations of the Swedish Patient Register. Although this register has nationwide coverage since 1987, and began in 1964 it will not have covered the childhood or adolescence (when some will have had head trauma) of many of those individuals diagnosed with CD ≥ 60 years. This is also obvious from Table Although the association between head trauma and later CD was only statistically significant in women, we found no statistical heterogeneity between men and women. While ORs were not statistically significantly different between calendar periods there was a trend towards a higher OR before 1990. One explanation for this could be the lower awareness of CD in the 1970s and 1980s, allowing surveillance bias after head trauma to play a greater role for the detection of CD in these years.onset. Many individuals go undiagnosed for several years [We ascertained CD through biopsy data. This informed us about the exact date of CD diagnosis, but we have no data on the exact date of CD al years , and sucal years , and we In a Swedish setting VA is seldom due to other causes than CD . When weet al. have shown that 91% of Swedish hospitals managing head injuries use the ICD-10 code “SO6” to code head trauma [We used ICD codes to identify head trauma. Bellner d trauma ; and we d trauma .In order to increase the specificity of our exposure variable, we carried out several sensitivity analyses. These analyses showed inconsistent results with one showing a negative association, a second a positive association, and a third a neutral association between head trauma and CD. The 95% CIs of the three analyses did however overlap and it should be noted that head trauma requiring health care in a neurosurgery department, indicating severe head trauma did not show an association with future CD (OR = 0.77). This observation, however does not necessarily argue against our hypothesis because the severity of the insult to the brain may not correlate with the likelihood of the development of autoimmunity to TG6. Furthermore patients with head injury that are admitted to neurosurgical units are very likely to receive steroids as a means of reducing swelling secondary to the head injury. Steroids are known to interfere with the immune response.Another explanation for the small increased risk of CD in our main analysis is surveillance bias. The highest ORs were seen in the first year after head trauma, and after that ORs went down towards 1. Head trauma can have long-term consequences including posttraumatic headache, necessitating regular health care contact where a CD may have been discovered only because the patient met with a physician for another reason (head trauma). However we cannot altogether rule out that the 10% excess risk of CD seen in this study is true, since it is consistent with our a-priori hypothesis. The observation that the highest ORs were seen in the first year after head trauma would be consistent with the timescale of an autoimmune response triggered by the monophasic event of head trauma without any chronic ongoing insult to the brain, but may also be due to increased testing for a number of diagnoses (including CD) in patients with brain trauma necessitating hospital contact.Finally, our earlier research has shown that CD is associated with a number of other immune-mediated diseases -35 and sIn conclusion, we found a small increased risk of CD in individuals with earlier head trauma. This excess risk may be due to surveillance bias or due to an autoimmune response against transglutaminases triggered by the brain injury.This project (2006/633-31/4) was approved by the Research Ethics Committee of the Karolinska Institute, Sweden on June 14, 2006.CD: Celiac disease; CI: Confidence interval; HR: Hazard ratio; VA: Villous atrophy.The authors declare that they have no conflict of interest.ICMJE criteria for authorship read and met: JFL, MH. Agree with the manuscript’s results and conclusions: JFL, MH. Designed the experiments/the study: JFL, MH. Collected data: JFL. Analyzed the data: JFL. Wrote the first draft of the paper: JFL. Contributed to study design, interpretation of data and writing: MH. Interpretation of data; approved the final version of the manuscript: JFL, MH. Responsible for data integrity: JFL. Obtained funding: JFL. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/13/105/prepub


SEPS1 was shown to increase pro-inflammatory cytokine expression. We examined whether this functional polymorphism was related to the risk of SPTB in a Chinese population. We also examined the impact of premature rupture of membranes (PROM) on susceptibility to SPTB. The SEPS1 G-105A polymorphism was genotyped in 569 preterm singleton neonates and 673 term neonates by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. χ2 tests and logistic regression analyses were used to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs). We observed that, compared with the GG genotype, –105A positive genotypes (GA + AA genotypes) were associated with significantly increased susceptibility to SPTB . The –105A positive genotypes were also significantly associated with increased susceptibility to SPTB, both in the patients with PROM  and in those without PROM . The –105A positive genotypes were also significantly associated with increased susceptibility to SPTB between extremely preterm neonates and controls  and between moderately preterm neonates and controls . Our findings suggest that the SEPS1 G-105A polymorphism contributes to the risk of developing SPTB in a Chinese population.Inflammation plays an important role in the etiology and pathophysiology of spontaneous preterm birth (SPTB), and selenoprotein S (SEPS1) is involved in regulating the inflammatory response. Recently the G-105A promoter polymorphism in  China contributes 7.8% of these premature births, with nearly 1.1 million preterm infants being born there every year, second only to India Preterm birth (PTB), defined as birth before 37 complete weeks of gestation, is the major cause of neonatal mortality and morbidity. PTB is associated with over 75% of long-term morbidity, including cerebral palsy, developmental delay, retinopathy of prematurity, and hearing and vision problems. PTB is a global problem, with approximately 15 million premature births occurring annually across the globe. This number is rising according to the World Health Organization (Genetic factors are known contributors to spontaneous preterm birth (SPTB) Evidence exists that inflammation plays a role in the pathophysiology of SPTB SEPS1 promoter region  impairs SEPS1 expression and amplifies the production of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) SEPS1 G-105A polymorphism in SPTB, however, has never been specifically investigated. In the present study we examined whether a functional SEPS1 G-105A promoter polymorphism has any bearing on SPTB risk in a Chinese population.A previous study discovered that a functional single nucleotide polymorphism (SNP) in the Subjects in this study were offspring of women receiving obstetrical care at the BaYi Children’s Hospital at General Hospital of Beijing PLA. Subjects were recruited sequentially between Jan. 2009 and May 2011. All subjects were unrelated ethnic Han Chinese residing in Beijing and its surrounding regions. Cases were neonates from pregnancies complicated by SPTB. Based on gestational age, SPTB is dividing into three sub-categories: moderately preterm (33 to 36 completed weeks of gestation), very preterm (<32 weeks) and extremely preterm (<28 weeks). Controls were randomly selected from singleton pregnancies delivered at term from mothers with no prior history of premature rupture of membranes (PROM) or PTB. The diagnosis of PROM was based on pooling of amniotic fluid in the vagina, amniotic fluid ferning patterns, and a positive nitrazine test. Pregnancies with fetal anomalies, trauma, connective tissue diseases, preeclampsia, intrauterine growth restriction, fetal distress, antepartum hemorrhage, or medical complications requiring induction of labor were excluded from both the case and control groups. Pregnancies who treated with antenatal steriods, tocolytics, progesterone, antibiotics, or undergone cerclage upon presentation of preterm were also excluded from both the case and control groups.For each participant, a neonatal peripheral blood sample was collected into tubes containing EDTA immediately after delivery. We stored the whole blood samples at 4°C upon collection. Then, all whole blood samples were stored at −80°C until genomic DNA extraction. At recruitment, demographic factors and medical history were collected using a structured questionnaire. This study was performed with the approval of the Ethical Committee of General Hospital of Beijing PLA and was conducted according to the principles expressed in the Declaration of Helsinki. At recruitment, written informed consent was obtained from all participants’ guardians.SEPS1 G-105A genotype using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Briefly, the PCR assay was performed in GeneAmp PCR System 9700 (Applied Biosystems). The primers 5′-TCCTTGGCTTCAGTGTCCAAT-3′ and 5′-CGCGGACAGAGACTCCTCTT-3′ were used to amplify the target region containing the G-105A polymorphism. PCR was performed with a 25 µL reaction mixture containing approximately 20 ng DNA, 0.2 µM of each primer, 0.2 mM deoxynucleoside triphosphates, and 0.5 unit Ex Taq Polymerase in 1X reaction buffer . The amplification reaction was carried out in the following conditions: an initial melting step of 2 min at 95°C, followed by 35 cycles of 30 sec at 94°C, 30 sec at 57°C and 30 sec at 72°C with a final elongation of 7 min at 72°C. The reaction yielded a 370 bp amplicon. An aliquot (5 µL) of PCR product was digested with 4 unit of 4 MscI (New England Biolabs) and separated on a 2.5% agarose gel. The presence of the A allele creates an MscI restriction site; digested amplicons from AA homozygotes appear as a 233 bp and a 137 bp band, homozygotes for the G allele appear as a 370 bp band, and heterozygotes have all three of these bands. To ensure quality control, genotyping was performed blinded to the case/control status of the subjects; 15% masked, random samples from cases (n = 85) and controls (n = 101) were validated by direct sequencing, and the results were 100% concordant.Genomic DNA was extracted from whole blood specimens using the RelaxGene Blood DNA System (TianGen Biotech Co. Ltd.) according to the manufacturer’s instructions. DNA samples were diluted to 10 ng/µL and distributed to 96-well plates (each 96-well plate contains 94 samples and 2 no-DNA controls). We then analyzed samples for the http://lgb.unige.ch/arlequin). The homogeneity of baseline characteristics between the two groups was tested by the χ2 test or Fisher exact test for categorical variables, as well as by the Mann-Whitney U test for continuous variables. The single allelic and single genotype frequencies in each of the two groups were analyzed using χ2 test. Association between the G-105A polymorphism and risk of SPTB were estimated by use of χ2 test and logistic regression analyses. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to measure the strength of association. An association was considered significant at a P value of <0.05, and all statistical tests were two-sided. These analyses were performed using SPSS software . The meta-analyses were performed using Review Manager version 5.0 . Statistical heterogeneity among studies was evaluated using the χ2 test, P values, and I2 statistics Genotype and allele frequencies for the G-105A polymorphism were determined by gene counting. The fitness to Hardy-Weinberg equilibrium was tested using the random-permutation procedure implemented in the Arlequin package (P<0.001), birth weight (g) (P<0.001), APGAR 1 (1 min after birth) (P<0.001), and APGAR 5 (5 min after birth) (P<0.001).All subjects were of Chinese Han descent. The baseline characteristics of the study population, including 569 infants (SPTB <37 weeks) and 673 controls, are shown in SEPS1 G-105A polymorphism were in respective Hardy-Weinberg equilibrium for both cases and controls . In the overall sample, the A allele was more prevalent among case infants (10%) than among control subjects (6%) . The frequencies of the GG, GA and AA genotypes among SPTB neonates varied significantly from those among controls . We used a dominant genetic model (frequency of GA heterozygotes plus frequency of AA homozygotes vs. frequency of GG homozygotes). Subjects carrying the –05A allele (GA + AA genotypes) had an elevated risk of SPTB compared to those with the GG genotype . In multivariate logistic regression analysis with maternal age at delivery (year) and neonatal sex adjusted, significant association was also observed between SPTB and G-105A polymorphism .Genotyping results are presented in P<0.001) and in those without PROM . In multivariate logistic regression analysis with maternal age at delivery (year) and neonatal sex adjusted, significant association was observed between susceptibility to SPTB and –105A positive genotypes both in the patients with PROM  and in those without PROM .The associations between the G-105A polymorphism and susceptibility to SPTB were further examined by stratifying patients by PROM status . The –10The frequencies of G-105A polymorphism genotypes were also compared between 425 preterm neonates with low birthweight and 144 neonates with normal birthweight . There wP = 0.002). There was a significant association between moderately preterm neonates and controls as well . However, only a borderline significant association was observed between very preterm neonates and controls .We also analyzed the association between the controls and three gestational age groupings: extremely preterm neonates, very preterm neonates, and moderately preterm neonates . The –10SEPS1 G-105A polymorphism on SPTB between stratified analysis of PROM, three gestational age groupings and overall analysis, we performed a meta-analysis. For comparison between subjects carrying the GG genotype and subjects carrying the −105A positive genotypes, the meta-analysis of data in preterm neonates delivered with or without PROM and controls showed significant association between SEPS1 G-105A polymorphism and SPTB  in our study, this assumption warrants further confirmation in future studies.Considering that SPTB etiologies vary based on gestational age at delivery, we analyzed the associations between controls and three gestational age groupings: extremely preterm (<28 weeks), very preterm (<32 weeks), and moderately preterm (33 to 36 completed weeks of gestation). We found that the G-105A polymorphism was significantly associated with SPTB in the extremely preterm and moderately preterm groups, while we observed only a borderline significant association in the very preterm group. Interestingly, several other studies also suggested differences of susceptibility between gestational age groupings SEPS1 polymorphism in the etiology of SPTB. Secondly, we cannot rule out that the presence of polymorphisms in other genes, especially other genes involved in the inflammation, could affect the occurrence of the SPTB. We selected SEPS1 G-105A polymorphism because it was strongly associated with circulating levels of pro-inflammatory cytokines. However, the regulation of inflammation is complex, with other genes warranting investigation. Recently, other investigators have used proteomics In reviewing the results of this study, two potential limitations should be kept in mind. Firstly, in our study, the influence of maternal genomes on predispositions to SPTB was not considered. SPTB is a function of both maternal and fetal risk factors and their interactions at the genetic and biomarker levels. Additional well-designed case-control studies that include both maternal and fetal genomes are warranted to more fully understand the roles of the SEPS1 G-105A polymorphism was associated with the risk of SPTB in a Chinese population. If confirmed by other studies, our findings of genetic factors contributing to the pathogenesis of SPTB may have implications for the screening and treatment of this disorder.In conclusion, we found that the