Subarachnoid hemorrhage (SAH) is a devastating cause of stroke, occurring in relatively young people. It has been suggested that some immune-mediated diseases may be associated with an increased risk of SAH.We analysed a database of linked statistical records of hospital admissions and death certificates for the whole of England (1999–2011). Rate ratios for SAH were determined, comparing immune-mediated disease cohorts with comparison cohorts.There were significantly elevated risks of SAH after hospital admission for the following individual immune-mediated diseases: Addison’s disease, ankylosing spondylitis, autoimmune haemolytic anaemia, Crohn’s disease, diabetes mellitus, idiopathic thrombocytopenia purpura, myxoedema, pernicious anaemia, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjogren’s syndrome, SLE and thyrotoxicosis. Elevated risks that were greater than 2-fold were found for Addison’s disease (rate ratio (RR) = 2.01, 95% confidence interval 1.3-2.97), idiopathic thrombocytopenia purpura , primary biliary cirrhosis  and SLE .Our findings strongly support the suggestion that patients with some immune-mediated diseases have an increased risk of SAH. Further studies of the mechanisms behind this association are warranted. Subarachnoid haemorrhage (SAH) accounts for approximately 5% of all strokes . BecauseEstablished personal risk factors for SAH include smoking, hypertension and excessive alcohol intake . Non-modTo investigate this further for SAH, we undertook a record linkage study to determine the risk of SAH in individuals with selected immune-mediated diseases using an English national linked Hospital Episode Statistics (HES) dataset.We used the complete dataset of English national Hospital Episode Statistics (HES) from January 1999 to December 2011, inclusive, covering the population of England of about 50 million people. The HES data were provided by the English national Health and Social Care Information Centre (IC). Data from death registrations, covering the same population and time period, were provided by the Office for National Statistics (ONS). The dataset used in this study, in which successive records for each individual were linked together using personal identifiers irreversibly encrypted by the IC and ONS, was constructed by the Oxford record linkage group (file version fce_14yr_v01_admiyear). Approval for the construction and analysis of the linked dataset was given by the Central and South Bristol Research Ethics Committee (ref 04/Q2006/176).The basic methods were the same for the analysis of each disease and are described for SLE and SAH. A cohort of people with a record of hospital day case care or inpatient admission for SLE was constructed for those with a principal diagnosis of SLE, as a reason for hospital care, by identifying the first episode of day case care, or inpatient admission, for the condition in an NHS hospital during the study period. The International Classification of Disease (ICD) codes used for each immune-mediated disease are given in Table People were included in the SLE or reference cohort if they did not have an admission for SAH either before or at the same time as the admission for SLE or the reference condition. We then searched the database for any subsequent NHS hospital care for, or death from, SAH in these cohorts. We considered that rates of SAH in the reference cohort would approximate those in the general population of England while allowing for migration in and out of it .SLE/ESLE) / (OREF/EREF). The rate ratio, its confidence interval, and χ2 statistics for its significance were calculated using standard statistical methods [We calculated rates of SAH based on person-days. We took “date of entry” into each cohort as the date of first admission for SLE, or reference condition, and “date of exit” as the date of first record of SAH, death, or the end of data collection (31st December 2011), whichever was the earliest. We first calculated rates for SAH, stratified and then standardised by age (in five-year age groups), sex, calendar year of first recorded admission, region of residence, and quintile of patients’ Index of Deprivation score (as a measure of socio-economic status) . We used methods . We haveTable There were significantly elevated risks of SAH after hospital admission for the following individual immune-mediated diseases: Addison’s disease, ankylosing spondylitis, autoimmune haemolytic anaemia, Crohn’s disease, diabetes mellitus, idiopathic thrombocytopenia purpura, myxoedema, pernicious anaemia, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjogren’s syndrome, SLE and thyrotoxicosis Table .Levels of risk that were two-fold or higher were found for Addison’s disease (rate ratio (RR) = 2.01, 95% confidence interval 1.3-2.97), idiopathic thrombocytopenia purpura , primary biliary cirrhosis  and SLE .We studied the occurrence of a first admission for SAH within a year of the first admission for each immune-related disease to help establish whether any elevated risk of SAH was confined to the short-term (and therefore possibly related to the event of admission with the immune-mediated disease) or was more prolonged, although this analysis reduced statistical power. Considering SAH that occurred within a year following the first recorded admission for immune-mediated disease, there were significantly elevated risks for Addison’s disease, ankylosing spondylitis, coeliac disease, diabetes mellitus, idiopathic thrombocytopenia purpura, myxoedema, pernicious anaemia, primary biliary cirrhosis, rheumatoid arthritis, systemic lupus erythematosus and thyrotoxicosis Table .Considering SAH that occurred at least a year after admission for immune-mediated disease, associations were similar as to those observed for the overall analysis Table , except Previous reports, combined with the results we present here, suggest that there may be an association between some immune-mediated diseases and the risk of subsequent SAH. Of note, both our study and the Swedish study of haemorrhagic stroke  found inLittle is known about the cause of intracranial aneurysms or the process by which they form, grow, and rupture. The most common histological finding following an aneurysm is a decrease in the tunica media of the involved vessel causing defects of the normal arterial structure. These defects, combined with haemodynamic factors, lead to aneurysmal outpouchings at arterial branch points in the subarachnoid space at the base of the brain . SpontanA key strength of the dataset is its size with large numbers of fairly uncommon diseases. The risk of SAH was studied within a single population, using the same methodology, which means that direct comparisons of risk between different immune-mediated diseases can be made. The dataset has limitations. The data is based on prevalent cases of immune disease – the first recorded hospital admission or episode of day case care for each person with each condition – rather than being a cohort with follow-up from the date of first diagnosis. The dataset is limited to people who were admitted to hospital, or who received day case specialist care. This would not capture all people with each immune-mediated disease, although it should identify the great majority with subsequent diagnosed SAH. We lack treatment and disability data for the immune-mediated diseases; and we lack data on potential confounding factors such as detailed socioeconomic characteristics, ethnicity, smoking, alcohol intake and blood pressure. The effect of making multiple comparisons needs to be considered. It is possible that some of the associations that are significant at levels close to p < 0.05 may result from making multiple comparisons and the play of chance. This may particularly be so where there is no prior hypothesis to support the finding. On the other hand, even in a study with the number of comparisons that we have made, findings where the significance level is <0.001 or less, are unlikely to be attributable to chance alone. We studied 27 different immune-mediated diseases. At a significance level of p = 0.05, by chance alone one might expect one or two significant results. We have reported significant results for 15 of the 27: these associations with SAH are not the play of chance but a rather general characteristic of immune-mediated diseases.Our findings and their interpretation should be regarded as speculative rather than definitive. The results represent what can be done using very large, linked, routinely collected administrative datasets; but such datasets lack detail. Alternative designs like epidemiological field studies - e.g. interviewing patients with SAH and controls about uncommon prior immune-mediated diseases, or following up cohorts of people with and without (say) SLE to identify later risk of SAH - would be substantial undertakings. Nonetheless, further work is needed, in different study designs, to confirm or refute the findings. Further studies should look at individual immune-mediated diseases in greater depth to aid understanding of mechanisms behind any association. This may be particularly warranted in people with diseases at relatively high risk of SAH, such as SLE.The authors declare no conflicts of interest.MJG is the guarantor of and designed the study. OS and RG led the analysis. SVR and MJG contributed to the analysis and interpretation of the data. JP and LG added to interpretation of the results and to the manuscript. SVR wrote the first draft and all authors contributed to subsequent drafts and the final paper. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/13/176/prepub


APEX1) Asp148Glu (rs1130409), Xeroderma Pigmentosum group D (XPD) Lys751Gln (rs13181), X-ray repair cross-complementing group 1 (XRCC) Arg399Gln (rs25487) and X-ray repair cross-complementing group 3 (XRCC3) Thr241Met (rs861539) polymorphisms with PE in a Mexican population. Samples of 202 cases and 350 controls were genotyped using RTPCR. Association analyses based on a χ2 test and binary logistic regression were performed to determine the odds ratio (OR) and a 95% confidence interval (95% CI) for each polymorphism. The allelic frequencies of APEX1 Asp148Glu polymorphism showed statistical significant differences between preeclamptic and normal women (p = 0.036). Although neither of the polymorphisms proved to be a risk factor for the disease, the APEX1 Asp148Glu polymorphism showed a tendency of association  and a significant trend (p for trend = 0.048). A subgroup analyses revealed differences in the allelic frequencies of APEX1 Asp148Glu polymorphism between women with mild preeclampsia and severe preeclampsia (p = 0.035). In conclusion, our results reveal no association between XPD Lys751Gln, XRCC Arg399Gln and XRCC3 Thr241Met polymorphisms and the risk of PE in a Mexican mestizo population; however, the results in the APEX1 Asp148Glu polymorphism suggest the need for future studies using a larger sample size.Variations in genes involved in DNA repair systems have been proposed as risk factors for the development of preeclampsia (PE). We conducted a case-control study to investigate the association of Human apurinic/apyrimidinic (AP) endonuclease ( It is a major cause of maternal death and is responsible for high rates of fetal morbidity and mortality [ >300 mg/4 h that 2−, hydroxyl radical, and hydrogen peroxide (H2O2)—all of which are capable of damaging nucleic acids, proteins, and lipids if levels of these ROS overwhelm the intracellular anti-oxidative defenses [Increasing evidence suggests that oxidative stress plays an important role in the pathogenesis of PE ,5. In hedefenses .Most damaged DNA can be removed and recovered through pathways carried by DNA repairing enzymes. The normal function of these enzymes is, therefore, important for the maintenance of genomic integrity . A varieAPEX1) gene is located at chromosome 14q11.2 and codifies one of the main enzymes in BER pathway, which accounts for nearly all of the abasic site cleavage activity observed in cellular extracts [APEX1 Asp148Glu (rs1130409) polymorphism have been reported to have higher sensitivity to ionizing radiation [Human apurinic/apyrimidinic (AP) endonuclease  gene, also called the xeroderma pigmentosum group D (XPD) gene, is located at chromosome 19q13.3. The XPD protein is essential in the NER pathway. This enzyme has a dual role: (i) uncoiling the double helix at the site of DNA lesions and (ii) transcription [XPD Lys751Gln (rs13181) has been associated with increased DNA adduct levels [The excision repair cross-complementing rodent repair deficiency, group 2 (t levels –22 and wt levels  and witht levels –26.XRCC) gene is located at 19q13.2 and produce multidomain protein that acts as a scaffolding intermediate by interacting with Ligase III, DNA polymerase-b and poly-ADPribose polymerase (PARP) [The X-ray repair cross-complementing group 1 (e (PARP) ,28. XRCCe (PARP) . Substite (PARP) ,31.XRCC3) gene is located at chromosome 19q13.3 and is a member of the RecA/Rad51-related protein complex responsible for the homologous recombinational repair (HRR) of double-strand DNA and is necessary for the stability of the genome [XRCC3 gene at codon 241, causing an amino acid change  [The X-ray repair cross-complementing group 3 (e genome –34. The s861539) . Carriers861539) ,36.APEX1 Asp148Glu, XPD Lys751Gln, XRCC1 Arg399Gln and XRCC3 Thr241Met polymorphisms and the risk of preeclampsia in a Mexican population.At date, very few studies analyze the possible association between this polymorphisms and risk of preeclampsia ,38. In t2.2.1.p < 0.001, A total of 202 cases and 350 controls were included in this study. Of 202 cases, 32 (15.84%), 142 (70.29%) and 28 (13.86%) presented mild PE, severe PE and eclampsia, respectively. APEX1 Asp148Glu, XPD Lys751Gln, XRCC1 Arg399Gln and XRCC3 Thr241Met polymorphisms are show in APEX1 Asp148Glu, XPD Lys751Gln and XRCC3 polymorphisms in our control group were consistent with our previous studies [APEX1 Asp148Glu showed statistical significant differences between groups (p = 0.036). However, these differences were not observed in the genotypic frequencies (p = 0.143). No differences in allelic or genotypic frequencies between cases and controls were observed in any of the others polymorphisms tested (p > 0.05).Allelic and genotypic frequencies of APEX1 Asp148Glu, XPD Lys751Gln, XRCC1 Arg399Gln and XRCC3 Thr241Met polymorphisms between women with severe preeclampsia and mild preeclampsia  revealed no differences in genotypic frequencies of clampsia . RegardiAPEX1 Asp148Glu polymorphism showed a tendency of association . Furthermore, a significant trend was observed (p for trend = 0.048).The risk of preeclampsia by the presence of these polymorphisms was determined. A logistic regression model adjusted for age was used and the results of 2.2.et al. [vs. gestational age matched normotensive controls.One of the main features of preeclampsia is an inadequate trophoblast cell invasion that leads to an incomplete remodeling of the spiral artery, reduction in utero-placental perfusion, and a state of placental ischemia. A factor known to be increased in response to placental ischemia is the production of ROS. When ROS production exceeds the capacity of detoxification, they can cause oxidative damage to DNA . The bioet al.  demonstrDNA repair mechanisms are in place to protect against such damage and imply a role for DNA repair genes in the response of the placenta to ischemia. Oxidative DNA damage is repaired by both BER and NER mechanisms . TherefoGSTT1 null polymorphism might be associated with preeclampsia and that this risk increases with the combination of both GSTT1 and GSTM1 null polymorphisms [The majority of work has focused on evaluate genes involved in antioxidant defense systems rather than DNA repair systems. While some studies suggest the association between polymorphisms of genes involved in antioxidant systems and preeclampsia , others orphisms .et al. [APEX1, XRCC1 and XPD in a Turkish population. Although they report that none of the studied polymorphisms has been associated with the risk of PE, they suggest that their results need to be taken as preliminaries due to relatively small sample size. Furthermore, Saadat et al. [XRCC1 and XRCC7 and risk of PE in an Iranian population. They analyze 151 patients with preeclampsia and their results suggest that the 399Gln allele of the XRCC1 is a significant risk factor for PE development.On the other hand, to date, very few studies evaluate the relationship between polymorphisms in DNA repair genes and the risk of PE. Vural et al.  evaluatet et al.  investigAPEX1 Asp148Glu, XPD Lys751Gln, XRCC1 Arg399Gln and XRCC3 Thr241Met polymorphisms and the risk of PE in a Mexican population. Although our results showed no association between APEX1 Asp148Glu and PE like previously reported by Vural et al. [p for trend = 0.048). These results, together with the statistical significant difference observed in the allelic frequency of this polymorphism between women with mild preeclampsia and severe preeclampsia (p = 0.035), suggest a need for future studies with a larger sample to elucidate the role of this polymorphism in the PE in our population.In this study, we analyze the relation between l et al. , our datet al. [et al. [XRCC1 Arg399Gln polymorphism. With respect to the XPD Lys751Gln polymorphism our results are in agreement with Vural et al. [XRCC3 Thr241Met polymorphism and the risk to PE; the results of this study are the first to suggest no association.Our results in the other polymorphisms suggest no association with the risk of the PE. These results are in disagreement with Saadat et al. , but are [et al. , in the l et al. . FinallyThe limitations of our study include the lack of oxidative damage measurements in blood samples or placenta that might suggest a possible association between the levels of DNA damage, the genotypes analyzed and PE. Furthermore, our study had limited statistical power because of the low frequency of some of the variants genotypes.3.3.1.This case-control study was conducted between March 2011 and September 2013. The study was approved by the Ethics Investigation Committee in the Hospital General of the Health Secretary of Durango, Mexico, in accordance with the Code of Ethics of the Declaration of Helsinki. Signed informed consent was obtained from all patients and controls before participation in the study. We recruited 202 women diagnosed with preeclampsia (cases) and 350 normoevolutive pregnant women (controls). The inclusion criteria were all those women diagnosed with mild PE (blood pressure (BP) ≥ 140/90 mm Hg and proteinuria ≥ 30 mg/dL), severe PE (BP ≥ 160/110 mm Hg and proteinuria ≥ 2000 mg/dL) and eclampsia . Control group was conformed by healthy pregnant women attending at the same hospital; without hypertensive, pathological or metabolic disorders during pregnancy. The control group was followed to corroborate the normality of the blood pressure values.3.2.Genomic DNA from each individual was obtained from blood samples obtained by venous puncture using the QIAamp DNA Blood extraction kit . The concentration and quality were analyzed in a NanoDrop 2000 . The single nucleotide polymorphisms were analyzed using a 48-well plate StepOne Real Time PCR system . A typical RT-PCR reaction contained 10 ng of genomic DNA, 0.625 μL of 40X Taqman SNP genotyping assay and 5.0 μL of Taqman genotyping Master Mix . The predesigned assays were C___8921503_10, C___3145033_10, C____622564_10 and C___8901525_10 . The amplification conditions were initial denaturation at 95 °C for 10 min, 92 °C during 15 s, and 60 °C for 90 s (42 cycles) with one additional cycle at 60 °C during 30 s. Samples were processed by duplicate.3.3.t-test. The allele and genotype frequencies were calculated by direct counting. Deviation from the Hardy-Weinberg equilibrium (HWE) constant was tested using a χ2 test with 1 degree of freedom. The differences of distributions of the polymorphisms were performed by χ2 analysis using SPSS software ; p < 0.05 was considered statistically significant. Odds ratio was calculated from allelic and genotype frequencies with 95% confidence intervals (95% CI) using the SNPstats software program .The clinical characteristics were expressed as mean and were compared by using the Student’s 4.XPD Lys751Gln, XRCC Arg399Gln and XRCC3 Thr241Met polymorphisms and the risk of PE, the results in the APEX1 Asp148Glu polymorphism suggest the needed of future studies using a larger sample size. Furthermore, studies in other regions from Mexico also are needed to confirm our findings. Silva-Zolezzi et al. [Although our results suggest that there is no an association between i et al.  describe


In the environmental sensitivity-related illnesses (SRIs), multiple chemical sensitivity (MCS), chronic fatigue syndrome (FCS), and fibromyalgia (FM), the search for genetic polymorphisms of phase I/II xenobiotic-metabolizing enzymes as suitable diagnostic biomarkers produced so far inconclusive results, due to patient heterogeneity, geographic/ethnic differences in genetic backgrounds, and different methodological approaches. Here, we compared the frequency of gene polymorphisms of selected cytochrome P450 (CYP) metabolizing enzymes and, for the first time, the frequency of the xenobiotic sensor Aryl hydrocarbon receptor (AHR) in the three cohorts of 156 diagnosed MCS, 94 suspected MCS, and 80 FM/FCS patients versus 113 healthy controls. We found significantly higher frequency of polymorphisms CYP2C9∗2, CYP2C9∗3, CYP2C19∗2, CYP2D6∗4 and CYP2D6∗41 in patients compared with controls. This confirms that these genetic variants represent a genetic risk factor for SRI. Moreover, the compound heterozygosity for CYP2C9∗2 and ∗3 variants was useful to discriminate between either MCS or FM/CFS versus SMCS, while the PM ∗41/∗41 genotype discriminated between MCS and either SMCS or FM/CFS. The compound heterozygosity for CYP2C9 ∗1/∗3 and CYP2D6 ∗1/∗4 differentiated MCS and SMCS cases from FM/CFS ones. Interestingly, despite the distribution of the AHR Arg554Lys variant did not result significantly different between SRI cases and controls, it resulted useful for the discrimination between MCS and SMCS cases when considered within haplotypes in combination with CYP2C19 ∗1/∗2 and CYP2D6 ∗1/∗4. Results allowed us to propose the genotyping for these specific CYP variants, together with the AHR Arg554Lys variant, as reliable, cost-effective genetic parameters to be included in the still undefined biomarkers' panel for laboratory diagnosis of the main types of environmental-borne SRI. In the last years, much attention has been paid to a variety of pathological conditions sharing the common feature of an aberrant response triggered by airborne or other routes of exposure to low doses of environmental pollutants or xenobiotics, such as chemicals, drugs, heavy metals, electromagnetic, or nuclear radiations, in concentrations far below average reference levels admitted for environmental toxicants –4. Indeein-utero sensitization [SRI symptoms appear mainly in adult life, with higher prevalence in women, although a growing number of pediatric cases have been recently registered, and evidence is accumulating for a role of tization , 9. For tization , 11, eittization ; (ii) thtization –18.To date, the diagnosis of MCS is based on the compliance to Cullen's inclusion anamnestic criteria  and on tThe classification as “idiopathic” for these environmental intolerances arises from the poor current knowledge of their etiology and pathogenesis and the absence of recognized genetic and metabolic markers . HoweverLeading studies on chemically hypersensitive individuals in European and North American populations have been so far focused on single-nucleotide polymorphisms (SNPs) in genes coding for a variety of phase I and phase II metabolizing enzymes and their receptors , 27–32. Moreover, the identification of genetic markers specific for different SRI would be extremely useful for a better diagnosis assessment of MCS, FM, CFS and other idiopathic environmental intolerances. this work was aimed at assessing the distribution of some selected gene polymorphisms in representative groups of Italian hypersensitive individuals fully or partially diagnosed with MCS, or affected by its more common comorbidities, FM or FCS, as compared with sex- and age-matched healthy controls.In these groups, we analyzed the frequency of some well-known polymorphic variants of cytochrome P450 (CYPs) enzymes, namely, , commonly investigated in different clinical conditions including MCS , 33, 34.Because of their critical role in the xenobiotic-induced toxicity, the potentially wide array of altered gene polymorphisms of the complex drug-metabolizing network in individuals affected by environmental intolerances so far not conclusively demonstrated in spite of rather extensive investigations, still remains of utmost interest for patient management and possibly also for therapeutic approaches.Patients of case cohorts were selected on the basis of their diagnosis made according to Cullen's criteria  and QEESOne hundred and fifty-six Italian consecutive MCS patients , 94 consecutive SMCS patients , partly corresponding to the diagnostic criteria reported above, and 80 consecutive patients  presenting either fibromyalgia or chronic fatigue syndrome (FM/CFS group), were enrolled for this study by specialized clinicians, who performed anamnestic and lifestyle data collection, at Istituto Dermopatico dell'Immacolata, IRCCS, according to a study protocol approved by IDI Ethical Committee (no. 121/CE/2008).μL, as determined by luminol-dependent chemiluminescent response to phorbol 12-myristate 13-acetate (PMA) [One hundred and thirteen healthy Italian subjects  matched for sex and age with patient group were selected as controls (Ctr) at Istituto Dermopatico dell'Immacolata (IDI IRCCS) and Messina University according to the established criteria of (i) an absence of any clinically diagnosed disease, in particular allergic or immunologic disturbances, and (ii) no drug or nutraceutical supplement since at least six weeks at the time of blood sampling, (iii) whole blood total production of reactive oxygen and nitrogen species (ROS/RNS) below 650 cps/te (PMA)   according to the manufacturer's instructions. DNA was quantified spectrophotometrically at 260 nm, aliquoted, and stored at −20°C until assayed.Genomic DNA was purified from 400 Genotyping of SRI patients and control subjects for eight single nucleotide polymorphisms in drug metabolism- and inflammation-related genes was carried out by real-time PCR allelic discrimination using predesigned TaqMan SNP genotyping assays available from Applied Biosystems . The polymorphisms analyzed were those of genes coding for: cytochrome P450 (CYP), family 2, subfamily C, polypeptide 9 and 19, namely, CYP2C9*2 , CYP2C9*3 , and CYP2C19*2 ; CYP2 subfamily D, polypeptide 6, namely, CYP2D6*4  and CYP2D6*41 ; and aryl hydrocarbon receptor (AHR) Arg554Lys variant .μL containing 1x TaqMan Genotyping Master Mix, 1x TaqMan-specific assay, and 10 ng genomic DNA, using thermal cycling conditions suggested by manufacturer's protocols.Genotyping reactions were set up in a 96-well plate on a 7900HT Fast Real-Time PCR System , and were carried out in a final volume of 20 P ≤ 0.05 were considered as significant.Allele and genotype frequencies obtained on patients' and control groups were compared by Fisher test analysis. Software employed was GraphPad Prism 4 . Values of The main categories of co-morbidities resulting from anamnestic analysis are compared in MCS and SMCS patients and reported in Genotype and allele frequencies of selected polymorphisms in drug metabolism-related genes examined in SRI patients  and controls are shown in The analysis of the distribution of CYP2C9 gene variants showed that the allele CYP2C9*2 was more present than the CYP2C9*3 both in MCS as well as in SMCS patients and in healthy subjects but not in FM/CFS group. However, both mutated alleles were more frequent in cases than in controls as the prevalence of CYP2C9*2 was around 1.5-fold higher in patients than in controls and that of CYP2C9*3 was 7-fold, 11-fold, and 21-fold higher in MCS, SMCS, and FM/CFS patients, respectively, than in controls . HoweverThe calculation of odds ratio (ORs) showed that the presence of genotype Ht *1/*2 increases 2.4-fold the risk for developing MCS, while having the genotype Ht *1/*3 causes a 7.5-, 12-, and 26-fold increase of the risk for developing MCS, SMCS, and FM/CFS, respectively.Genotyping for the CYP2C19 gene variants showed that the frequency of the mutated *2 allele was significantly higher in MCS cases than in all other groups. Interestingly, the lowest frequency for this allele was observed in SMCS cases; moreover, healthy subjects and FM/CFS patients had a similar *2 allele frequency . The CYPOR calculation showed that a mutated CYP2C19* background was associated with a threefold increased risk for developing MCS.The analysis of genetic background at the CYP2D6 gene locus showed that the CYP2D6*4 was the most represented gene variant in all subgroups of SRI cases compared with the CYP2D6*41; moreover, this latter variant was absent in the control population.The comparison of allele frequencies showed that CYP2D6*4 allele had a highly significant, different frequency among all cases compared with controls, being two-threefold higher in patients than in healthy subjects. The CYP2D6*41 allele, that was absent in control population, had the highest frequency in FM/CFS group.P = 0.06) in comparison with controls.Both CYP2D6*4 and CYP2D6*41 alleles were largely represented by heterozygous individuals but displayed a different variability among the sampled subgroups. The CYP2D6 *1/*4 heterozygous genotype was more frequent in MCS cases than in either SMCS or FM/CFS patients and controls. However, the frequencies of Ht *1/*4 genotype in all three patient groups resulted significantly higher than in healthy subjects. Poor metabolizers, homozygotes *4/*4 were more frequent in the FM/CFS patients than in all other groups , showingThe CYP2D6 *1/*41 heterozygous genotype had a higher frequency in MCS group than in the other patients, having a similar distribution, and was absent in the control population, reaching a statistically significant difference. Poor metabolizers, compound heterozygotes *4/*41, and homozygotes *41/*41 were more frequent in FM/CFS patients than in SMCS as well as MCS cases, these latter lacking of the PM *41/*41 genotype, and both were absent in the control population .The calculation of odds ratio indicated that a genetic background positive for the presence of genotype CYP2D6 Ht *1/*4 increased three-fold and two-fold the risk for developing MCS and either SMCS or FM/CFS, respectively, while the same risk was 52-fold, 38-fold, and 36-fold increased by the presence of CYP2D6 Ht *1/*41.Genotyping for the Arg554Lys variant of AHR gene showed for the first time that the Lys-mutated variant was less frequent in MCS and SMCS cases, displaying similar distributions, than in FM/CFS patients and controls, and was entirely represented by the heterozygous genotype in all subgroups of cases, while the control population included both heterozygotes and homozygotes. Moreover, the frequency of heterozygotes was higher in the FM/CFS patients than in MCS, SMCS, and control groups, all showing similar frequencies . HoweverThe analysis of the distribution of two or more combined mutant alleles, that is, the frequency of given haplotypes in the various sampled population, is reported in P < 0.001).The most frequent haplotype in MCS cases was the CYP2C19 Ht *1/*2 - CYP2D6 Ht *1/*4- AHR Arg554Lys (9.1%), that was not present neither in SMCS cases nor in other patients (P < 0.05).In the SMCS cases the most represented haplotype was the CYP2C9 Ht *1/*2-CYP2D6 Ht *1/*4, that was absent in the group of other patients and had a significantly lower frequency in MCS (P < 0.01). Moreover, the haplotype CYP2C9 Ht *1/*3 - CYP2D6 Ht *1/*4 was only represented in MCS cases and SMCS, while the haplotype CYP2C9 Ht *1/*3- CYP2D6 Ht *1/*4 was only present in MCS cases. On the contrary, the combination of four mutated alleles either in heterozygosis or homozygosis was only observed in the subgroup of FM/CFS patients.In the subgroup of FM/CFS patients the most frequent haplotype was the CYP2C19 Ht *1/*2 - CYP2D6 Ht *1/*4, that showed a significantly higher distribution compared with SMCS cases , glutathione-S-transferases (GSTs), UDP-glucuronosyl transferases (UGTs), catechol-O-methyltransferases (COMTs), N-acetyl transferases (NATs), paraoxonase 1 and 2 , methylenetetrahydrofolate reductase (MTHFR), and of cholecystokinin 2 receptor (CCKR2) , 27–32, Results, as a whole, have not been encouraging, given that the complexity and high costs of the investigations in that contrasting results were reported by different groups and the differences in genotype distribution between cases and controls were often not reaching statistical significance. However, a reliable between-groups comparison of outcomes from these studies was hard, due to the lack of homogeneity with regard to sample size, gender, and ethno-geographical features, of case/control populations examined. Furthermore, in general, positive findings from genetic association studies seem to be difficult to replicate and possibly inflated by chance .Another critical issue is the heterogeneity of SRI, most of which exhibit overlapping symptoms with other common pathological conditions. Indeed, a diagnostic panel including defined criteria for diagnosis assessment, would be very important for etiological studies. Even though the MCS case definitions and the grading of chemical sensitivity in general populations used in the previous studies cited appear to be very similar, the underlying classification differences cannot be ruled out as they contribute to the inconsistency among published studies. In this regard, all patients included in our study have been diagnosed consecutively according to Cullen's criteria and adapted QEESI questionnaire scoring , 20, 25,Importantly, an additional critical issue is the use of genotyping techniques having 100% sensitivity and specificity for the detection of heterozygous genotypes, the most common form by which a mutant allele is present in a given population. In this regard, most of the published genetic investigations on MCS patient, including our previous report on 110 Italian subjects , employeHere, we investigated the distribution of some gene variants of clinically relevant drug metabolism-related proteins, that is, selected CYP enzyme isoforms, namely, CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2D6*4, and CYP2D6*41 already addressed in previous studies producing conflicting data. We reported here for the first time that the examined variants of CYP isoforms have a significantly different distribution in SRI patients versus controls. Most importantly, some of these variants may be useful for an objectively based discrimination between different types of SRI, given the observed significant differences after between-groups comparison of allele and genotype frequencies. In particular, allele and heterozygous genotype frequencies observed in all subgroups of SRI patients for the variant CYP2C9*3 showed significant or even highly significant differences with those observed in healthy subjects. These differences allowed us to propose the presence of the genetic variant CYP2C9*3 as a candidate marker of disease state with specific reference to SRI, as also confirmed by calculation of disease risk by Odds Ratio (OR), that was increased in a range from 7- to 26-fold for MCS, SMCS, and FM/CFS conditions, respectively. In particular, highly discriminant between pathological condition and healthy state was the presence of the homozygous genotype PM *3/*3 and the compound heterozygous one PM *2/*3 that was not recorded in control subjects. Moreover, the presence of the heterozygous genotype Ht *1/*3 may be useful for discrimination between MCS and FM/CFS patients, as the difference in genotype frequencies are highly significant.The examination of genetic background for CYP2C9*2 showed that the allele *2 frequency may discriminate MCS patients and SMCS patients from FM/CFS ones and that the frequency of genotype Ht*1/*2 differentiates MCS patients from controls. As a whole, the search for this CYP2C9 variant may be quite useful in population-based studies for the classification of different SRI.Similar results were obtained after comparison of allele and genotype frequencies for CYP2D6 variants in patients and controls, even though variable significance level for differences wre found. Both allele and heterozygous genotype frequencies for CYP2D6*4 and *41 resulted useful for discriminating between intolerance syndromes and healthy state. In particular, a genetic background positive for the presence of either genotype CYP2D6 Ht *1/*4 or Ht *1/*41 increased up to 3-fold and 50-fold the risk for developing SRI see . NotablyInterestingly, the analysis of allele and genotype distribution for the CYP2C19 variants showed that the examination of genetic background for this CYP isoform may be highly useful to diagnose MCS patients compared with healthy subjects, since individuals carrier of the heterozygous genotype CYP2C19 Ht *1/*2 has a threefold increased risk of developing MCS. Most importantly, the presence of genotype Ht *1/*2 is highly discriminant between MCS and either SMCS or FM/CFS patients.Allele and genotype distribution for different CYP2C9 and CYP2D6 variants as well as for the CYP2C19 variant in MCS patients and healthy subjects recruited for this study resulted different, though not statistically significant from previously reported frequencies in Italian MCS patients by our group  and fromFinally, some gene variants, both single or combined together, may be useful for the discrimination between different types of SRI or for the confirmation of clinically suspected MCS cases. In particular, the compound heterozygosity for CYP2C9 *2 and *3 variants may discriminate between the MCS and “other patients” groups versus SMCS, and the PM *41/*41 genotype may discriminate between MCS versus SMCS as well as versus patients with other pathologies. The compound heterozygosity for CYP2C9 Ht *1/*3 and CYP2D6 Ht *1/*4 may discriminate MCS cases as well as SMCS versus patients with other pathologies.As a new direction of investigation, we here inquired if a described gene polymorphism of the transcription factor AHR - AHR Arg554Lys may be present with significant frequencies in a population of patients affected by specific SRI categories, fully diagnosed MCS, suspected MCS, and the FM/CFS group, in comparison with healthy individuals. Interestingly, although the distribution of the AHR Arg554Lys gene variant did not result significantly different between SRI cases and controls , it provIn conclusion, on the basis of these observations, we propose the genotyping for CYP2C9*2 and *3, CYP2C19*2, and CYP2D6 *4 and *41 variants, together with the AHR Arg554Lys variant to be included in the panel of diagnostic biomarkers under construction aimed at the laboratory diagnosis of SRI and at the discrimination of the different specific conditions grouped under the collective definitions of “environmental-borne sensitivity-related illnesses,” more largely known as “idiopathic environmental intolerances”.A further step of our study design will be the correlation between a given genotype and the corresponding biochemical profile as described by De Luca et al. , both to


The progesterone receptor (PgR), a sex steroid hormone receptor that binds progesterone is critical for normal breast development. The PgR  promoter polymorphism is associated with cancer risk possibly by altering the expression of progesterone receptor B isoform. Previous studies have provided inconsistent results. To validate the association between the PgR +331G/A polymorphism and female reproductive cancer risk , we performed a meta-analysis of 19 studies  by using the CMA Version 2 software. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. The overall results indicated that the variant allele and genotypes were associated with a mild increase in overall female reproductive cancer risk . The results suggest that the PgR +331G/A polymorphism might be associated with an increased female reproductive cancer risk. It is now well established that cancer is a multifactorial disease with an orchestrated relationship between genetic and environmental factors In vitro over-expression of GATA-5 with hPgR luciferase construct showed greater transcriptional activity with +331AA than with +331GG included in the luciferase construct thereby contributing to breast tumorigenesis The progesterone receptor (PgR) is a member of a large ligand-activated nuclear receptor family characterised by a central DNA binding domain, a carboxyl-terminal ligand binding domain and multiple activation (AF) and inhibitory (IF) functional elements. The PgR, which is located on chromosome 11q22, and the oestrogen receptor (ER) have diverse reproductive functions associated with the establishment and maintenance of pregnancy, alveolar development and mammary epithelial development Recently, many studies have investigated the role of the PgR +331G/A polymorphism in the etiology of various types of cancer, i.e., breast, ovary and endometrial cancer. However, the results of these studies remain inconclusive. To clarify the role of +331G/A PgR polymorphism in female reproductive cancers, we performed a meta-analysis of all of the eligible case-control studies to derive overall cancer risk associated this polymorphism .Recent publications were identified through a literature search using the keywords “Progesterone receptor polymorphism,” “PgR polymorphism” or “PR polymorphism”, and “+331G>A”, or “+331G/A” and “cancer” in Pubmed and cross-references were checked that were not available in Pubmed or Science Direct (published before July 2012). Only those articles written in English were selected for the study. The following criteria were used for inclusion of identified articles for our meta-analysis: (a) evaluation of +331 G/A and cancer risk, (b) case-control study or cohort design and (c) studies that contained available genotype frequencies. The major reason of exclusion of some investigations was the absence of usable data reported in those studies. Finally, the data were extracted from 19 case-control studies totalling to 19,978 cases and 24,525 controls for +331G/A PgR polymorphism.Two investigators (SC and DRM) independently extracted all of the data and jointly reached the consensus for all of the articles that were included in the study. Disagreement between the authors was resolved after discussion amongst the authors. The following information was sought from each article: first author's name, year of publication, source of control, country, ethnicity and numbers of cases and controls, genotype frequencies and allele frequencies for each case and control.http://www.meta-analysis.com/pages/comparisons.html). The strength of the association between the PgR +331G/A polymorphism and risk of cancer was measured by odd ratios (ORs) with 95% confidence intervals (CIs). We examined the association between the allele A of the PgR +331G/A polymorphism and cancer risk, and made comparisons with the dominant genetic model (AA+AG vs. GG). A recessive genetic model was not performed as the data were not available for the homozygous mutant (AA) in the studied cases. The heterogeneity assumption was evaluated with an I2-based Cochran's Q statistic test. A significant p value (<0.10) was used to indicate heterogeneity among studies, and the combined OR was calculated by using a random effect model 2 statistic was used to quantify inter-study variability. This statistic ranged from 0 to 100%, where a value of 0% indicated no observed heterogeneity, and as the values increased the degree of heterogeneity increased  The statistical analysis for the current meta-analysis study was performed by using the comprehensive meta-analysis (CMA) V2 software . Meta-analysis is a powerful tool which combines results of independent similar studies and derive a definitive conclusion For the association between PgR +331G/A polymorphism and cancer susceptibility, articles were retrieved based on the established search criteria. Nineteen studies met the inclusion criteria, the characteristics of which are reported in Begg's Funnel plot and Egger's test was conducted to assess whether there was any publication bias in the studies included in our meta-analysis. The shape of the funnel did not elucidate any obvious asymmetry in all of the comparison models. Thereafter, Egger's test was used to provide statistical evidence of the funnel plot symmetry and did not show any publication bias .2 statistics were used to test for heterogeneity among the studies. No heterogeneity was observed in either allele (A vs. G) as well as the dominant genotype model for overall cancer, which was included for the analysis .Q-test and IOur meta-analysis identified an evident mild association between PgR (+331G/A) polymorphism and an increased cancer risk. Compared with the wild-type G allele, the overall variant A allele was associated with a mild increased cancer risk  . In addiGenetic epidemiological studies have suggested the relationship between different SNPs and disease. However, robust statistical powers with genotype-phenotype investigation are essential to detect the mild, moderate or strong association with the disease. The progesterone hormone mediates its physiological function through the PgR, a steroid receptor of class I nuclear receptor super-family. Two different isoforms of PgR (PgRA and PgRB), which are transcribed from two different promoters of the same gene In previous published pooled studies, Yang and colleagues have reported an association between PgR +331 G/A variant and breast cancer risk A genome-wide association studies (GWAS) have been carried out for various cancers  and several susceptible alleles have been identified −/− mice (deficient in PgRA) with E2 and progesterone resulted in a progesterone-dependent cell proliferation, which was not detected in E2 and progesterone–treated wild-type or PRAKO mice, suggesting that PgRB has a role in uterine endometrium proliferation. Furthermore, the PgRB isoform could also elicit normal proliferation and differentiation as observed in PRAKO−/− mammary epithelium through progesterone. During endometriosis, only the PgRA isoform is expressed and the absence of PgRB is suggested due to the inappropriate cycling of the endometrial gland The progesterone hormone exerts its physiologic effect exclusively through the presence of the PgR as shown in mouse models Although earlier reports on the association of PgR (+331G/A) polymorphism and cancer are inconsistent, the current meta-analysis has provided a definitive conclusion. Inconsistencies among the CG association studies could be attributed to small sample sizes, improper clinical categorisation and the inclusion of different ethnicities.A mild association between PgR +331G/A polymorphism and female reproductive cancer risk was detected. As the eligible case-control studies cannot provide a casual relationship, large and well-designed genotype-phenotype studies on different cancer are necessary to derive a definitive role of this SNP with cancer.Checklist S1PRISMA 2009 checklist.(DOC)Click here for additional data file.


Background. Bisphenol A (BPA) is detected in the urine of >95% of US adults. Recent evidence from population-based studies suggests that BPA is associated with individual components for metabolic syndrome (MetS). However, no previous study has examined the direct association between BPA and MetS. Methods. We examined 2,104 participants from the National Health and Nutrition Examination Survey 2003–2008. The main outcome was the presence of MetS (n = 741). Results. Increasing levels of urinary BPA were positively associated with MetS, independent of confounders such as age, gender, race/ethnicity, smoking, alcohol intake, physical activity, and urinary creatinine. Compared to tertile 1 (referent), the multivariable adjusted odds ratio  of MetS in tertile 3 was 1.51 (1.07–2.12); P-trend was 0.02. Conclusions. Urinary BPA levels are positively associated with MetS, in a representative sample of US adults and independent of traditional risk factors for MetS. Future, prospective studies are needed to confirm our findings. According to national biomonitoring surveys conducted by the Centers for Disease Control and Prevention, the plasticizer, bisphenol A (BPA), is present in the urine of more than 95% of US adults , 2. BPA The current study is based on data from NHANES 2003–2008 –14. In bN = 5,231). We further excluded subjects with missing data on waist circumference, fasting serum glucose, serum triglycerides, serum high-density lipoprotein (HDL) for the definition of MetS, and other covariates used in our multivariable models. The final sample for the analysis comprised of 2,104 participants (51.0% women), of which 741 had MetS. Subjects who were excluded due to missing covariates were in general similar to the final study sample in terms of age, sex, race/ethnicity, smoking status, alcohol intake, and moderate physical activity (see the Appendix).The current study sample consisted of participants aged ≥18 years among whom urinary BPA was available  guidelines  and inclUrinary BPA was categorized into tertiles . We hypothesized that high BPA levels are associated with MetS. The odds ratio [(OR) ] of MetS for BPA was calculated by taking the lowest tertile (tertile1) as the referent, using multivariable logistic regression models. We used two models: the age and sex-adjusted model and the multivariable model, additionally adjusting for race/ethnicity, annual household income, smoking status, alcohol intake, moderate physical activity, and urinary creatinine (mg/dL). Trends in the OR of MetS across increasing urinary BPA categories were determined by modeling BPA as an ordinal variable. Sample weights that account for the unequal probabilities of selection, oversampling, and nonresponse were applied for all analyses using SAS  and SUDAAN software; standard errors (SEs) were estimated using the Taylor series linearization method.P values for trend were also significant (P-trend = 0.02). In In a representative sample of US adults, we found that increasing levels of urinary BPA were positively associated with MetS. The observed association was found to be independent of confounding factors such as age, gender, race/ethnicity, smoking, alcohol intake, moderate physical activity levels, and urinary creatinine. To our knowledge, our study is the first report on a positive association between BPA and MetS in humans.BPA is a constituent monomer in polycarbonate plastics, used extensively in the manufacture of several consumer grade products including food packaging, bottled water and the lining of canned foods . Recent Several lines of recent evidence suggest that our findings of an association between BPA and MS are plausible. Previous studies based on animal models provide evidence towards both the endocrine disrupting and estrogen-like effects of BPA and suggest that BPA exposure is related to increased insulin resistance  and, theThe main strengths of our study include its nationally representative sample, use of rigorous study methods to collect the data, and the availability of extensive data on confounders –14. The Previous studies have suggested the inclusion of several additional markers associated with insulin resistance and increased cardiovascular risk, such as hyperuricemia , nonalcoIn conclusion, we found that in a nationally representative sample of US adults, higher exposure to BPA was positively associated with MetS independent of confounding factors such as age, gender, race/ethnicity, smoking, alcohol, moderate physical activity and urinary creatinine. If confirmed in future prospective studies, reducing environmental exposure to BPA may potentially have a role in the prevention of MetS.


The objective here was to summarize the evidence for, and quantify the link between, serum markers of lipid metabolism and risk of obesity-related cancers. PubMed and Embase were searched using predefined inclusion criteria to conduct meta-analyses on the association between serum levels of TG, TC, HDL, ApoA-I, and risk of 11 obesity-related cancers. Pooled relative risks (RRs) and 95% confidence intervals were estimated using random-effects analyses. 28 studies were included. Associations between abnormal lipid components and risk of obesity-related cancers when using clinical cutpoints  were apparent in all models. RRs were 1.18 (95% CI: 1.08–1.29) for TC, 1.20 (1.07–1.35) for TG, 1.15 (1.01–1.32) for HDL, and 1.42 (1.17–1.74) for ApoA-I. High levels of TC and TG, as well as low levels of HDL and ApoA-I, were consistently associated with increased risk of obesity-related cancers. The modest RRs suggest serum lipids to be associated with the risk of cancer, but indicate it is likely that other markers of the metabolism and/or lifestyle factors may also be involved. Future intervention studies involving lifestyle modification would provide insight into the potential biological role of lipid metabolism in tumorigenesis. Obesity is a major worldwide problem, over 30% of adults in Western populations are obese, and there is growing evidence of the associated health risks associated –5. The lThe underlying mechanisms of action are not clear , 18–20. With these meta-analyses, we aimed to summarize and quantify the evidence for the link between markers of lipid metabolism and risk of obesity-related cancers. We examined the associations between four components of the lipid profile measured in serum , triglycerides (TGs), high-density lipoprotein (HDL), and apolipoprotein A-I (ApoA)) and risk of cancers previously shown to be linked with obesity.We used computerised literature search databases (PubMed search followed by an Embase search) to identify full text and abstracts published to date. Searches were conducted both with and without MeSH terms . Except for English language, human subjects, adults, and publications within the last 10 years no additional restrictions were added to the search. We also included “grey literature,” such as letters and abstracts presented in relevant conference meetings. All references of the selected articles were checked, including hand searches.The final collection of selected studies was chosen based on the following criteria: the publication pertained to an epidemiological study (cohort or case-control studies), which measured the serum concentration of at least one of the selected lipid components  prior to cancer diagnosis; the analytical methods were well described, with sufficient data available; the cancers included must have previously been linked to an increased risk associated with obesity. Those included were colorectal, breast, prostate, endometrial, pancreatic, liver, ovarian, kidney, gallbladder, leukaemia, and oesophageal cancer . To inclThe following details were recorded for each study: author, year of publication, country where the study was undertaken, serum lipid component levels (mmol/l), study type (case-control or cohort), cancer type, number of cases and total subjects for each level of the lipid component(s) measured. To allow for ease of comparison, all values in conventional units (mg/dL) were converted into SI units (mmol/l) using conversion factors .Q-statistic as well as the I2 statistic [The effect of each lipid component on cancer risk was evaluated by calculating the random effects summary relative risk to allow for possible heterogeneity between study results. The analyses were conducted for dichotomized values of TC, TGs, HDL, and apoA-I). The following clinical cutpoints were used TC ≥ 6.50; TG ≥ 1.71; HDL ≤ 1.03; ApoA-I ≤ 1.05 mmol/L, all of which mirrored the NCEP and WHO guidelines as closely as practicable –39. Sometatistic . Sufficin = 10), while a further three were excluded because serum lipid components were not the exposure of interest, and three were removed because incident cancer risk was not the outcome variable in the analysis.The initial searches produced a total of 701 articles. 33 studies were selected for further evaluation based on information from abstracts. Of these, 17 were excluded and a further 12 were added from hand searches and references of included studies, giving a total of 28 studies used in the primary data analysis. Eight studies were conducted in Asia, 12 in Europe, and eight in the USA . All stuQ-statistic and I2-statistic suggested heterogeneity , which warranted the use of a random-effects model. The association between TGs and overall cancer risk resulted in a pooled relative risk of 1.20 (95% CI 1.07–1.35). The pooled relative risk was 1.15 (95% CI 1.01–1.32) when studying the association between HDL and risk of obesity-related cancers. The pooled effects relative risk of overall cancer was 1.42 (95% CI 1.17–1.74) for ApoA-I  . The Q-sr ApoA-I .P value of 0.193 when studying TC). Begg's test did not indicate significant publication bias (P = 0.506), which is evident from the funnel plot, as there is a relatively symmetric distribution observed among studies with small sample size  = 0.98 (0.81–1.18)) and (RR (95% CI) = 1.20 (1.04–1.38) for case-control and cohort studies on TC, resp.). We investigated this further with a metaregression, but did not find a statistically significant effect , whereas it was 1.08 (95% CI: 0.89–1.31) and 1.20 (95% CI: 0.44–3.26) for breast and colorectal cancers, respectively.These meta-analyses summarize the current evidence for a link between serum markers of lipid metabolism and risk of obesity-related cancers. All pooled models showed evidence for an association between abnormal lipid components and risk of obesity-related cancers when using clinical cutpoints. de novo, is involved in tumorigenesis [α (TNF-α) which consequently reduces tissue damage, infiltration of macrophages and neutrophils, and attenuates tumour formation [The precise aetiology of the link between obesity and risk of cancer has yet to be determined, but there has been growing evidence for a role of lipid metabolism in tumour development . Apart figenesis –47. For igenesis . In addiigenesis , 49. Furigenesis , 51. Finigenesis . These lormation . TherefoRecent years have seen a multitude of reviews and meta-analyses comparing obesity and specific cancer risks; results varied widely depending on the type of cancer investigated, with relative risks ranging from 1.02 to 4.10 . Additionally, our clearly defined objective criteria for exposure, outcome, and other study characteristics were specified a priori. There was no evidence of publication bias in these analyses.A number of the studies subdivided levels of lipid components, but this was not performed consistently across the studies. Studies which had not dichotomised serum lipid levels from the outset were divided into two groups based on their serum lipid level (“high” and “low”) to mirror the NCEP and WHO guidelines as closely as practicable , 62. ThiHeterogeneity among studies may also arise from different method of assessment of serum lipids. By performing random-effects analyses, we have taken into account between-study variation. Within-person variation is a likely interference with results as the one measurement taken may not be representative for a person's average, or previous lipid levels. However, this variation will be present in all studies using a single measurement. In addition, adjustments made for confounding factors  were not consistent across included studies and some sample sizes were relatively small or excluded one gender. Again, random effects analyses take into account this heterogeneity and in addition we included a metaregression analysis for study type. In addition, the studies did not provide age-specific data, so it was not possible to conduct age-specific meta-analyses which presents us with a limitation. Persons younger than middle aged more rarely have abnormal lipid profiles and are also considerably less likely to be diagnosed with the cancers of interest than in those people aged over 50. Thus, this leaves our study population with a relatively low probability of having both sufficient exposure and number of cases in the lower age range. We do not believe that this will have had a major effect on our results, although it is worth considering that this may have diluted the strength of our findings somewhat. Due to the information provided in the included studies, we had no means to adjust our analyses for cancer screening practices. Undoubtedly, these practices vary around the world and thus the differences could lead to the introduction of detection bias. Finally, the analyses of the three individual cancers  did not produce statistically significant relative risks, which most likely follows from a lack of power due to the limited number of studies available for inclusion. Future research, with larger sample sizes, repeated measurements, and consistent adjustments for confounding could provide information to inform a more reliable estimate of links between serum lipid components and cancer risk. Abnormal levels of all lipid components studied were statistically significantly associated with an increased risk of obesity-related cancers, with the strongest association for serum ApoA-I. Despite a suggestion for a link between the lipid metabolism and risk of cancer, the magnitude of the pooled relative risk was relatively small. This may be because the studied lipid components are markers of obesity or because they are markers of other lifestyle factors potentially associated with tumorigenesis. Since lipid components are easily modified through lifestyle interventions such as diet or exercise, research into serum lipid components and cancer risk presents a prime opportunity for intervention studies to help provide the desired insight into their biological role.


Postural balance is vital for safely carrying out many daily activities, such as locomotion. The purpose of this study was to determine how changes in normal standing (NS) and standing with toe-extension (SWT) impact postural control during quiet standing. Furthermore, the research aimed to examine the extent to which the effect of these factors differed between genders.F2, 28 = 3.357, p = 0.077). The main difference between the stability index scores was significant . The Bonferroni post-hoc test showed significant differences between the OSI and MLSI (p<0.001); the OSI and APSI (p<0.001); and the MLSI and the APSI (p<0.001). Significant differences were found during NS (p<0.001), for the MLSI when compared with the APSI, but this was not found during the SWT condition. Additionally, no gender effects were proven to exist that altered postural sway during quiet standing.Thirty healthy young adults  with no prior lower limb injuries participated in the study. A postural stability test using the Biodex Balance System was used for both NS and SWT conditions. The three measurements from the BBS were Overall Stability Index (OSI), Medial-Lateral Stability Index (MLSI) and Anterior-Posterior Stability Index (APSI). No significant difference was found between NS and SWT in the OSI, MLSI or APSI (This study reveals significant interaction between the stability indices measured; OSI, APSI and MLSI in both NS and SWT. Standing with toe extended does not have a significant impact on an individual’s ability to control their balance during normal quiet standing. However, the findings revealed that the sway tendency in the medial-lateral direction might serve as a factor in an individual’s ability to regain balance. Since balance is a vital prerequisite component of life for all human beings, balance control has been examined extensively in a number of studies. All movements that are performed under static or dynamic conditions are necessary to maintaining a good quality of life and hence it is important that individuals can achieve body equilibrium and maintain stability during quiet standing and ambulatory activities.Quiet standing is a complex task that involves the integration of multiple body segments, joints and sensory systems in order to regulate balance while attempting to stay upright in a static position without moving. Current statistics show that there are approximately 13,042,000 fatal falls throughout the population of the United states in year 2010 and a lack of balance control against perturbation is believed to be one of the biggest contributors to such accident In general, the somatosensory, vestibular and visual systems are believed to be the key physiological inputs of balance control Numerous studies have investigated the important role that the function of the foot plays in standing; heel-toe standing, heel-standing and full toe-standing In recent studies, the Biodex Balance System SD  has been more frequently used as a tool for balance assessment than the formally-popular force platform. The BBS is a multiaxial device that evaluates and measures the CoP for up to 20° of platform tilt in a 360° range of motion. BSS can compute three measures: the Overall Stability Index (OSI), Medial-Lateral Stability Index (MLSI) and Anterior-Posterior Stability Index (APSI). These variables were used in this study to measure and evaluate balance performance. The purpose of this study was to determine how changes in normal standing (NS) and standing with toe-extension (SWT) conditions impact postural control. Furthermore, the study sought to examine the extent to which these impacts differ according to gender. The researchers hypothesized that the standing postures of NS and SWT would not impact the postural sway in terms of the OSI, APSI or MLSI.The study protocol was reviewed and approved by the Medical Ethic Committee in University of Malaya Medical Centre. All participants gave their written informed consent to participate in the study.Thirty healthy young adults  with no prior lower-limb injuries were recruited for this study. None of the participants had experienced previous balance training using BBS, or had suffered from any neurological, vestibular or balance impairments. The research incorporated a crossover study design, where all participants underwent the same test protocols. In order to certify the health condition of the participants with regards to their daily routines and lifestyle, a basic lifestyle survey was undertaken before the study began. Participants who engaged in an active lifestyle and who generally wore flat shoes were selected for this study.The BBS used in this study contained four strain gauges under a circular platform in order to measure the displacement of CoP at a sampling rate of 20 Hz. For the OSI, MLSI and APSI stability scores, these indices were the measures of standard deviation, which were assessed along the path of sway around the zero point from the center of the platform of BBS. The units were recorded in degrees. The foot displacements that occurred on the medial-lateral (ML) axis were labeled as “x-direction”, while those on the anterior-posterior (AP) axis were labeled as “y-direction,” and these variables were measured as the MLSI and APSI respectively. In turn, the OSI, which is sensitive to the change in body sway across the ML and AP axes, was derived from the MLSI and APSI. The formulas for OSI, MLSI and APSI are shown below:Arnold and Schmitz In the current study, the BBS was used to evaluate the static postural control during (i) normal standing (NS) , and ii. For theAll statistical analysis was performed using SPSS for Windows . A 2×3×2 (standing posture × stability index × gender) mixed factor repeated measures analysis of variance (ANOVA) was used for the purposes of the analysis. There was no interaction of gender and stability index so the groups were collapsed for gender. A 2-way interaction was seen for standing posture and stability index. The Shapiro-Wilk Test was used to assess the normality of the data. The test of normality verified that all the data produced was normally distributed. The data was normalized with respect to body mass and relative stability was used in the data analysis in order to avoid a potential misinterpretation of data and to reduce the absolute stability differences F2, 28 = 3.357, p = 0.077). The main effect of balance was significant . The Bonferroni post hoc test showed significant differences between the OSI with MLSI (p<0.001), the OSI with APSI (p<0.001) and the MLSI with APSI (p<0.001). The standing posture × stability index interaction was significant .The descriptive statistical analysis on the demographic characteristics for all participants is tabulated in p<0.001), while differences were shown between the OSI and APSI, and the OSI and MLSI in SWT (p<0.001). The mean of the relative stability index for both NS and SWT conditions are displayed in With the available number of participants in this study, the within condition analysis revealed significant differences between the OSI with APSI, the OSI with MLSI, and the APSI with MLSI in NS . Meanwhile, for the female group (N = 15), the results exhibited similar findings (main effect p<0.001). No differences were observed between the NS and SWT conditions between the male and female groups. Additionally, no participant grasped the holding rails to regain balance during the tests.Females displayed a greater sway than males across all the conditions, although no significant differences was observed between the OSI, MLSI and APSI scores. When comparing the data of NS and SWT conditions within the male group (N = 15), significant differences were found between the OSI with APSI, the OSI with MLSI, and the APSI with MLSI , the current study showed that gender does not influence human balance in the NS and SWT conditions, since no differences in the stability scores were found between the male and female participants. This is in contrast with previous studies, which reported that males had a greater postural sway than females during quiet standing In spite of being closely matched for age  from one specific geographical area and, as such, the data is limited.In conclusion, this study has demonstrated that differences between the NS and SWT conditions do not lead to differences in postural control. However, a small alteration in postural control during SWT shows a trend of greater amount of postural sway than NS, although this is not significantly different. The findings also revealed the interactive effect of postural control in term of the OSI, MLSI and APSI. Gender does not appear to effect static postural stability.


Objective. Parkinson's disease (PD) is a severe neurological disease and its risk factors remain largely unknown. A meta-analysis was carried out to investigate the relationship of overweight and obesity with PD. Methods. We used PubMed, EMBASE, and the Chinese National Knowledge Infrastructure (CNKI) databases to identify studies of associations between overweight/obesity and PD. Overweight, obesity, and PD were used as keywords, and published works were retrieved until September 30, 2013. The extracted data were classified  according to BMI values and analyzed using RevMan5.2 and Stata11.0. Results. Four cohort studies and three case-control studies were used to evaluate the association between overweight/obesity and PD, including 2857 PD patients and 5, 683, 939 cases of non-PD controls. There was a statistically significant difference between 25 ≤ BMI < 30  and BMI < 25 in the cohort study , but there was no difference between BMI ≥ 30  and BMI < 25 or BMI ≥ 30  and 25 ≤ BMI < 30, where the respective RR was 1.16 and 0.84; the respective 95% CI was 0.67–2.01 and 0.61–1.15, respectively, and the P values were 0.60 and 0.28, respectively. Case-control studies showed that there was no statistical difference between any two groups. Conclusion. Meta-analysis showed that overweight might be a potential risk factor of PD. Demonstration of a causal role of overweight/obesity in PD development could have important therapeutic implications. Parkinson's disease (PD) is a severe neurodegenerative disease that results from massive death of dopaminergic neurons in the substantia nigra. However, key pathogenic factors or the pathogenesis of PD remains largely obscure. Previous studies have shown that risk factors such as age, oxidative stress, mitochondrial dysfunction, environmental toxins, nerve inflammation, and genetic factors might be associated with risk of developing PD. In addition, factors that affect an individual's general body shape, such as exercise and diet, also impact on PD. Logroscino had previously shown that a high-fat diet, especially one with increased intake of animal fat, is a risk factor for PD pathogenesis . De Lau Globally, there are more than 300 million adults who are obese and 1 billion who are overweight . Obesity and overweight pose a major risk for developing serious chronic diseases , includi2 receptor availability in the striatum [Some studies showed that dopamine, a major neurotransmitter in PD, plays important roles in the regulation of food intake , 10. Patstriatum . Obese pstriatum , 15, andstriatum . Althougstriatum , 18, somstriatum , 20. ThuWe identified all studies that assessed an association between overweight/obesity and the risk of PD in humans. We developed a search engine that was adapted for PubMed, EMBASE, and the China National Knowledge Infrastructure (CNKI) up until September 30, 2013. This was done using the following search terms: “overweight” or “obesity” or “obese” or “adiposity” or “body mass index” (BMI) and “Parkinson disease,” without any language or publication year restrictions. If more than one article was published using the same case series, only the study with the largest sample size was selected. In addition, we examined the reference lists of relevant original papers and review articles. in vitro studies or other studies that included gene polymorphisms, news stories, commentaries, and letters to the editor.We included all studies on a case-control or a cohort study of PD, or we examined the association between BMI  and PD. We excluded papers without original data, animal data, orWith the purpose of extracting the necessary characteristics, all relevant articles were collated independently by two reviewers (Jinhu Chen and Yanqin Wang). Both reviewers checked for any encountered discrepancies and reached a consensus. For each selected publication, we focused on the key study characteristics, including publication year, country of origin of where the study was done, the study design, and participant characteristics and demographic information  of both PD patients and control subjects.RR values or OR values and the 95% CI, from which we constructed the forest map. We used the I2 statistic to investigate the heterogeneity among studies. If there was a statistical difference in terms of heterogeneity (P ≤ 0.10), a random-effects model was selected to pool the data. Otherwise, a fixed-effects model was used. Publication bias was evaluated using the funnel plot and the Egger test. Fail-safe numbers were calculated to estimate the stability of the results, α = 0.05.All analyses were performed using Review Manager (version 5.1.2) and STATA (version 11.0) software programs. We organized the data, established the database, and verified the collated data according to the requirements of the meta-analysis. Then we calculated the combined effects of the A total of seven references that matched the research criteria of the study design were adopted. Among them, three were case-control studies (including 685 PD patients and 686 controls) and four studies were cohort studies (including 2172 PD patients and 5683253 non-PD observation objects). The related literature was published from 2004 to June 2013, including 2857 PD patients and 5683939 non-PD observation objects. The basic characteristics of the study are shown in I2 values were 87%, 77%, 92%, 90%, and 76%, resp., and P values were =0.0005, <0.01, <0.00001, <0.00001, and =0.006, resp.). A random-effects model was applied for these groups. The combined effects OR with a 95% CI were, respectively, (A1) 0.73 , (A3) 0.81 , and the combined effects RR with a 95% CI were, respectively, (B1) 1.16 , (B2) 1.39 , and (B3) 0.84 . There was no heterogeneity observed within studies of groups A2 . The combined effects OR were 0.91 . Overall, there was a statistical difference found between 25 ≤ BMI < 30 and BMI > 25 in the B2 cohort study group. The remainder of the cohort study groups did not display any statistically significant difference . In this study, we focused on the relationship between overweight/obesity and the risk of PD. The reason for this difference remains unknown, and a potential mechanism might involve obese patients who receive better quality medical treatment, and thus further investigation is warranted.Bousquet et al.  found thThe present meta-analysis has several limitations. First, the limited number of studies has caused our inability to eliminate the heterogeneity and perform stratified analysis. However, the outcomes of this study demonstrate that we have paid poor attention to this line of investigation. Clearly, it is very important that more research is done in the area of PD, their related conditions, and the incidence and impact of obesity/overweight, particularly with a larger study population size. Second, the fail-safe number also suggested that results from A2 were unstable. However, this data does not affect our conclusions made from the cohort study. Moreover, to eliminate the influence of confounding factors on the results of this study, BMI, gender, and other impacting factors should be considered in multicentered and demographically stratified analyses.In summary, cohort studies have shown that overweight could be considered a potential risk for PD. We should strengthen relationship studies aimed at furthering our understanding of overweight, obesity, and PD, pay particular attention to the role that is played by body weight in the onset of PD, and thereby strengthen prevention management strategies in the future.


Several genome-wide association studies on lung cancer (LC) have reported similar findings of a new susceptibility locus, 3q28. After that, a number of studies reported that the rs10937405, and rs4488809 polymorphism in chromosome 3q28 has been implicated in LC risk. However, the studies have yielded contradictory results.PubMed, ISI web of science, EMBASE and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. Data were abstracted independently by two reviewers. A meta-analysis was performed to examine the association between rs10937405, rs4488809 polymorphism at 3q28 and susceptibility to LC. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Heterogeneity and publication bias were also tested.−5) and 1.19  was found for the rs10937405 and rs4488809 polymorphism respectively. Similar results were also observed using dominant or recessive genetic model. After stratified by ethnicity, significant associations were found among East Asians ; whereas no significant associations were found among Caucasians for rs10937405. In the sub-group analysis by sample size, significantly increased risks were found for these polymorphisms in all genetic models. When analyzed according to histological type, the effects of rs10937405, and rs4488809 at 3q28 on the risk of lung cancer were significant mostly for lung adenocarcinoma.A total of 9 studies including 35,961 LC cases and 57,790 controls were involved in this meta-analysis. An overall random-effects per-allele OR of1.19 (95% CI: 1.14–1.25; P<10Our findings demonstrated that rs10937405-G allele and rs4488809-G allele might be risk-conferring factors for the development of lung cancer, especially for East Asian populations. Lung cancer (LC) is the most common malignancy and the leading cause of cancer death worldwide, with an estimated 5-year survival rate of 15% Recently, spectacular advance was made in identifying susceptible genes involved in LC through genome-wide association strategy (GWAS). Genomic regions at chromosomes 15q25.1  Genetic association studies published before the end of October 2013 on LC and polymorphisms within chromosome 3q28 were identified through a search of PubMed, Web of Science, EMBASE, and CNKI  without language restriction. Search term combinations were keywords relating to the chromosome 3q28  in combination with words related to LC . In addition, studies were identified by a manual search of the reference lists of reviews and retrieved studies. All studies were carefully evaluated to identify duplicate data. Criteria used to determine duplicate data included study period, hospital, treatment information and any additional inclusion criteria.To include relevant studies in this meta-analysis, the following criteria were used: (1) case-control or cohort studies, (2) assessing the association between 3q28 polymorphisms and LC risk, (3) identification of LC cases was confirmed histologically or pathologically, and (4) providing sufficient data to calculate the odds ratio (OR) with its 95 confidence interval (CI) and P-value. The major reasons for exclusion of studies were (1) overlapping data, (2) case-only studies, (3) family-based studies and review articles. If more than one article using the same data was published, only the study with the largest dataset was included into the meta-analysis.Two investigators extracted information from all eligible publications independently according to the inclusion criteria listed above. For conflicting evaluation, an agreement was reached following discussion among all authors. For each study, the following characteristics were collected: first author’s name, year of publication, ethnicity, identification of cancer cases, histological type, age, sex, smoking status (never smokers or ever smokers), source of control groups , matching factors, Hardy-Weinberg equilibrium (HWE) status among controls, number of cases and controls, genotype frequency and genotyping methods. For studies including subjects of different ethnic groups, data were extracted separately and categorized as East Asians and Caucasians.For association studies with inconsistent results on the same polymorphisms, the methodological quality should be assessed by appropriate criteria to limit the risk of introducing bias into meta-analyses or systematic reviews. A procedure known as ‘extended-quality score’, has been developed to assess the quality of association studies. The procedure scores each paper categorizing it as having ‘high’, ‘median’ or ‘poor’ quality. Detailed procedure of the quality assessment was previously described 2 tests. OR with 95% CIs was used to assess the strength of association between the 3q28 polymorphisms  and LC risk. The per-allele OR of the risk allele was estimated. Then we estimated the risks of these polymorphisms on LC under dominant and recessive genetic models. Random-effects and fixed-effect summary measures were calculated as inverse-variance-weighted average of the log odds ratio. The results of random-effects summary were reported in the text because it takes into account the variation between studies. Heterogeneity across individual studies was calculated using the Cochran χ2 based Q test and I2 test followed by subsidiary analysis or by random-effects regression models with restricted maximum likelihood estimation 2 values <25% correspond to no or little heterogeneity, values 25–50% correspond to moderate heterogeneity, and values >50% correspond to strong heterogeneity between studies. Sources of heterogeneity were investigated by stratified meta-analyses based on ethnicity, and sample size (No. cases ≥1000 or <1000). Ethnic group was defined as East Asians , and Caucasians (i.e. people of European origin). In addition, ethnicity, sample size, age, sex and genotyping method was analyzed as covariates in meta-regression. The significance of the pooled OR was determined by Z test. Publication bias was assessed with the Egger test and Begg test Deviation from HWE for controls was examined by χBased on our search strategy, the primary screening produced 97 potentially relevant articles. 88 articles were excluded because they clearly did not meet the inclusion criteria or overlapping references. A total of 9 eligible studies −5, P(Q)<10−5; −5, P(Q)<10−4] and 1.25 , respectively. After adjusting for multiple testing using Bonferroni correction, all significant associations for rs10937405 under various genetic models remained. Significant heterogeneity was present among the 23 data sets (P<0.05). In meta-regression analysis, age (P = 0.26), sex (P = 0.11), sample size (P = 0.06), and genotyping method (P = 0.78), did not significantly explained such heterogeneity. By contrast, ethnicity (P = 0.001) was significantly correlated with the magnitude of the genetic effect.Overall, there was evidence of an association between increased risk of LC and the rs10937405 polymorphism in different genetic models when all the eligible studies were pooled into the meta-analysis. Using random effect model, the summary per-allele OR of the rs10937405 G variant for LC was 1.19  and for large studies of 1.16 . However, no significant results were detected in the Caucasian populations . Subsidiary analyses of sample size yielded a per-allele OR for small studies of 1.27  and squamous cell carcinoma , while no significant associations were detected for small cell carcinoma <10arcinoma . We invearcinoma .−5; −5). Significantly increased LC risks were also found using dominant  and recessive model . Since all included studies concerning rs4488809 polymorphism were conducted in East Asian populations, we then conducted subgroup analysis by sample size. In the stratified analysis by sample size, significant risks were found among larger studies in all genetic models  without significant between-study heterogeneity . Similar significant associations were also observed among small studies using dominant and recessive genetic models <10arcinoma . Associaarcinoma .In meta-regression, sample size (P = 0.02) explained a large part of the heterogeneity, whereas sex distribution (P = 0.29), mean age (P = 0.14), and genotyping method (P = 0.31) explained little heterogeneity.A single study involved in the meta-analysis was deleted each time to reflect the influence of the individual data-set to the pooled ORs, and the corresponding pooled ORs were not qualitatively altered  and S3. GWAS have led to the identification of multiple new genetic variants associated with lung cancer risk. Most of these lung cancer GWAS and replication studies have been conducted in European populations In the stratified analysis by ethnicity, significant associations were found in East Asians for rs10937405 polymorphism in all genetic models; while no associations were found in Caucasians, suggesting a possible role of ethnic differences in genetic backgrounds and the environment they lived in When analyzed according to histological type, the effects of rs10937405, and rs4488809 at 3q28 on the risk of lung cancer were significant mostly for adenocarcinoma. However, adenocarcinoma accounts for about 50% of all histological types of lung cancer While it will be challenging to identify the precise mechanism by which 3q28 variation affects lung cancer development, accumulation of DNA damage and lack of response to genotoxic stress is recognized to contribute to lung carcinogenesis. TP63  is a member of the tumor suppressor P53 gene family, which is pivotal to cellular differentiation and responsiveness to cellular stress The strengths of this study include the very large sample size, no deviation from HWE, and the high quality of the qualified studies. However, our current study should be interpreted with several technical limitations in mind. Firstly, the vast majority of white subjects in the study are of East Asian descent, and statistical power for analyses in other ethnicities is limited. Because the sample size was relatively smaller for Caucasian studies, the main conclusions from this manuscript are based on analyses among white East Asian populations. Future studies including larger numbers of Caucasian or African are necessary to clarify the consistency of findings across ethnic groups. Secondly, our results were based on unadjusted estimates, while a more precise analysis should be conducted if individual data were available, which would allow for the adjustment by other covariates including age, family history, environmental factors and lifestyle. Thirdly, the subgroup meta-analyses considering associations between the two polymorphisms and smoking behavior, sex, as well as between various histologic type of lung cancer were performed on the basis of a fraction of all the possible data to be pooled, so selection bias may have occurred and our results may be overinflated. Nevertheless, the total number of subjects included in this part of the analysis comprises the largest sample size so far.Despite these limitations, our meta-analysis showed that rs10937405, and rs4488809 polymorphism at 3q28 might be risk-conferring factor for the development of lung cancer, especially for East Asian populations. Larger studies of different ethnic populations, especially with detailed individual information, are needed to confirm our findings. Since it is unlikely that genetic variation alone will explain the lung cancer burden, further research is needed to identify environmental exposures and gene–environment interactions in these populations. Further, the functional genetic variants and mechanisms underpinning this association will require additional studies.Figure S1Study selection process.(TIF)Click here for additional data file.Figure S2Result of sensitivity analyses for 3q28-rs10937405 polymorphism and LC risk.(TIF)Click here for additional data file.Figure S3Result of sensitivity analyses for 3q28-rs4488809 polymorphism and LC risk.(TIF)Click here for additional data file.Figure S4Begg’s funnel plot of 3q28-rs10937405 polymorphism and lung cancer risk.(TIF)Click here for additional data file.Figure S5Begg’s funnel plot of 3q28-rs4488809 polymorphism and lung cancer.(TIF)Click here for additional data file.Checklist S1(DOC)Click here for additional data file.