Individual variations in gastric cancer risk have been associated in the last decade with specific variant alleles of different genes that are present in a significant proportion of the population. Polymorphisms may modify the effects of environmental exposures, and these gene-environment interactions could partly explain the high variation of gastric cancer incidence around the world. The aim of this report is to carry out a systematic review of the published meta-analyses of studies investigating the association between gene polymorphisms and gastric cancer risk, and describe their impact at population level. Priorities on the design of further primary studies are then provided.A structured bibliographic search on Medline and EMBASE databases has been performed to identify meta-analyses on genetic susceptibility to gastric cancer, without restriction criteria. We report the main results of the meta-analyses and we describe the subgroup analyses performed, focusing on the detection of statistical heterogeneity. We investigated publication bias by pooling the primary studies included in the meta-analyses, and we computed the population attributable risk (PAR) for each polymorphism.IL-1β, IL-1RN, IL-8), detoxification of carcinogens , folate metabolism (MTHFR), intercellular adhesion (E-cadherin) and cell cycle regulation (p53). According to their random-Odds Ratios, individuals carrying one of the IL-1RN *2, IL-1β -511T variant alleles or homozygotes for MTHFR 677T are significantly at higher risk of gastric cancer than those with the wild type homozygote genotypes, showing high PARs. The main sources of heterogeneity in the meta-analyses were ethnicity, quality of the primary study, and selected environmental co-exposures. Effect modification by Helicobacter pylori infection for subjects carrying the unfavourable variant of IL-1 polymorphisms and by low folate intake for individuals homozygotes for MTHFR 677T allele has been reported, while genes involved in the detoxification of carcinogens show synergistic interactions. Publication bias was observed .Twelve meta-analyses and one pooled-analysis of community based genetic association studies were included, focusing on nine genes involved in inflammation (per se. Nevertheless, the risk increase by interacting with environmental exposures and in combination with additional unfavourable polymorphisms. Unfortunately meta-analyses are underpowered for many subgroup analyses, so additional primary studies performed on larger population and collecting data on environmental and genetic co-exposures are demanded.The published meta-analyses included in our systematic review focused on polymorphisms having a small effect in increasing gastric cancer risk  Helicobacter pylori infection, tobacco smoking, low fruit and vegetable intake, high meat and salt intake, and the lack of food refrigeration have been shown to be the major non-genetic determinants  , using tet al. . StatistIL-1A, IL-1B, IL-1RN, IL-8), detoxification of carcinogens , folate metabolism (MTHFR), intercellular adhesion (E-cadherin) and cell cycle regulation (p53) pyrene-7,8-diol epoxide, the activated form of benzo[α]pyrene, and smaller reactive hydrocarbons, such as ethylene oxide and diepoxybutane [Glutathione S-tranferase (GST) is a family of genes, mainly involved in cell protection against electrophiles, including several environmental carcinogens, as well as endogenous products of oxidative stress . These pficities ,62. GSTMxybutane ,63, whicxybutane .GSTM1) is mainly expressed in liver, brain and stomach. The GSTM1 null genotype is found in 10-60% of individuals ranging from 50% in Caucasians and Asians to 25% in Africans [GSTM1 null genotype and gastric cancer was firstly investigated by Strange et al. in 1991 [1. Glutathione S transferase M1 (Africans . The ass in 1991 . Two metGSTM1 status and gastric cancer included 15 primary studies in English language and was published in 2005 [p for heterogeneity <0.01) . The heterogeneity slightly decreased after stratifying by ethnicity , source of controls  and study power  (Table 1). Caucasians showed a significantly increased risk  while studies with at least 80% power provided the lowest estimate . As for gene-environmental analysis, the meta-analysis showed an OR of 2.93  for ever-smokers with GSTM1 null compared to never-smokers with GSTM1 wild type genotype . Data on other types of interacting carcinogens, such as Helicobacter pylori infection and dietary compounds, were not available to perform any subgroup meta-analyses.The first meta-analysis evaluating the association between  in 2005 . The metGSTT1) is mainly expressed along the human gastrointestinal tract. The null genotype of GSTT1 is present in 13-31% among Caucasians and 36-55% among Asians. The association between GSTT1 null genotype and gastric cancer was firstly investigated by Deakin et al. in 1996 [1) [p for heterogeneity > 0.05) for the association between GSTT1 null genotype and gastric cancer. The meta-analysis of Boccia et al. [p for heterogeneity = 0.48). According to Saadat [et al. (p for heterogeneity = 0.87) [Glutathione S transferase T1 ( in 1996 . Two met1996 [1) ,28. The 1996 [1)  includedo Saadat , among tet al. [p for heterogeneity = 0.41). As for gene-environment interaction analysis, Saadat [p>005) for GSTT1 null individuals compared to those with the normal genotype ever smokers. The identical subgroup analysis was performed by Boccia et al. [ p for heterogeneity = 0. 03) [GSTT1 and GSTM1 genotypes were combined in the two meta-analyses, using as reference group those carrying both homozygous wild genotypes. Saadat [GSTM1 and GSTT1 null genotypes if compared to those with both wild-type variant . A similar result  was shown by Boccia et al. [GSTT1 and GSTM1 genotypes, taking into account the effects of each of the functional polymorphisms on gastric cancer risk [Helicobacter pylori infection and food consumption, in a way that was not enough to perform any subgroup meta-analyses.Both meta-analyses reported the absence of statistically significant association after restricting the analysis to the source of control or studies’ power, however Boccia et al.  showed a, Saadat  reporteda et al. , with th= 0. 03) . As for . Saadat  extractea et al. , by poolcer risk . Only feMTHFR is expressed ubiquitously and two functional polymorphisms, C677T and A1298C, have been identified [MTFR 677 have significantly lower plasma folate levels than those with the wild-type genotype, while for the MTFR 1298 variant the evidence is inconsistent [Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolic pathway that irreversibly catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the primary circulating form of folate and a cosubstrate for homocysteine methylation to methionine. Folic acid, a form of the water-soluble Vitamin B9, is a precursor of the metabolic pathway leading to DNA methylation which functions as a regulatory mechanism of gene expression. In addition folate plays an important role in transferring single-carbon methyl units during the synthesis of DNA and RNA and it is also involved in DNA repair. Folate intake is provided by diet and serum folate levels could be impaired by alcohol drinking, smoking habits and altered activity of several enzymes, such as MTHFR, serine hydroxymethyltransferase, thymidylate synthase and methionine synthase -69. MTHFentified . Frequenentified ,71. Indinsistent . Low folnsistent .MTHFR polymorphisms and gastric cancer was firstly investigated by Shen et al. in 2001 [MTHFR polymorphisms and gastric cancer [et al. [MTHFR 677TT genotype showed a higher risk of gastric cardia adenocarcinoma  and gastric cancer  compared with those wild-type homozygotes [p for heterogeneity = 0.29 and 0.12, respectively). The meta-analysis published by Zintzaras [p for heterogeneity = 0.66). Stratification by gastric cancer site failed to decrease heterogeneity, while for East Asian studies a very low heterogeneity was observed (p for heterogeneity = 0.96 in the recessive model). The meta-analysis by Boccia et al. [p for heterogeneity = 0.37) for gastric cancer and MTHFR TT genotype compared to the 677 CC. The subgroup analysis are reported on Table 1. Since no data for interaction analyses were available to perform subgroup meta-analyses according to folate, alcohol and smoking, a pooled-analysis was carried out by Boccia et al. [C677T and A1298C, respectively. Overall, the pooled analysis showed that MTHFR 677 TT individuals have an OR of 1.49  for gastric cancer, thus confirming previous meta-analyses based on an unadjusted estimates. Sensitivity analyses based on ethnicity and gastric cancer site provided similar results, with a lower heterogeneity among East Asians (p for heterogeneity = 0.34). When results from the pooled analysis of four studies on C677T were stratified according to folate levels, results showed an increased risk among individuals with low levels  respect to those with high folate levels . No interaction was detected from the stratified analyses according to alcohol and smoking habits, with decreased heterogeneity only in the unexposed subgroups .The association between  in 2001 . In the c cancer ,24,25. Aa et al.  which ina et al. . Data onet al. (7 studies) (Table 1) [et al. [MTHFR A1298C polymorphism and gastric cancer even when restricting the analysis to studies conducted among East-Asians or studies whose controls were in Hardy-Weinberg equilibrium. Absence of statistically significant association of 1298C variant allele and gastric cancer was reported in all genetic models, from Zintzaras   and BoccTable 1) . The sub [et al.  provided [et al.  showed ap53 tumor suppressor gene is one of the most commonly mutated genes in all types of human cancer and encodes a transcription factor involved in cell cycle regulation. The p53 acts as a tumor suppressor gene by inducing cell cycle arrest or apoptosis and requires loss of function mutations for cancer development. Even if p53 gene is highly polymorphic, with at least 13 single nucleotide polymorphisms described [p53 exon4 Arg72Pro polymorphism is the only whose role has been extensively studied in relation to gastric cancer. A polymorphism in this codon, which consists in a single base pair change of either arginine (Arg) or proline (Pro), has been suggested to modulate p53-dependent apoptosis and modify sensitivity to chemotherapeutic agents [p53 gene in gastric cancer were firstly investigated by Shepherd et al. in 2000 [p for heterogeneity = 0.0001) as follows: 64% of whites had the Arg/Arg genotype compared with 24% of blacks [The escribed , the p53c agents ,77. The p53 codon 72 polymorphism and gastric cancer was firstly investigated by Hiyama et al. in 2002 [p53 exon4 Arg72Pro polymorphism and gastric cancer including 12 case-control studies has been recently published  [p for heterogeneity = 0.01). Heterogeneity was tested by subgroup analyses on ethnicity, tumour location, stage, Lauren’s classification and histological type. A significantly lower frequency of the Arg/Arg genotype in gastric cancer cases compared with controls was reported among Asians , while not among Caucasians. Considering cases-only analyses performed on Asiatic case-control studies, a significantly higher frequency of variant homozygous genotype was found for gastric cardia cancer with respect to other locations , and for advanced stages (III/IV) respect to those with early stages (I/II) . Data on other potential carcinogens such Helicobacter pylori infection and diet were insufficient to perform any subgroup meta-analyses.The association between  in 2002 . A meta-E-cadherin gene encodes a transmembrane glycoprotein, mainly involved in the establishment and maintanance of intercellular adhesion, cell polarity and the normal architecture of epithelial tissues [et al. [E-cadherin gene promoter, showing that the A allele decreased the transcriptional efficiency by 68% if compared to the wild-type C allele, probably due to a stronger transcriptional factor binding activity of the C allele than the variant allele A. Therefore the -160 C/A polymorphism might alter E-cadherin expression, increasing susceptibility to epithelial cancers. The frequency of the mutant allele -160A varied significantly among different ethnic groups and geographic areas, ranging from 43.4-23.3% of Europeans and 0-61% in Asians [The  tissues  as well  tissues . E-cadhe tissues . The los tissues . Li et a [et al.  identifin Asians . E-cadherin polymorphism and gastric cancer was firstly investigated by Wu et al. in 2002 [E-cadherin polymorphism and gastric cancer [1). The combined OR was not significant for the -160A allele carriers compared with the homozygous wild-type genotype . The heterogeneity substantially decreased when Asian and European were analysed separately, resulting in a significantly higher risk for gastric cancer among carriers of the variant A allele among Caucasians , and a decreased risk among Asians . The association between  in 2002 . A recenc cancer , includiQ or I2 statistics [An important aim of meta-analyses is to assess the extent to which different studies provide similar or dissimilar results, which is usually assessed by statistical tests such as atistics , and to atistics . Among t IL-1 -511T polymorphisms [IL-1 +3954T [E cadherin -160A [GSTT1 null [MTHFR 677T in the pooled analysis [IL-1 -31, IL-1 -511 and CYP2E1 PstI/RsaI. Furthermore, the studies scored as of high quality reported stronger effect estimates than those of low quality in 3 [1). When results were stratified for ethnicity, heterogeneity strongly decreases fororphisms , IL-1 +31 +3954T ,23, E cain -160A , GSTT1 nTT1 null  and MTHFanalysis , as possanalysis ,23,26,28ity in 3 ,26,28 ou1). Lastly, interaction between two polymorphisms might be an additional source of heterogeneity, and this was investigated in 3 meta-analyses [1). The subgroup analyses exploring gene-gene interaction were performed by comparing the effect of one polymorphism after stratifying for a second genetic risk factor, or by comparing homozygotes for both the unfavourable variants with double wild-type homozygotes. In both instances the heterogeneity decreased and the ORs increased, although reaching statistically significant results only when comparing opposite homozygotes [GSTs null genotypes as well as the relationship between GSTM1 and CYP2E1 unfavourable variants suggest that a wide portion of gastric cancer could be attributable to the inheritance of both unfavourable polymorphisms. Unluckily, these are the only reported gene-gene interaction meta-analyses, which were clearly limited from the few amount of original gene-gene interaction data from the individual studies. As example, though 17 of 18 published studies collected data on both GSTM1 and GSTT1 genotypes, only 5 authors reported case-control data according the two gene variants, thus limiting the power of subgroup meta-analysis. In this sense, large pooled analysis on gene-gene interaction and ad-hoc multiple genotyping conducted within consortia are strongly desirable.Subgroup analyses according to environmental co-exposures showed a decreased statistical heterogeneity, as expected. The final effect of a functional genetic variant on a certain disease is expected to change in presence of its environmental substrate, so that the effect estimate might be extremely heterogeneous among studies if this aspect is not taken into account. In the reviewed meta-analyses, stratified analyses according to environmental exposures biologically related to the polymorphisms showed a decreased heterogeneity in almost all the instances  and was confirmed by Egger (p = 0.029.) and Begg tests (p = 0.005). We also aimed to explore if the publication period affected the publication bias, and results show that the small outlier studies reporting statistically significant results were mainly published as first, while smaller studies which appear in the right side of the plot are the recently published ones . A time-dependent asymmetry was confirmed by Egger and Begg tests, with p values of 0.002 and 0.008 in the subgroup of papers published during the second period of time, and 0.14 and 0.72 in the first period, respectively. Publication bias could also occur in the subgroup analyses, when collected data are reported by the authors in the full-text or indicated by the indexers in record field of bibliographic databases only if they are interesting. However, this issue is solved in the meta-analyses directly asking authors of the published papers to provide individual data [An accurate bibliographic search that foresee the retrieval of local literature can help minimizing this bias, however ascertaining the extent of publication bias is difficult, and typically we have no idea to what extent unpublished data distorts the literature. In almost all the included meta-analyses, publication bias was evaluated by visual inspection of funnel plot and/or with any asymmetry test, with observed asymmetry only in limited cases and of limited extent. However, asymmetry tests have limited power when the number of included studies is small. In this review we aimed to identify the presence and the source of publication bias, and a funnel plot was derived pooling all the primary data included in the meta-analyses, using the ratio of the study OR for the unfavourable polymorphism and the OR of the corresponding meta-analysis. This computation allows to have comparable values for different studies datasets included in the meta-analyses. A slight asymmetry resulted by visual inspection , and MTHFR 677T (homozygous status). A borderline significant increased risk was also shown for GSTM1 null variant. Few subgroups meta-analyses were performed due to absence of published data in the primary studies. Among them, however, some demonstrated a strongly increased risk for gastric cancer among those carrying the unfavourable variant of IL- who are contemporarily Helicobacter pylori positive [GSTM1 null and CYP2E1 PstI/RsaI homozygous variant [GSTM1 null and GSTT1 null [MTHFR C677T and gastric cancer, that was published together with a meta-analysis on the same research question, demonstrated that the risk of gastric cancer among those carrying the homozygous variant genotype actually increases only when the folate intake was low [Overall, by summarizing the results of the published meta-analyses of the association between SNPs and gastric cancer, a statistically significant increased risk was reported for 3 polymorphisms, namely the positive , those c variant , and thoTT1 null ,28. Last was low . 2. From our computation, the most impacting polymorphisms are E-cadherin -160A and IL-1-511T (which might account for around 20% among Caucasians), MTHFR 677T variant and GSTM1 null (both 10% in Asians and Caucasians), IL-1RN *2 and IL-8 -251A . The ORs and allele frequencies used for computing the PAR, however, are taken from population of different geographic areas, although the same ethnic group, which could bias the results. As such, further data are needed to obtain a reliable estimate of the PAR, including data concerning gene-gene or gene-environment interactions, in order to identify population subgroups for which the impact of a certain polymorphism might be particularly high .The actual impact of polymorphisms on gastric cancer risk in the population depends on both the strength of association and on the frequencies of variant alleles, which vary among ethnic groups. Calculating PAR for each polymorphism among Asians and Caucasians will provide the proportion of gastric cancer cases attributable to the presence of the variant genotype, as shown in Table MTHFR 677T allele when the folate status was low and IL-1RN *2 allele when Helicobacter pylori positive. At the moment the potential public health impact for both gene tests is limited, however, because of the limited amount of data on which results are based on. As for MTHFR gene, a proper evaluation of the clinical utility of MTHFR C677T testing for identifying gastric cancer susceptibility among populations with folate deficiency, as well as the introduction of specific folate supplementation (versus no folate supplementation) are therefore warranted. Identically, the evaluation of screening programs for Helicobacter pylori infection could be targeted according to the genetic make up of individuals, but this require a more extensive evaluation.The integration of genome-based knowledge into healthcare has the potential to improve primary and secondary prevention . Among t


AATD is one of the most common inherited disorders in the World. However, it is generally accepted that AATD in North African populations is not a risk factor for lung and/or liver disease, based on a number of small studies. We therefore planned a screening study for detection of AATD in patients with OLD in a cohort of patients from Kairouan in central Tunisia. Methods: One hundred twenty patients with OLD  were enrolled in the screening programme. Laboratory diagnosis for AATD was performed according to current diagnostic standards.We found that 6/120 OLD patients carried an AAT deficient allele, 1 PI*MZ, 1 PI*MPlowel, 3 PI*MMmalton, 1 PI*MMwurzburg.this pilot study demonstrated that alleles related to deficiency of AAT are not absent in the Tunisian population, and that rare AATD variants prevailed over commonest PI*Z variant. These results would support a larger scale screening for AATD in Tunisia. SERPINA1, located on chromosome 14q31-32.3 within the SERPIN cluster . According to our protocol for detection of rare AATD variants, such samples with inconsistent AAT level/genotype were suitable for sequencing . In the ]. AccordSERPINA 1 PI*S and PI*Z deficiency alleles are extremely rare in North African populations [Meta-analysis of available data showed that ulations ,13. Receulations -17, as wSERPINA1 gene investigation to variants not detectable by rapid PI*S and PI*Z genotyping: by this strategy, we found 5 more deficiency variants (frequency as a whole 2%) detected on the heterozygous state. Such a condition of a relatively higher frequency of rare than common AATD variants, is shared by Central – Southern regions of Italy, in which PI*Mmalton and PI*Mprocida variants seem to prevail over PI*Z [SERPINA1 Null mutation, first described in an Egyptian family, and for that reason called Q0*cairo [In this study, we extended the ver PI*Z . Interesver PI*Z ,26. A noQ0*cairo  has beenQ0*cairo ,28-30.This study strengthens the concept that for a correct laboratory diagnosis of AATD, there is a need of a combination of biochemical and biomolecular methods , otherwiSevere AATD diagnosis in the North African countries might be beneficial to the treatment of patients with the introduction of AAT replacement therapy in these populations. Furthermore, AATD carrier diagnosis might provide genetic counseling to persons who are planning a pregnancy or are in the prenatal period . In addiThis investigation, performed for the first time with current diagnostic standards in a North African population, highlights the implication of AATD in development of OLD in this area, whereas previous data excluded a role for AATD in the African continent. This would suggest that, similarly to what happens in the Caucasians, also in Northern Africans AATD is an underdiagnosed condition, and therefore investigations in larger sample sizes would be advisable. It seems also likely that targeted detection strategy to identify affected individuals produces a rate of detecting disease higher than the population-based screening programs. Such approach may also contribute to change the widespread concept concerning the AAT deficiency epidemiology in North African and others populations.The authors declare that they have no competing interests.SD, MZ, IF and IC designed the study and drafted the Manuscript. FA and JK participated in data collection. SO, RS and MG participated in laboratory investigations. JBC, AHK and ML supervised the study process, revised and edited the final manuscript.


Bacillus thuringiensis (Bt). We performed meta-analyses on a modified public database to synthesize current knowledge about the effects of Bt cotton, maize and potato on the abundance and interactions of arthropod non-target functional guilds.Uncertainty persists over the environmental effects of genetically-engineered crops that produce the insecticidal Cry proteins of We compared the abundance of predators, parasitoids, omnivores, detritivores and herbivores under scenarios in which neither, only the non-Bt crops, or both Bt and non-Bt crops received insecticide treatments. Predators were less abundant in Bt cotton compared to unsprayed non-Bt controls. As expected, fewer specialist parasitoids of the target pest occurred in Bt maize fields compared to unsprayed non-Bt controls, but no significant reduction was detected for other parasitoids. Numbers of predators and herbivores were higher in Bt crops compared to sprayed non-Bt controls, and type of insecticide influenced the magnitude of the difference. Omnivores and detritivores were more abundant in insecticide-treated controls and for the latter guild this was associated with reductions of their predators in sprayed non-Bt maize. No differences in abundance were found when both Bt and non-Bt crops were sprayed. Predator-to-prey ratios were unchanged by either Bt crops or the use of insecticides; ratios were higher in Bt maize relative to the sprayed non-Bt control.per se but also to reflect the replacement of existing agricultural practices. Results will provide researchers with information to design more robust experiments and will inform the decisions of diverse stakeholders regarding the safety of transgenic insecticidal crops.Overall, we find no uniform effects of Bt cotton, maize and potato on the functional guilds of non-target arthropods. Use of and type of insecticides influenced the magnitude and direction of effects; insecticde effects were much larger than those of Bt crops. These meta-analyses underscore the importance of using controls not only to isolate the effects of a Bt crop  Bacillus thuringiensis Berliner (Bt) for control of lepidopteran and coleopteran pests. The potential environmental impact of these insect-resistant GE crops has been debated vigorously with most of the focus on non-target organisms, and to a lesser extent, their associated ecosystem function Meeting future food, feed and fiber needs without compromising environmental integrity is a central challenge for agriculture globally Declines in insecticide use are associated with the increasing adoption of Bt maize and cotton While previous analyses contribute substantially to understanding the impacts on species and taxa, we have lacked a broader perspective of how Bt crops may affect ecological functions of the complex insect communities associated with agroecosystems. Arthropods within agroecosystems provide numerous ecological services and economic benefits to land managers. Predators, omnivores, and parasitoids consume insect pests and weed seeds Here, we utilize a modified subset of the 171-study non-target database compiled by Marvier et al. http://delphi.nceas.ucsb.edu/btcrops. Briefly, the studies in the full dataset include 1) field crops that were genetically modified to express one or more Cry proteins from B. thuringiensis, 2) studies that measured the effect of the GE crop on abundance or other attributes of non-target arthropod taxa relative to a non-transgenic control, 3) studies that reported means accompanied by standard deviations (or standard error) and sample size and 4) were published in English. Our analyses were restricted to field studies measuring arthropod abundance in cotton, maize and potato. There were not sufficient studies to directly examine biodiversity or natural enemy function. Our database included studies conducted between 1992 and early 2006.We used a modified subset of the full meta-dataset discussed by Marvier et al. To avoid non-independence issues in our meta-analyses, this field/abundance dataset was further filtered and partitioned. First, three distinct types of comparisons were recognized and analyzed separately. The first set of studies contrasted Bt with non-Bt plots, neither of which received any additional insecticide treatments. This comparison addresses the hypothesis that the toxins in the Bt plant directly or indirectly affect arthropod abundance. It also can be viewed as a comparison between the Bt crop and its associated unsprayed refuge We further eliminated redundant taxonomic categories presented within the same study. For example, a study might include data on individual species and also on pooled taxonomic groups containing these same species. In filtering non-independent data, we always retained the finest taxonomic level possible . Some studies also reported multiple stages of the same species. In these cases we retained the least mobile, but feeding, stage when possible. Thus for example, we retained larvae or nymphs in preference to eggs or adults and retained adults or larvae/nymphs in preference to eggs. Our reasoning was that less mobile stages would experience higher and longer exposure to potential toxins than adults that might be transient residents. Eggs would be the least likely to be exposed. Finally, when studies included measures of both seasonal abundance (averaged over multiple sample dates) and peak abundance (highest density on any given sample date), we retained the seasonal mean. Peak abundances were used only if seasonal mean data were absent. All observations in the database are based on a single season; thus, reported differences in density reflect within-season differences and not cumulative changes over years. In total, the database we used in our analyses contained 2981 observations from 131 experiments reported in 47 published field studies. The database is summarized in Two additional descriptor columns were added to or modified from the full database of Marvier et al. We assigned functional categories based on a crop production perspective when ecological function of an organism varied with life stage; e.g., syrphid larvae are predators but adults may be classified as pollinators or herbivores. Although many predators have omnivorous habits, relying on nectar, pollen, and fungal spores or seeds in addition to prey, the ‘omnivore’ category was reserved for those whose diet is generally regarded as equally comprised of prey and non-prey foods . The ‘mixed’ category refers to higher taxonomic groupings  where members fell into more than one functional group. A summary of the taxa associated with each functional group is presented in Each taxon's feeding style was added to the database to describe the way in which it obtains its food and is potentially exposed to Bt toxins. The categories included piercing, chewing, mandibulate-sucking, rasping, lapping, chewing-lapping and unknown. Most of these categories were derived from the literature While both functional guild and feeding style classifications are unavoidably subjective to some degree, every effort was made to designate these species according to the prevailing understanding and knowledge in the entomological community.d, a weighted mean effect size estimator that is calculated as the difference between an experimental (Bt) and control (non-Bt) mean response divided by a pooled standard deviation and corrected for small sample size bias Bt crop compared with the non-Bt control while a positive effect size would indicate higher abundance in the Bt crop. All analyses were conducted using MetaWin All the meta-analyses presented herein use Hedges' Two general sets of analyses were conducted on our final database. The first evaluated the robustness of the data set and its sensitivity to various factors that could influence the interpretation of results. We tested for publication bias using a weighted histogram of effect sizes A series of sensitivity analyses were conducted to gauge the effect of 1) various experimental design factors , 2) individual studies included in the meta-analysis that vary in size, and 3) different Bt toxins produced in the crops. In order to examine any systematic effects of design factors on effect size we conducted weighted (effect size variance) regressions of the absolute values of the effect sizes based on abundances for each design factor. Analyses were conducted on all crops pooled and separately for cotton, maize and potato for each of the control contrasts noted above. To examine sensitivity to individual studies, we conducted a set of functional guild analyses (see below) where each relevant study (depending on crop and control contrast) was eliminated one at a time. Finally, we contrasted lepidopteran-specific versus coleopteran-specific toxins for maize, and the effect of single versus dual gene Bt cottons.2 = 580, P<0.01 for cotton; χ2 = 1632, P<0.01 for maize; χ2 = 72, P<0.01 for potato), we used feeding style to examine heterogeneity within a functional guild or further clarify factors influencing the direction and magnitude of effect sizes. We analyzed functional guilds separately for cotton, maize and potato within each of the three control contrasts. In addition to estimating confidence intervals, MetaWin also estimates total heterogeneity (between-sample variance) and tests its significance with the χ2 distribution using n-1 degrees of freedom. Significant heterogeneity suggests a non-normal distribution of effect size due to the presence of different subcategories within the functional guild. When significant heterogeneity was indicated, we attempted to partition sources of variation by examining taxonomic groups, and feeding style within functional guilds. We also examined the influence of insecticide type when they were used in control plots. Insecticide data were not available in the database for studies in which both experimental and control plots were sprayed.We used a one-way, fixed effects model to test effect sizes relative to functional guilds. Because functional guild and feeding style were not independent classifications of the taxa examined (Likelihood ratio χPredatorMean) and herbivores (HerbivoreMean) for each relevant study and used these measures to estimate the quotient of predators over herbivores (prey). The variance of this quotient is given asHerbivoreVar and PredatorVar are the sum of variances of individual herbivores or predators in a given study. We assumed that the covariance between predators and herbivores was zero, and thus this variance estimate is conservative. Species of predators from the studies included were largely generalists so that these ratios reflect general pest management services provided by non-target arthropods. We restricted the designation of prey solely to the herbivore functional group to achieve consistency across studies. Omnivores could function as both predator and herbivores and detritivores are examined in another analysis (see below). We also did not include parasitoids in the ratio. Hedges' d effect sizes were calculated from these predator-to-prey quotients and their variance terms. As before, a negative effect size would indicate a lower ratio in the Bt crop. The sample size was assumed to be the number of true replicate plots in the experimental design of each study.We examined community level responses using predator/prey ratios to provide an alternate measure of impact on pest management services. To estimate predator to prey ratios, we identified studies in our database in which both predator and herbivore functional groups were measured. We then summed the mean abundance of predators . For cotton, only two out of 72 analyses (2.8%) resulted in different interpretations. In one case a significant positive effect size, indicating a higher abundance in Bt treatments, became nonsignificant with the elimination of a relatively large study while another changed from nonsignificant to positive with the elimination of a small study. Likewise, in maize only five of 204 (2.4%) analyses differed. Three negative effects, or reduced abundance in Bt treatments, became nonsignificant with the elimination of two large and one medium-sized study, and two positive effects (higher abundance in Bt treatments) became nonsignificant after the elimination of a large and medium study. In contrast, there were only two studies for each of the three control comparisons in potatoes and the elimination of each study in turn resulted in an 11.1%  change in results. Elimination of the largest study resulted in positive effect sizes becoming nonsignificant. Given that Bt potatoes are no longer commercially planted and that we expect no forthcoming studies unless commercial viability changes, we present our results but note their limitations. A synthesis here will provide a starting point for future studies if commercial plantings resume.Macrocentrus spp.) decreased with the lepidopteran-specific cry protein but not with the coleopteran-specific cry protein (see below for more detail). Due to the strong decrease in abundance in this functional guild in lepidopteran-specific Bt maize, the response was also negative when all maize Cry proteins were pooled. Based on these general results, we examined all non-target effects by pooling all events within each of cotton and maize to maximize sample sizes for each comparison. Only a single construct (Cry3A) was present for potatoes.A final sensitivity analysis examined responses to different Cry toxins or combination in cotton and maize. Qualitatively, we found no differences in responses by functional guild or all taxa pooled between single (Cry1Ac) and dual (Cry1Ac+Cry2Ab2 or Cry1Ac+Cry2Aa) toxin cotton events. Likewise we found only one qualitative difference in non-target response to lepidopteran-specific  and coleopteran-specific (Cry3Bb) maize events. The abundance of the parasitoid functional guild (consisting largely of Chrysoperla (n = 5), Orius (n = 9), Geocoris (n = 15) and of two species associated with predicted or documented nontarget pest outbreaks in Bt cotton  were similar in Bt and non-Bt cotton.In cotton, there were slightly fewer predators in Bt cotton fields compared to unsprayed, non-transgenic fields , but M. grandii abundance was severely reduced by Bt maize . Higher numbers of the generalist predator, Coleomegilla maculata, were associated with Bt maize  but numbers of other common predatory genera  were similar in Bt and non-Bt maize.In maize, analyses revealed a large reduction of parasitoids in Bt fields  and herbivores  in Bt potato fields than in unsprayed control fields . SignifiWe found no evidence for changes in the ratio of predators to non-target herbivores in any Bt crop. Data for this analysis were available from 12, 25 and 2 experiments in cotton, maize and potato, respectively.Most of the detritivores in the database were Collembola, and carabid and staphylinid beetles were their primary predators. We found no significant effects of Bt crops on detritivores overall, on any of the five collembolan families or their carabid and staphylinid beetle predators, or on the non-collembolan detritivore families Lathridiidae and Japygidae.Geocoris spp.  in Bt cotton but no detectable difference in Orius spp. (n = 2) or Chrysoperla spp. (n = 2) for the limited studies available. There was a greater abundance of the non-target pest species B. tabaci  in Bt cotton fields compared to a non-transgenic control sprayed with insecticide, but no detectable change in abundance with the small number of studies on Lygus spp. (n = 2).In cotton, there were many more predators, herbivores and mixed-guild taxa in unsprayed Bt cotton fields than in insecticide sprayed controls . For comThere was significant heterogeneity within effect sizes for predators, herbivores and omnivores. Overall sample sizes were limited but analyses by feeding style or taxonomic order within these functional groups revealed highly variable responses. Predator effect sizes were consistently positive but varied in magnitude from 0.2 (Neuroptera) to 1.2 (Diptera). Consistently positive effect sizes were also observed for Hemipteran herbivores and ranged from 0.9 (Miridae) to 3.2 (Cicadellidae). For other functional guilds, none of the effect sizes for orders or family were significant. In contrast to maize (see below), the use of pyrethroid insecticides in control fields did not influence effect sizes nor explain overall heterogeneity.Coleomegilla (n = 20), Hippodamia (n = 7) or Chrysoperla (n = 13), but the predator Orius spp. and the parasitoid Macrocentrus were more abundant in Bt maize than in non-Bt maize plots treated with insecticides . Partitioning by taxonomic groupings or the target toxin (Lepidoptera versus Coleoptera) did not reduce heterogeneity within predators. However, insecticides differentially affected predator populations. Specifically, application of the pyrethroid insecticides lambda-cyhalothrin, cyfluthrin, and bifenthrin in non-Bt control fields resulted in comparatively fewer predators within these treated control plots. Omitting studies involving these pyrethroids revealed a much smaller and homogeneous effect size . Predator abundance in Bt fields was still significantly higher compared with insecticide-treated plots, but the difference was less marked without the pyrethroids , and Araneae .In maize, the abundance of predators  and members of the mixed functional guild  were higher in Bt maize compared to insecticide-sprayed controls . Signifiethroids . CompareP = 0.17, n = 236, E = 0.17±0.09).In contrast to the positive effects on most functional guilds, there were fewer omnivores  and detritivores  in Bt maize than in insecticide-treated controls. The decline in omnivores was completely explained by effects on Formicidae  and removal of this group led to an insignificant effect size . Significant heterogeneity existed in effect sizes for the detritivore category. One factor that explained some of the variability is that the pyrethroid, cyfluthrin, had little effect on the detritivores, whereas the other pyrethroids were detrimental to this group. Eliminating the cyfluthrin studies (n = 6) was sufficient to eliminate the heterogeneity  and Cicadellidae occurred in higher abundance in the Bt maize . In contrast to patterns associated with predators and detritivores, type of insecticide did not explain the heterogeneity in herbivore responses. The pyrethroid-treated controls accounted for 85% of the herbivore records. Individual pyrethroids had variable effects on this group, and none yielded strong effects on the herbivores. An underlying factor associated with the heterogeneity of the herbivore guild remained unidentified, but many possible factors were eliminated .Bt maize treated with insecticides. The majority of this functional group is comprised of carabids (n = 33), nitidulids (n = 26), and mites (n = 23).The “mixed” functional group was more abundant in Bt maize  compared with non-For potatoes, the abundance of predators , but not herbivores, was significantly higher in the Bt crop . ResponsBt maize plots than in the insecticide controls . Significant heterogeneity for the predator: prey response existed in all three crops, but again sample sizes were too small to explore the cause of this variability.No significant change in predator-prey ratios was detected in cotton or potato; in maize there was a significantly higher predator- prey ratio in The higher abundance of detritivores in sprayed non-Bt maize appeared to be driven primarily by two families of Collembola with a high proportion of surface-active species , Orius (n = 18) and Chrysoperla (n = 12) or the pest Lygus spp. (n = 20) were similar between crops. No studies were available for B. tabaci. Significant heterogeneity existed within the predator, herbivore and omnivore functional guilds. Further analyses by feeding style and taxonomic level revealed variable but consistently nonsignificant effect sizes within these guilds. No studies using maize were available for this comparison. In potatoes, studies available measured effects on only two functional groups: predators (n = 27) and herbivores (n = 4), and neither effect was significant  and potato (n = 2), and we detected no change in predator-prey ratios.Coleomegilla, in Bt fields compared to unsprayed non-Bt fields. Therefore, we identified a species-specific effect in Bt maize but no consistent effects on any of the functional guilds.When comparing Bt plants to their non-transgenic counterparts without any additional insecticides, meta-analysis revealed no uniform negative or positive effects on ecological functional guilds. Predators were slightly lower in abundance in Bt cotton but no other effects were detected for other functional guilds in this crop. This negative effect on predators was not seen in the two other cropping systems; in fact, this guild was favored by Bt potato. The small negative effect on predators as a group was not driven by any common individual species that we analyzed but rather by more moderate reductions in two predaceous families (Nabidae and Coccinellidae), a pattern identified in several non-target studies M. grandii, which specializes on the target pest. From the limited number of studies on other parasitoids, there was no detectable effect on parasitoids; however, more studies will be needed to resolve whether there is a general effect on parasitoids  in Bt cotton fields. Ponsard et al. Geocoris punctipes and Orius tristicolor when these predators fed on Cry1Ac intoxicated prey in the laboratory, and Gutierrez et al. Lygus spp. and B. tabaci in Bt cotton. Our meta-analyses showed no change in the abundance of Geocoris spp., Orius spp., Lygus spp. or B. tabaci in Bt cotton over multiple studies, even though ingestion of Bt toxins have been confirmed for the two predator genera Chrysoperla spp. in Bt cotton or Bt maize. This group has been the subject of intense debate in the literature  would suggest that the abundances of both herbivores and predators were affected equally by insecticide use so that the ratio does not change compared with an untreated situation. These meta-analysis results based on synthesizing data on all predators and herbivores within multiple studies are consistent with the findings of predator to prey ratios calculated for two insect pests in the cotton system As more data accumulate on the ecological impacts of Bt crops or other GE organisms, syntheses like meta-analyses will continue to be a useful tool to guide the decisions of diverse stakeholders such as developers, regulators, researchers, growers and consumers. With emphasis on guilds, our analyses focused on ecological function rather than on biodiversity or taxon-based abundance M. grandii, but relatively few field studies have been conducted on other parasitoids. Choosing other species that account for larger parasitism rates in agricultural systems will improve our understanding of how Bt crops affect parasitoids and whether any effects are due to the direct effect of Bt toxin or to prey in poor condition from feeding on Bt toxin. Our experience with the database also points to the need for more consistent reporting of data in the literature. In order to include studies in meta-analyses that require measures of error, publications need to report sample sizes and standard errors (or standard deviations). A large number of comparisons in the database compiled by Marvier et al. Our synthesis of available studies also reveals where research efforts have been intensive and where gaps exist. For example, studies have consistently documented impacts on the parasitoid Debate over issues of food and environmental safety, regulatory oversight, and welfare of the farming community as a whole are likely to continue as GE technology moves forward with new crops, new traits and new adopting countries. Our meta-analysis reinforces the notion that Bt crops are one tool in the integrated pest management toolbox and that their comparative environmental impact on non-target organisms will depend on how these tools are integrated and applied within agricultural production systems.A number of reviews have provided qualitative syntheses of the impact of Bt crops on non-target organisms The examination of non-target and other ecological effects from Bt and other GE crops is a quickly growing field of investigation with new studies being published at a rapid rate. Although there have been several dozen new non-target studies published since the database was compiled, cumulative meta-analysis indicates a convergence of the results presented here . TherefoAppendix S1Dataset used for analyses(4.46 MB XLS)Click here for additional data file.Appendix S2Taxonomic groups associated with functional guilds.(0.16 MB DOC)Click here for additional data file.Appendix S3Cumulative meta-analyses for effects on functional guilds(0.44 MB DOC)Click here for additional data file.


Pro- and anti-inflammatory cytokines, including interleukin 10 (IL-10), play an essential role in atherogenesis. Increased IL-10 production has been found among carriers of the IL10 [TCATA] haplotype, which is formed by five polymorphisms at position -3575, -2763, -1082, -819, and -592 in the promoter region of the IL10 gene. Due to linkage disequilibrium, the presence of the [TCATA] haplotype can be unequivocally determined by analysis of the IL10-592C>A polymorphism. The purpose of the present study was to investigate a hypothesized association between the haplotype-tagging IL10 -592C>A polymorphism and the presence of retinal artery occlusion (RAO).The present case-control study was comprised of 194 patients with RAO and 257 normal control subjects. Genotypes of the IL10 -592C>A polymorphism were determined by fluorogenic exonuclease (TaqMan) assay.Carriers of the IL10 -592A-allele, indicating the presence of the IL10 [TCATA] haplotype, were found significantly more often in controls than among patients with RAO . In a logistic regression analysis after adjusting for age, sex, arterial hypertension, diabetes mellitus, hypercholesterolemia, and smoking habits, carriage of the IL10 -592A-allele was associated with an odds ratio of 0.65 (95% CI: 0.44-0.97) for RAO.Our data suggest that the IL10 [TCATA] haplotype, identified by the presence of the IL10 -592A-allele, may exert a protective effect against RAO. Retinal artery occlusion (RAO) is a vision-threatening disease, primarily affecting patients older than 60 years. Insufficient blood flow in the retinal arteries leading to infarction of the affected retinal tissue is caused by several different mechanisms including embolization, hemorrhage under an atherosclerotic plaque, and thrombus formation ,2. AmongAtherosclerosis is a chronic low-grade inflammatory disease . Both prIL-10 in atherogenesis comes from animal experiments, demonstrating that increased IL-10 expression leads to reduced formation of early and advanced atherosclerotic lesions, whereas IL-10 deficiency is associated with enhanced atherogenesis -19.In humans, IL-10 production is to a large extent genetically determined ,21. The The purpose of the present study was to investigate a hypothesized association between the haplotype-tagging IL10 -592C>A polymorphism and the presence of RAO.The present retrospective case-control study consisted of 194 patients with RAO and 257 control subjects. All participants, who were seen at the local department of ophthalmology between October 1998 and July 2006, gave written informed consent prior to being enrolled. The study was conducted in accordance with the guidelines of the National Gene Technology Act and the local Ethics Committee.All participants underwent an ophthalmologic examination that included visual acuity tests as well as, slit-lamp and fundus examinations. The diagnosis of RAO was made by fundus examination in which superficial retinal whitening was found in the distribution of the affected retinal artery. Since second eye involvement occurred in two patients, 93 eyes were diagnosed with central retinal artery occlusion (CRAO), while branch retinal artery occlusion (BRAO) was present in 103 eyes. Patients with RAO due to giant cell arteritis or other types of vasculitis were considered ineligible for participation.The control group was comprised of patients who had been seen at the local department of ophthalmology for reasons other than RAO. Those with a history of retinal vascular occlusion or vasculitis were deemed ineligible.Arterial hypertension was defined by systolic blood pressure greater or equal to 140 mm Hg and/or diastolic blood pressure greater or equal to 90 mm Hg, and/or the current intake of antihypertensive drugs. Subjects were classified as diabetics, if they were being treated for insulin- or non-insulin-dependent diabetes. Hypercholesterolemia was defined by the intake of lipid-lowering drugs and/or a fasting plasma cholesterol level >200 mg/dL. Patients were further classified as current or non-smokers.2O and 2 μl DNA. Reactions were overlaid with 15 μl mineral oil. Cycling parameters were as follows: 1 min 94 °C for primary denaturation, followed by 40 cycles of 15 s 92 °C and 1 min 60 °C. Fluorescence was measured in a lambda Fluoro 320 Plus plate reader (MWG Biotech AG) using excitation/emission filters of 485/530 nm for FAM-labeled probes  and 530/572 nm for VIC-labeled probes . The data were exported into Excel format and depicted and analyzed as a scatter plot.Genomic DNA was isolated from peripheral blood lymphocytes by standard methods and stored at -20 °C. Genotypes of the IL10 -592C>A polymorphism were determined by a 5'-exonuclease assay (TaqMan) using a procedure described by Langsenlehner, et al. . Primer SPSS for Windows  was used for statistical analyses. Continuous variables were analyzed by Student's t-test and are presented as means±SD. Categorial variables are presented as percentages and were compared by chi-square test. Odds ratios and 95% confidence intervals (CI) were determined by logistic regression analysis. The criterion for statistical significance was p less than or equal to 0.05.Clinical characteristics of patients and control subjects are shown in In a subgroup analysis, prevalences of the CC, CA and AA genotypes did not significantly differ between eyes with CRAO  and those with BRAO .No deviation from the genotype distribution predicted by the Hardy-Weinberg equilibrium was observed in either patients or controls, and allelic frequencies in the control group were similar to those previously reported by other investigators ,25.The production of IL-10 has been shown to be under tight genetic control with heritability estimates up to 74% . The IL1To the best of our knowledge, the present study is the first to investigate the haplotype-tagging IL10 -592C>A polymorphism in patients with RAO. Genotyping was performed in 194 patients and 257 control subjects. Carriers of the -592A-allele (AA+CA), which indicates the presence of the high IL-10-producing [TCATA] haplotype, were found significantly more often in controls than among patients with RAO. A subgroup analysis revealed a similar genotype distribution between eyes with BRAO and CRAO, indicating that this polymorphism is a risk factor for both types of RAO. In a logistic regression analysis, after adjusting for age, sex, arterial hypertension, hypercholesterolemia, diabetes mellitus, and smoking habits the presence of the IL10 -592A-allele was associated with an odds ratio of 0.65 for RAO, suggesting a protective effect against RAO.Besides arterial hypertension and cigarette smoking, which are known to initiate or promote atherogenesis , atherosAs a potential limitation of our study, IL-10 plasma concentrations were not determined. The purpose of our study, however, was to investigate the role of a haplotype-tagging genetic polymorphism, since in contrast to plasma cytokine concentrations, genetic variants do not change over life-time. Beside the [TCATA] haplotype, other polymorphisms in the IL10 gene might also influence IL-10 expression and thereby affect RAO risk. Further studies focusing on these gene variants may provide additional insight in the role of IL10 in RAO.In conclusion, our study demonstrates that the IL10 [TCATA] haplotype, indicated by the presence of the IL10 -592A-allele, may be associated with a protective effect against RAO. Yet, large prospective studies are warranted to confirm the contribution of these IL10 promoter gene polymorphisms to the risk of RAO.


Evaluation of the diagnostic accuracy of stress perfusion cardiovascular magnetic resonance for the diagnosis of significant obstructive coronary artery disease (CAD) through meta-analysis of the available data.Original articles in any language published before July 2009 were selected from available databases  using the combined search terms of magnetic resonance, perfusion, and coronary angiography; with the exploded term coronary artery disease. Statistical analysis was only performed on studies that: (1) used a [greater than or equal to] 1.5 Tesla MR scanner; (2) employed invasive coronary angiography as the reference standard for diagnosing significant obstructive CAD, defined as a [greater than or equal to] 50% diameter stenosis; and (3) provided sufficient data to permit analysis.From the 263 citations identified, 55 relevant original articles were selected. Only 35 fulfilled all of the inclusion criteria, and of these 26 presented data on patient-based analysis. The overall patient-based analysis demonstrated a sensitivity of 89% (95% CI: 88-91%), and a specificity of 80% (95% CI: 78-83%). Adenosine stress perfusion CMR had better sensitivity than with dipyridamole (90% (88-92%) versus 86% (80-90%), P = 0.022), and a tendency to a better specificity (81% (78-84%) versus 77% (71-82%), P = 0.065).Stress perfusion CMR is highly sensitive for detection of CAD but its specificity remains moderate. Perfusion cardiovascular magnetic resonance (CMR) is an emerging technique for the detection of coronary artery disease (CAD). The technique is attractive because of its non-invasive nature and safe characteristics, and might potentially play a major role in future diagnosis and risk stratification guidelines for patients with suspected CAD. Several small studies have evaluated the diagnostic performance of stress perfusion CMR and some of those have been included in a previous meta-analysis . In the magnetic resonance, perfusion, and coronary angiography, with the exploded terms coronary artery disease; the MEDLINE, Cochrane Library and BioMedCentral databases were searched independently by two investigators  for all publications, in any language, before July 2009. In addition, the published reference lists of these articles were systematically searched.Using the combined medical subject headings (MeSH) of The search results were collated by the same two investigators , and duplicate or overlapping papers removed. Studies were eligible if:  stress pData extraction was performed independently by the two investigators  for each study. The following fields were recorded: study population size; gender distribution; mean age and standard deviation; number of patients with documented CAD; prevalence of CAD; relative timing of the two imaging procedures; the degree of blinding in interpretation of test results ; type and brand of MR machine used; the type of perfusion stressor , and the number of side effects; the dose and injection rate of Gadolinium administrated; and the modality of MR image analysis . Any discrepancies were resolved by discussion and consensus between the two investigators. Where available, data was recorded separately at the level of coronary territories and coronary arteries. The study quality conformed to the Quality Assessment of Studies of Diagnostic Accuracy included in Systematic Reviews guidelines . In one Data analysis was performed at the level of the patient, the coronary territory and the coronary artery. Sensitivity and specificity were calculated using the TP, TN, FP, and FN rates ,4. From P ≤ .10). Since diagnostic parameters are, by definition, interdependent, independent weighting may sometimes give spurious results and provide biased estimates; to overcome the interdependence problem, we computed the weighted symmetric summary receiver operating characteristic curve, with pertinent areas under the curve, using the Moses-Shapiro-Littenberg method [All these measures of diagnostic accuracy were calculated for each individual study and reported as point estimates with 95% confidence intervals. They were then combined using a random-effects model and each point estimate weighted by the inverse of the sum of its variance and the between-study variance. We also assessed between-study statistical heterogeneity using the Cochran Q chi-square tests  demonstrated a sensitivity of 89% (95% CI: 88-91%), a specificity of 80% (95% CI: 78-83%), a PLR of 4.18 (3.31-5.27), a NLR of 0.15 (95% CI: 0.11-0.20), a DOR of 33.65 (95% CI: 22.09-51.27), and an AUC of 0.92  the results were: a sensitivity of 90% (88-92%), a specificity of 81% 78-84%), a PLR of 4.47 (3.39-5.88), a NLR of 0.14 (0.11-0.18), a DOR of 37.17 (25.16-54.91), and an AUC of 0.93. Statistical heterogeneity was observed for all relevant diagnostic performance measures. With dipyridamole as the stressor , the results were: a sensitivity of 86% (80-90%), a specificity of 77% (71-82%), a PLR of 2.97 (2.16-4.09), a NLR of 0.20 (0.09-0.45), a DOR of 17.03 (5.56-52.18), and an AUC of 0.84. Statistical heterogeneity was observed for all relevant diagnostic performance measures, except specificity and positive likelihood ratio. ROC curves for stress perfusion CMR performed with adenosine or dipyridamole are shown in Figure 8-84%, a A sensitivity analysis was carried out based on the equipment used . For 3 Tesla , results were: a sensitivity of 92% (87-95%), a specificity of 78% (69-85%), a PLR of 3.96 (2.78-5.63), a NLR of 0.12 (0.07-0.20), and a DOR of 35.74 (17.13-74.53). For 1.5 Tesla , results were: a sensitivity 89% (87-91%), a specificity of 80% (78-83%), a PLR of 4.26 (3.26-5.55), a NLR of 0.15 (0.11-0.20), and a DOR of 34.25 (21.26-55.17).Per-territory results, pooled from 17 studies corresponding to 2,709 coronary territories, demonstrated a sensitivity of 82% (79-84%), a specificity of 84% (82-85%), a PLR of 4.90 (3.66-6.55), a NLR of 0.23 (0.20-0.27), and a DOR of 23.23 (18.33-29.45). At the territory level heterogeneity was significant for all relevant diagnostic performance measures except sensitivity, negative likelihood ratio and diagnostic odd ratios.Per-artery analysis pooled 8 datasets and demonstrated for left anterior descending artery (LAD), circumflex artery (CX) and right coronary artery (RCA), respectively, sensitivities of 83%, 76% and 78% and specificities of 83%, 87%, and 87%. Statistical heterogeneity was observed for all the performance measurements except sensitivity and negative likelihood ratio for LAD and CX, and diagnostic odds ratio for CX.This meta-analysis showed stress perfusion CMR to have a high sensitivity (89%) and a moderate specificity (80%) at patient level for the diagnosis of significant obstructive CAD in patients with high prevalence of CAD (57%). We included twelve more studies (on stress perfusion CMR) than the previous meta-analysis by Nandalur et al. , which sAlternatively, because CA detects luminal morphology rather than the functional significance of a stenosis, a false positive CMR results may in fact represent a 'false negative' angiogram in the context of angiographically 'invisible' small vessel disease capable of inducing subendocardial ischemia . This poAnother point to outline is that for some studies ,17,19, dIn addition, there was a large range of contrast doses used in the individual studies, with the dose of gadolinium administered in the included studies varying by 6-fold, with dose ranging from 0.025 to 0.15 mmole/kg. Although currently there is no consensus regarding the optimal dose and injection rates for perfusion CMR, two multicenter dose-ranging studies have evaluated the impact of contrast dose on the performance of perfusion CMR using a visual analysis ,47. In tIn this meta-analysis, 18 studies were based on stress perfusion CMR alone ,37,39,44Having access to data from different sequences  is especially useful when one component shows a borderline result or is affected by image artefacts. Most of the authors have argued that rest perfusion is an important component because, in combination with late enhancement CMR, it can help distinguish true defects from artefacts on the stress perfusion images.The fact that the meta-analysis demonstrated a low NLR for stress perfusion CMR suggests that a negative test result may in fact be more clinically useful. This is in keeping with several reports, in different clinical settings, of improved prognosis associated with a normal adenosine stress perfusion CMR scan -50. ThisFrom this analysis, visual assessment of stress perfusion CMR provided a higher sensitivity but a lower specificity than semi-quantitative assessment. Currently there is no consensus on the superiority of visual over semi-quantitative assessment, or on which method of semi-quantitative assessment should be used. However, the drawbacks of semi-quantitative assessment are that it is more time-consuming, hence not ideal for day-to-day clinical purposes, and the lack of any homogeneous post-processing protocols. Therefore, visual assessment is currently the method most often used in routine clinical practice.Only 4 studies were performed using 3T CMR, which provides improved resolution ,38,39,43The results of the per- territory-based analysis showed the anticipated decrease in sensitivity and increase in specificity seen when moving from the level of the patient to that of the coronary territory. Among the 8 studies that performed a coronary-artery level analysis, stress perfusion CMR had a higher sensitivity for detection of significant coronary disease in the LAD artery, compared with the CX and RCA. A possible explanation for this finding may have been the use of a surface radiofrequency coil, which led to lower signal intensities in the more distant inferior and lateral segments.Although conventional CA is the established technique for diagnosing significant CAD in routine clinical practice, it remains an imperfect reference standard due to its inability to evaluate the hemodynamic significance of a stenosis.Substantial inter-study heterogeneity in multiple performance characteristics were observed. Therefore, the pooled performance indices and their interpretation have to be treated with a degree of caution, even though the random-effects model used throughout the analysis should have compensated for this. The observed heterogeneity may have been due to variations in: (i) the image acquisition technique ; (ii) the interpretation method ; (iii) the patient selection criteria ; and (iv) in the definition of significant obstructive CAD (50% or 70%). We noticed, as expected, that studies which performed analysis for 50% and for 70% coronary artery stenosis thresholds, reported an increased sensitivity and a decreased specificity when moving thresholds from 50% to 70% ,33,36.These general limitations of stress perfusion CMR could be addressed in future multi-centre studies if standardized imaging protocols, post-processing techniques and patient selection criteria are employed.Stress Perfusion CMR has a high sensitivity and moderate specificity for the diagnosis of significant obstructive CAD compared with CA in patients with a high prevalence of the disease.Future technical developments that increase spatial and temporal resolution whilst reducing artefacts may further improve the diagnostic performance of stress perfusion CMR, and in particular improve its specificity . CurrentThe authors declare that they have no competing interests.MiH conceived of the study, and participated in its design and coordination and drafted the manuscript. GF, MaH participated in its design and coordination and helped to draft the manuscript. GN, JE, helped to draft the manuscript. RM participated in the design of the study and performed the statistical analysis. All authors read and approved the final manuscript.


Toxoplasma gondii, the agent of toxoplasmosis, has a complex life cycle. In humans, the parasite may be acquired either through ingestion of contaminated meat or through oocysts present in the environment. The importance of each source of contamination varies locally according to the environment characteristics and to differences concerning human eating habits and the presence of cats; thus, the risk factors may be determined through fine-scale studies. Here, we searched for factors associated with seropositivity in the population of two adjacent villages in Lorraine region, France.All voluntary inhabitants filled out a questionnaire and gave a blood sample. The seroprevalence was estimated globally and according to the inhabitants' ages using a cubic spline regression. A mixed logistic regression model was used to quantify the effect of individual and household factors on the probability of seropositivity.th and 95th percentile of the household seropositivity distribution).Based on serological results from 273 persons, we estimated seroprevalence to be 47% . That seroprevalence increased with age: the slope was the steepest up to the age of 40 years , but that increase was not significant afterwards. The probability of seropositivity tended to be higher in men than in women  and in subjects eating raw vegetables at least once a week than in the others . These effects were close to statistical significance. The multivariable analysis highlighted a significant seroprevalence heterogeneity among households. That seroprevalence varied between 6 and 91% (5The major finding is the household effect, with a strong heterogeneity of seroprevalence among households. This effect may be explained by common exposures of household members to local risk factors. Future work will quantify the link between the presence of oocysts in the soil and the seroprevalence of exposed households using a spatial analysis. Toxoplasma gondii (T. gondii), the agent of toxoplasmosis, is one of the most widespread parasite species worldwide: in 2000, Tenter et al. estimated that one third of the human population might be parasitized [T. gondii infection is generally subclinical or mild. However, during pregnancy, the risk of materno-foetal transmission may have serious consequences for the foetus: abortion or congenital infection [T. gondii may also cause severe encephalitis among immunosuppressed patients via acute infection or reactivation of a latent infection: encephalitis is the most frequent neurological infection among patients with acquired immunodeficiency syndrome [asitized . In healnfection . T. gondsyndrome .T. gondii is complex: post-natal human infection may result from ingestion of tissue cysts contained in raw or undercooked meat from intermediate hosts or from ingestion or inhalation of oocysts shed by definitive hosts (felids) and disseminated in soil and water. Because virtually all mammals and birds may serve as intermediate hosts and because of the high resistance of T. gondii sporulated oocysts in the environment [Prevention of human toxoplasmosis relies on the knowledge of the disease epidemiology. However, the life cycle of ironment , possiblGiven the multiplicity of those sources, the epidemiological situation of toxoplasmosis is spatially contrasted: incidence and prevalence values vary among countries and even among regions within countries ,7. The rToxoplasma seroprevalence in a geographically-defined population, to describe the relationship between seroprevalence and factors like age and sex, and to search for other factors associated with prevalence at the scale of that population.The present survey on toxoplasmosis in the human population of two adjacent rural villages is a part of an analysis of toxoplasmosis dynamics. The aims were to provide a population-based estimate of We studied the population of two villages, Barisey-la-Côte and Barisey-au-Plain, located in Lorraine region, Northeastern France. Since 1991, Barisey-la-Côte has been the site of a long-term survey on cat population biology and epidemiology ,11, inclIn the two villages, field investigators contacted directly 422 persons and failed to contact only 12 other identified individuals. Eighty-four percent of contacted persons accepted to fill out the questionnaire (353 answers) and 61% accepted to give a blood sample (256 samples). A previous positive serological status was more frequently a cause of refusal to provide a new blood sample than a negative status: 17/18 previously positive individuals versus 12/48 previously negative individuals. We included in the analysis the 17 previously positive subjects and thus analyzed the serological status of 273 subjects. The study involved 138 households. Twenty-five households (18%) had a single member, 75 (54.5%) two members, 21 (15%) three members, 11 (8%) four members, and 6 (4.5%) had 5 members.The questionnaire sought information on: a) demographic characteristics: sex, age, localization of the accommodation; b) exposure to soil oocysts: number of years spent in the village, occupation related to agriculture, having a garden, time spent in the garden for gardening or other activities; c) exposure to contamination by food: use of bottled or tap water, frequency of meat consumption , frequency of consumption of undercooked beef, lamb, or pork, frequency of consumption of raw vegetables; d) contact with cats: presence of cats around the house, number of cats fed at home, cat litter in the house, total number of cats bred during life; e) history of toxoplasmosis: previous serological testing for toxoplasmosis and result, medical problem related to toxoplasmosis. The following classes were used to describe the frequency of meat or vegetable consumption: less than weekly, weekly, daily, more that once per day.Toxoplasma-specific IgG and IgM using ELISA  with a lysate of the parasite as antigen.Sera were kept frozen at -20°C and sent to the Department of Parasitology  to be blindly tested for According to the results of the IgM serology, there were no recent infections in the study population. Among the 256 subjects who had an IgM serology, the titer was zero in 248 (97%) and between 3 and 5 (under the threshold of positivity) in the remaining eight subjects. Therefore, the seroprevalence was determined only on IgG serology results. Among the 256 subjects, 116 (45.3%) had a clearly negative result (titer under 10 IU), 29 (11.3%) an uncertain result (titer between 10 and 25 IU) and 111 (43.4%) a clearly positive result .T. gondii  was estimated among the 273 subjects with known serological status. A cubic regression spline was used to represent the functional form of the link between seroprevalence and age.The seroprevalence of A mixed logistic regression model with two levels  was used to quantify the effects of individual and household factors on the probability of seropositivity. This model allowed us to take into account the fact that individuals from the same household would be exposed to a common environment and to quantify and explain the heterogeneity of seropositivity among households. The individual factors considered for this model were the demographic characteristics , the eating habits , and the contact with cats and soil. To explain heterogeneity of seropositivity among households, these individual factors were aggregated to build household factors: the mean age of household members and various percentages of household members having the same eating habits or contact patterns with cats and soil. The parameters of the model were estimated with a Bayesian method. The analysis was carried out with WinBugs 1.4  that uses Gibbs sampling.Among the 273 subjects of the study, 61% (166/273) were living in Barisey-au-Plain, 56% were women (152/273), and 64% (175/273) were aged 20 to 60 years old. More than 90% of the inhabitants had gardens, consumed meat and raw vegetables at least once a week, and were in contact with cats around or in their houses . The functional form of the change of seroprevalence over age showed a strong increase between 7 and 40 years but a weaker increase after the age of 40 years . None of the household factors we built to measure common eating habits or common exposures to cat or soil was able to explain that heterogeneity among households.After taking into account the mean age of household members in order to exclude a possible cohort effect Table , the anaT. gondii antibodies, the higher risks being those of people living in non-urbanized areas [In our specific rural setting, the overall seroprevalence and relationship with age were comparable to the values recently observed in neighboring geographical areas. In a recent population-based survey in the Netherlands, 40.5% of persons carried anti-ed areas . In Franed areas . Althouged areas  and of 2ed areas . The reled areas ,15. In ted areas . Here, wThere was a trend, although only close to statistical significance, towards a higher probability of seropositivity in men than in women. This result has not been found in other large population-based surveys ,14,16 orToxoplasma seroprevalence was not significantly associated with any of the factors related to meat consumption. In the univariate analysis, consumption of rabbit meat was the meat consumption factor with the highest estimated Odds Ratio, but this effect was far from statistical significance (Table ce Table , possiblT. gondii oocysts from the soil and from locally available raw vegetables. A study conducted in an urban area with high densities of stray cat populations showed that high concentrations of oocysts can be detected in soil samples using real-time PCR [Consumption of raw vegetables was the only factor related to the eating habits that had a strong effect, close to statistical significance. This factor was also found associated with toxoplasmosis in Slovakia , in Norwtime PCR .Toxoplasma seroprevalence. Actually, previous studies have found contradictory results about the link between contact with cats and the risk of toxoplasmosis. One study found that an increase in the number of seropositive cats trapped on the farm increased the risk of human infection [T. gondii seropositivity [Contrarily to the hypothesis that owning cats constitutes a significant risk factor, contact with cats, measured by the number of cats bred during life, was not found clearly associated with nfection . Some hasitivity ,21 whilesitivity ,20. Kortsitivity  found onAn important factor not reported before is the household effect: the probabilities of seropositivity for subjects belonging to the same household were closer than for subjects belonging to different households. This effect persisted after taking into account the mean age of household members; thus, it was not due to close ages within households. The heterogeneity, already found at country and region scales ,7, was aThe major finding of our study was the household effect, with a strong heterogeneity of seroprevalence among households. This effect could be explained by common exposure of subjects sharing the same household to local risk factors. Our future work will be directed towards building quantitative factors measuring the presence of oocysts in the soil and towards quantifying the link between these factors and the seroprevalence of exposed households using a spatial analysis.The authors declare that they have no competing interests.EGF conceived of and coordinated the study. She participated in its design and drafted the introduction and the discussion of the manuscript. BR participated in the design of the study, performed the statistical analysis and helped to draft the manuscript. MR participated in the design of the study, supervised the statistical analysis and drafted the methods and the results of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/9/76/prepub


The anti-platelet agent clopidogrel bisulfate (sold under the trade name Plavix in the United States) is a widely prescribed medication for the prevention of blood clots in patients with acute coronary syndrome, in those who have suffered other cardiovascular disease-related events such as ischemic stroke, and in patients who are undergoing percutaneous coronary intervention. Response to clopidogrel varies substantially due to genetic and acquired factors. Patients who experience recurrent cardiovascular ischemic or thrombotic events while taking clopidogrel are typically described as non-responsive or resistant. The drug's oxidation is mainly dependent on the cytochrome P450 enzyme 2C19 (CYP2C19). Patients with certain genetic variants in CYP2C19 have been found to have lower levels of the active metabolite, less platelet inhibition, and greater risk of major adverse cardiovascular events such as heart attack, stroke, and death. Testing for CYP2C19 polymorphisms may identify patients who will not respond adequately to the standard clopidogrel regimen and who should, consequently, be given an alternate treatment strategy. This article outlines the evidence concerning pharmacogenetic testing for clopidogrel response, including data on clinical validity and clinical utility, and summarizes the currently available tests marketed for this purpose. Pharmacogenetic testing to identify patients at risk of an inadequate response to the standard clopidogrel regimen so that alternate treatment strategies can be initiated, with the goal of preventing adverse cardiovascular events such as stent thromboses, recurrent ischemic events, and death.Test DescriptionCYP1A2, CYP3A4, and CYP3A5) have been studied for an association with antiplatelet response and clinical outcomes in those taking clopidogrel. However, despite the many enzymes known to be involved in the metabolism of clopidogrel, only genetic variation in CYP2C19 has been consistently and significantly associated with clopidogrel response in multiple populations Genetic polymorphisms in several genes . These tests differ in genotyping methodology, sample type required, and availability (direct-to-consumer or physician-ordered). However, all tests include, at a minimum, the most common alleles , which have been shown to account for most of the variability in response to clopidogrel CYP2C19*17, has been described that is associated with increased enzymatic activity and ultra-rapid drug metabolism The numerous commercial pharmacogenetic tests that are available genotype variants in Each test includes: CYP2C19. Analysis of multiple single nucleotide polymorphisms in Genotype-based prediction of CYP2C19 enzymatic activity to categorize patients as: Extensive metabolizers [carrying two "normal" alleles ]. Intermediate metabolizers [carrying one reduced-function allele ]. Poor metabolizers [carrying two reduced-function alleles ]. Ultra-rapid metabolizers .Table 1.  Pharmacogenetic Tests for Clopidogrel ResponseCYP2C19 that either do not specify that the test is for pharmacogenetic purposes, or do not specifically mention that the test can be used in determining response to clopidogrel. Such tests have not been included in this table.Note:  These tests were found through Google searches combining terms such as “clopidogrel”, “genetic test” and “CYP2C19” and by searching individual websites of known commercial genetics companies (such as Pathway Genomics).  Attempts were made to make this table comprehensive. However, there are tests that genotype variants in Disclaimer:Inclusion of tests in this table does not constitute an endorsement of any test by the Centers for Disease Control and Prevention (CDC) nor the Department of Health and Human Services (DHHS) of the U.S. government. No endorsement should be inferred.Clopidogrel is the second highest top-selling drug in the world Estimates of the prevalence of laboratory-defined clopidogrel non-responsiveness vary widely, but have been estimated at 21-26% overall An inadequate response to clopidogrel can cause stent thromboses, recurrent ischemic events, and death CYP2C19 allele  that could affect clopidogrel response: ≈ 30-50% of Asians, 11-16% of Caucasians, and 14-25% of African-Americans CYP2C19 "poor metabolizer" phenotype is exhibited by 10-25% of Asians, 2-3% of Caucasians, and 4% of African-Americans CYP2C19*2 and *3 account for more than 95% of cases of the "poor metabolizer" phenotype CYP2C19*17 is estimated as 18-27% among Caucasians, 17-18% among Africans/African-Americans, and 0.5 – 4% among Asians Sizeable proportions of some populations possess at least one loss-of-function Recently, the U.S. Food and Drug Administration (FDA) issued a black box warning for clopidogrel due to the reduced effectiveness of the drug in poor metabolizers Systematic evidence reviewsNone.Recommendations by independent groupNone.Guidelines by professional groupsIn July 2010, the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) published a Clinical Alert in response to the FDA's black box warning on clopidogrel The evidence base is insufficient to recommend routine genetic testing at the present time. "Clinical judgment is required to assess clinical risk and variability in patients considered to be at increased risk. Genetic testing to determine if a patient is predisposed to poor clopidogrel metabolism ("poor metabolizers") may be considered before starting clopidogrel therapy in patients believed to be at moderate or high risk for poor outcomes. This might include, among others, patients undergoing elective high-risk PCI procedures ." Other guidelines CYP2C19 is a significant and independent predictor of clopidogrel pharmacokinetics, pharmacodynamics and clinical response”, which prompted the FDA to change clopidogrel’s prescribing information CYP2C19 genetic testing in patients prescribed clopidogrelThe FDA neither mandated nor explicitly recommended , and the agency did not offer any specific guidance on drug dosing in CYP2C19 variant allele carriers CYP2C19 poor metabolizers The U.S. Food and Drug Administration (FDA) determined in 2009 that the available data have “provided compelling evidence that genetic variation in Analytic Validity:Test accuracy and reliability in identifying CYP2C19 genotypes .When reported, accuracy of the various genotyping methods/platforms used in commercial tests is noted as ≥ 99% CYP2C19 genotyping assays, along with their reliability, specificity, and reproducibility, is extremely limited Cross validation of the techniques used in Clinical Validity:Test accuracy and reliability in predicting response to clopidogrel . CYP2C19 alleles to clopidogrel response Numerous published studies have examined the relationship of HuGE Navigator: query "clopidogrel and CYP2C19"            CYP2C19 genotype; these studies differed in the populations tested and the specific pharmacokinetic or pharmacodynamic measure(s) that were employed  was 45.1% and 75.0%, respectively   Measures of sensitivity and specificity can be calculated from data reported in some of the other published studies. Only one clinical trial explicitly reported measures of clinical validity. In the EXCELSIOR  trial, the sensitivity and specificity of No investigators explicitly included estimates of positive predictive value (PPV) or negative predictive value (NPV) for clopidogrel response in their original published reports. Using data from the EXCELSIOR report Clinical Utility: Net benefit of test in improving health outcomes.CYP2C19*2 variant and cardiovascular recurrences in 8,043 coronary artery disease patients taking clopidogrel. The authors found a statistically significant increased risk of major adverse cardiovascular events in CYP2C19*2 carriers (RR = 1.96) and an even greater risk when stent thrombosis was analyzed separately using four studies that included 4,975 patients (RR = 3.82) A recent meta-analysis of seven prospective cohort studies was published that examined the CYP2C19*2 variant and the incidence of major adverse cardiovascular events (MACE) and mortality in patients taking clopidogrel CYP2C19*2 carriers had a statistically significant increased risk of MACE (OR = 1.29) using data from ten studies . Carriers of *2 also had statistically significant increases in risk for stent thrombosis  and death . Four studies including 5,694 patients allowed the separate assessment of heterozygotes and homozygotes of the *2 allele. Increased risks for MACE and stent thrombosis were noted for both groups, though the odds ratio for MACE was significant only for homozygotes  A more recent meta-analysis that was not restricted to prospective cohort studies examined the CYP2C19 loss-of-function variants using data from two studies. They estimate the PPV for a cardiovascular event is between 12% Hulot and Fuster CYP2C19 genotypes only among patients taking clopidogrel. In the only published study to date that included a placebo-controlled group, neither CYP2C19*2 or *3 allele carriage nor metabolizer phenotype influenced the effect of clopidogrel on cardiovascular disease-related outcomes compared to the placebo group Most studies have examined CYP2C19*17 may also identify individuals at increased risk for bleeding events Tests that assay CYP2C19 testing prior to administration of clopidogrel in improving health outcomes. There are no published clinical trial data evaluating the net benefit of CYP2C19*2 carriers was independent of patients' baseline cardiovascular risk It is unknown if the risk from a given individual's genomic profile changes over time, depending on the specific clinical scenario  CYP2C19 genotypes, such as reduced-function alleles in the presence of *17. The only study to directly assess the combined effect of *17 and reduced-function alleles  found a gradient of effect on pharmacodynamic response to clopidogrel The response to clopidogrel is unclear for some CYP2C19 alleles does not capture all of the genetic variability in pharmacodynamic, pharmacokinetic, or clinical responses to clopidogrel. Variants in the ABCB1 gene also seem to be potentially important to the interindividual variability in these phenotypes Genotyping only for Currently, there are no standardized clinical guidelines to manage patients with an inadequate response to clopidogrel. Typically, one or more alternatives are tried: higher loading or maintenance doses of clopidogrel, dual therapy with aspirin if this has not already been initiated, or treatment with another antiplatelet medication Any benefits of DNA testing may be hampered by the following considerations: http://www.cypalleles.ki.se/cyp2c19.htm), last accessed: March 17, 2010. Human Cytochrome P450 (CYP) Allele Nomenclature Committee, CYP2C19 allele nomenclature (HuGE Navigator: query "clopidogrel and CYP2C19" U.S. Food and Drug Administration: Table of Valid Genomic Biomarkers in the Context of Approved Drug LabelsClinicalTrials.gov: Clopidogrel and CYP2C19. Note: not all clinical trials list a pharmacogenetic component to their study, even if one exists.  For instance, some studies have been found to include genetic analyses only after publication of those data. Consequently, searching for "clopidogrel and CYP2C19" or a similar search will not return all relevant studies.  PharmGKB:clopidogrel, clinical PGx for clopidogrelSeptember 16, 2010Last updated: I would like to thank Shelley Reyes, Nicole F. Dowling, and Cecelia Bellcross in the Office of Public Health Genomics for comments and guidance. This work was supported by the Office of Public Health Genomics, Office of Surveillance, Epidemiology, and Laboratory Services, Centers for Disease Control and Prevention.The author declares that no competing interests exist.The CDC does not offer medical advice to individuals. If you have specific concerns about your health or genetic testing, we suggest that you discuss them with your health care provider.