Potential functional allele A/T single nucleotide polymorphism (SNP) of Interleukin 8 (IL-8) promoter -251has been implicated in gastric cancer risk.We aimed to explore the role of A/T SNP of IL-8 -251 in the susceptibility to gastric cancer through a systematic review and meta-analysis. Each initially included article was scored for quality appraisal. Desirable data were extracted and registered into databases. Eighteen studies were ultimately eligible for the meta-analysis of IL-8 - 251 A/T SNP. We adopted the most probably appropriate genetic model (codominant model). Potential sources of heterogeneity were sought out via stratification and sensitivity analyses, and publication biases were estimated.Between IL-8 -251 AA genotype with gastric cancer risk, statistically significant association could be noted with overall gastric cancer, evidently noted in Asians, witnessed in high quality subgroup, and apparently noted in intestinal-type gastric cancer.Helicobacter Pylori infection status in our meta-analysis.Our meta-analysis indicates that IL-8 -251 AA genotype is associated with the overall risk of developing gastric cancer and may seem to be more susceptible to overall gastric cancer in Asian populations. IL-8 -251 AA genotype is more associated with the intestinal-type gastric cancer. IL-8 -251 AA genotype is not associated with The analyses suggest that IL-8 -251 AA genotype may be an important biomarker of gastric cancer susceptibility for Asians, especially for Chinese Han population, the assumption that needs to be further confirmed in future well-designed studies in China. Helicobacter pylori infection ultimately develop gastric cancer Nowadays, worldwide gastric cancer incidence has decreased but its mortality still ranks second IL-8, one of key members of the human α-chemokine subfamily, acts as a potent chemoattractant and activator of neutrophils In 2004, Savage et al. published the first study indicating that IL-8 -251A allele is associated with an increased risk for gastric cardia cancer Accordingly, the aim of our meta-analysis was to explore, using the most appropriate genetic model, the role of Il-8 -251 A/T SNP in the risk of developing gastric cancer and to identify possible sources of heterogeneity among the eligible studies.A systematic literature search was performed for articles regarding IL-8 -251 A/T SNP associated with the gastric cancer risk. The MEDLINE, EMBASE databases, Chinese National Knowledge Infrastructure (CNKI), Web of Science, and BIOSIS databases were used simultaneously with the combination of terms “Interleukin 8”, “IL-8”, “interleukin”, or “cytokine”; “gene”; “polymorphism”, “variant”, or “SNP”; and “gastric cancer”, “gastric carcinoma”, “diffuse gastric cancer” or “stomach cancer” from January 2000 to January 2011. The search was performed without any restriction on language. The scope of computerized literature search was expanded according to the reference lists of retrieved articles. The relevant original articles were also sought manually.Studies concerning the association of IL-8 -251 A/T SNP with the risk of developing gastric cancer were included if the following conditions were met: (i) any study described the association of IL-8 -251 A/T SNP with gastric cancer; (ii) any study reported the numbers of both controls and gastric cancer cases; (iii) results were expressed as odds ratio (OR) with 95% confidence intervals (CI); and (iv) studies were case-control or nested case-control ones.Table S1 online) cover credibility of controls, representativeness of cases, consolidation of gastric cancer, genotyping examination, and association assessment. Methodological quality was independently assessed by two investigators (J. Liu and B. Lin). Disagreements were resolved through discussion. Scores ranged from the lowest zero to the highest ten. Articles with the score lower than 6.5 were considered “low-or-moderate quality” ones, whereas those no lower than 6.5 were thought of as “high quality” ones.To identify high-quality studies, we mainly adopted predefined criteria for Quality Appraisal initially proposed by Thakkinstian et al. Helicobacter Pylori infection status.The following data from each article were extracted: authors, year of publication, country, ethnicity of participants , study design, source of controls, number of controls and of cases, genotyping method, distribution of age and gender, Lauren's classification , anatomical classification (cardia or non-cardia cancer) and The data were extracted and registered into two databases independently by two investigators (J. Liu and B.Lin) who were blind to journal names, institutions or fund grants. Any discrepancy between these two investigators was resolved by the investigator (H. Xue), who participated in the discussion with them and made an ultimate decision.All statistical analyses were performed using STATA statistical software . Two-sided Ps<0.05 were considered statistically significant.Hardy-Weinberg equilibrium (HWE) in controls was calculated again in our meta-analysis. The chi-square goodness of fit was used to test deviation from HWE (significant at the 0.05 level).1, OR2, and OR3 regarding IL-8 -251 A/T SNP were calculated for genotypes AA versus TT, TA versus TT, and AA versus TA, respectively.Odds ratios (OR) and 95% confidence intervals (95% CI) were used to assess the strength of associations between IL-8 -251 A/T SNP and gastric cancer risk. OR1 = OR3≠1 and OR2 = 1, a recessive model is suggested. If OR1 = OR2≠1 and OR3 = 1, a dominant model is implied. If OR2 = 1/OR3≠1 and OR1 = 1, a complete overdominant model is suggested. If OR1>OR2>1 and OR1>OR3>1, or OR1<OR2<1 and OR1<OR3<1, a codominant model is indicated The above pairwise differences were used to determine the most appropriate genetic model. If ORThe Q statistic was used to test for heterogeneity among the studies included in the meta-analysis. A fixed-effects model, using Mantel–Haenszel (M-H) method, was employed to calculate the pooled ORs when homogeneity existed on the basis of Q-test p value no less than 0.1.By contrast, a random-effects model, using DerSimonian and Laird method (D+L), was utilized if there was heterogeneity based on Q-test p value less than 0.1. The significance of pooled ORs was tested by Z test (P<0.05 was considered significant).Sensitivity analysis was performed, in which the meta-analysis estimates were computed after every one study being omitted in each turn.Finally, publication bias was assessed by performing funnel plots qualitatively, and estimated by Begg's and Egger's tests quantitatively.After comprehensive searching, a total of 261 articles in English and 8 in Chinese were retrieved. In our meta-analysis were initially included altogether 19 studies Traditionally speaking, any study that deviated from HWE should have been removed; however, Minelli C et al. recently pointed out that studies that appear to deviate from HWE should be investigated further rather than just excluded unless there are other grounds for doubting the quality of the study Thus, 18 studies 1 , OR2 , and OR3  of IL-8 -251 A/T SNP were 1.32 (p = 0.018), 1.12 (p = 0.082), and 1.17 (p = 0.092), respectively, possibly insinuating a codominant model effect of putative susceptible A allele (OR1>OR2>1 and OR1>OR3>1). To further determine whether the adoption of codominant genetic model is influenced by the study deviated from HWE 1 , OR2 , and OR3  of IL-8 -251 A/T SNP, after the study 1 , OR2 , and OR3  of IL-8 -251 A/T SNP among Asian participants, with both the inclusion and the exclusion of the study 1>OR2>1 and OR1>OR3>1 with almost all their p values statistically significantly less than 0.05 or one just reached 0.05). Thus, the inclusion of the study with deviation from HWE ORAs shown in The data were also stratified, in accordance with the quality appraisal scores, into high quality (scores no less than 6.5) and low-and-moderate quality (scores less than 6.5) subgroups. A statistically significant finding was witnessed in high quality subgroup but not in low-and-moderate quality counterpart, given that the pooled ORs  were 1.38  for the former and1.23  for the latter (AA vs TT), and 1.25  for the former and 1.03  for the latter (AA vs TA), respectively.The data were additionally stratified, in line with publication time, into the earlier publication subgroup (articles published before or in 2005) and the later publication subgroup (articles published after 2005). No statistically significant findings were observed on the grounds that the pooled ORs  were 1.39  in the former and 1.28  in the latter (AA vs TT), and 1.23  in the former and 1.13  in the latter (AA vs TA), respectively.When gastric cancer was classified into non-cardia  and cardia subtypes, no statistically significant findings were found among non-cardia type or among cardia type on the grounds that the pooled ORs  were 1.05  among non-cardia type and 1.20  among cardia type (AA vs TT), and 0.85 (0.70–1.04 p = 0.122) among non-cardia type and 1.22  among cardia type (AA vs TA).In terms of pathology, gastric cancer could be classified into intestinal, diffuse, or mixed subtypes, and a statistically significant finding was observed in intestinal-type cancer but not in diffuse-type cancer (AA vs TT), for the pooled ORs  were 1.37  in the former and 1.24  in the latter (AA vs TT).Helicobacter pylori infection status, no statistically significant findings were found among Helicobacter pylori positive cancer patients (compared with Helicobacter pylori positive controls) or among Helicobacter pylori negative cancer patients (compared with Helicobacter pylori negative controls), for pooled ORs  were 1.56  in the former and 0.99  in the latter (AA vs TT), and 1.22  in the former and 0.88 (0.57–1.38), p = 0.589) in the latter (AA vs TA), as shown in In terms of And when genotyping techniques were considered, a statistically significant finding was noted in other genotyping technique subgroup but not in traditional PCR-RFLP subgroup (AA vs TT). In the PCR-RFLP subgroup and in other genotyping technique subgroup, pooled ORs  were 1.28  in the former and 1.34  in the latter (AA vs TT).Meta-analyses were conducted repeatedly when each particular study had been removed. The results indicated that fixed-effects estimates and/or random-effects estimates before and after the deletion of each study were similar at large, suggesting high stability of the meta-analysis results. As shown in Cumulative meta-analyses of IL-8 -251 A/T SNP association were also conducted among Asians via the assortment of both total number of sample size  part A aPublication bias was preliminarily examined by funnel plots qualitatively and estimated by Begg's and Egger's tests quantitatively. Its funnel plot  showed tIn our meta-analysis, a statistically significant finding could be noted (AA vs TT) with the overall risk of developing gastric cancer; the apparently opposite tendency could be noted between Caucasians and Asians, and statistically significant findings were even more apparently noted in Asians, especially in Chinese Han population, but not in Caucasians (AA vs TT). Our meta-analyses suggest that IL-8 -251 AA genotype may be an important biomarker of gastric cancer susceptibility for Asians, especially for Chinese Han population, the assumption that needs to be further confirmed in future well-designed studies in China.Based on the findings of cumulative meta-analyses, the inclinations, though undulated, toward significant associations in Asians could be obviously seen when sorted by total sample size (AA vs TT). The IL-8 -251 AA genotype may seem to be more susceptible to gastric cancer in Asians. Thus, the different or even conflicting risk associations, if so, among different ethnicities should be further meticulously investigated and reconfirmed in the future.Our subgroup analyses also indicate that significant associations could be found in the small-and-moderate sample subgroup but not in the large sample counterpart (AA vs TT). In large sample subgroup the influences of ORs in the studies conducted by Lee et al. Additionally, 8 Helicobacter pylori infection is associated with increased epithelial IL-8 expression and mucosal secretion of IL-8 and Helicobacter pylori induced IL-8 expression in gastric epithelial cells is associated H pylori with CagA positive phenotype Helicobacter pylori positive or negative cancer patients, which is inconsistent with the finding reported by Liu et al. Helicobacter pylori infection subgroup analysis in our meta-analysis but not in the meta-analysis by Liu et al. revealed in their Helicobacter pylori infection status and IL-8 -251 A/T SNP should be further meticulously investigated in the future.Furthermore, With the advent of sophisticated genotyping technologies like seminested polymerase chain reaction, TaqMan allelic discrimination test, or real-time PCR, we may witness an upsurge of genetic association studies in the future. In our meta-analysis, statistically significant finding could be noted in other genotyping technique subgroups but not in conventional PCR-RFLP subgroup. The difference should be concerned with caution. We propose that the sensitivity and specificity of those genotyping techniques need to be further explored so as to seek out the optimal approaches which could minimize the genotyping errors Up to now, two genome-wide association (GWA) studies related to gastric cancer have been published Finally, the strength of our meta-analysis could be summarized as follows. We sought to find as many publications as we could by means of various searching approaches. The study that appeared to deviate from HWE was not excluded mechanically in our meta-analysis unless there are other convincing grounds for doubting the quality of the study Certainly, there are some unavoidable limitations in our meta-analysis. Firstly, the offered information from the included studies is inconsistent. Put it another way, the information about overall gastric cancer susceptibility is predominantly provided, while more important information about pathologic subtypes or anatomic subtypes of gastric cancer is less provided. Thus, the specific subtype results should be considered with caution. Secondly, with the merely published studies included in our meta-analysis, publication bias is very likely to occur, though no or a little statistically significant publication bias is indicated in our meta-analysis. Thirdly, moderate to severe heterogeneity could be witnessed among the included studies. So as to minimize the potential bias, we designed a rigorous protocol before conducting meta-analysis, and performed a scrupulous search for published studies using explicit methods for study selection, data extraction, statistical analysis, adoption of the most appropriate genetic model and sensitivity analysis.Helicobacter pylori infection status in our meta-analysis.In conclusion, IL-8 -251 AA genotype is associated with the overall risk of developing gastric cancer and may seem to be more susceptible to overall gastric cancer in Asian populations, especially for Chinese Han population. IL-8 -251 AA genotype is more associated with the intestinal-type gastric cancer. IL-8 -251 AA genotype is not associated with Table S1Scales for Quality Assessment.(DOC)Click here for additional data file.


ABCB1 gene product P-glycoprotein (P-gp) plays a prominent role as an antiapoptotic factor in addition to its efflux transporter function. ABCB1 polymorphism has been found to be associated with downregulation of P-gp expression. We hypothesized that a similar polymorphism will be found in patients with CoA deposition, as the polymorphism predisposes the hippocampal neuronal and glial cells to seizure-induced excitotoxic damage and CoA formation ensues as a buffer response.Mesial temporal lobe epilepsy (MTLE) is the most common medically refractory epilepsy syndrome in adults, and hippocampal sclerosis (HS) is the most frequently encountered lesion in patients with MTLE. Premature accumulation of corpora amylacea (CoA), which plays an important role in the sequestration of toxic cellular metabolites, is found in the hippocampus of 50–60% of the patients who undergo surgery for medically refractory MTLE-HS. However, the etiopathogenesis and clinical importance of this phenomenon are still uncertain. The ABCB1 gene Ex06+139C/T (rs1202168), Ex 12 C1236T (rs1128503), Ex 17-76T/A (rs1922242), Ex 21 G2677T/A (rs2032582), Ex26 C3435T (rs1045642) among 46 MTLE-HS patients of south Indian ancestry with and without CoA accumulation.We compared five single nucleotide polymorphisms in the P = 0.016).We found that subjects carrying the Ex-76T/A polymorphism (TA genotype) had a five-times higher risk of developing CoA accumulation than subjects without this genotype (Odds ratio 5.0, 95% confidence intervals 1.34-18.55; We speculate that rs1922242 polymorphism results in the downregulation of P-gp function, which predisposes the hippocampal cells to seizure-induced apoptosis, and CoA gets accumulated as a buffer response. ABCB1 gene, is postulated to mediate at least part of the drug resistance.[ABCB1 in the epileptic foci of drug-resistant epilepsy was found to be several-fold elevated in both animal and human studies, indicating its significant role in epilepsy. The C3435T, a major allelic variant of the ABCB1 gene, is proposed to play a crucial role in drug resistance in epilepsy. The C/C genotype carriers reportedly are at a higher risk of pharmacoresistance to AEDs, and this issue has been extensively investigated with conflicting results.[ABCB1 C3435T polymorphism and the risk of drug resistance, suggesting a revision in contribution of this polymorphism in the multi-drug transporters hypothesis of drug resistance in epilepsy.[ABCB1 gene products might be a tissue response to the oxidative stress of epilepsy. Uwai et al. reported an intron 16 polymorphism (Ex-76 T/A) that resulted in downregulation of P-gp function in renal carcinoma cells.[ABCB1 polymorphisms in the premature accumulation of CoA by comparing the distribution of single nucleotide polymorphisms (SNPs) between groups of MTLE-HS patients with and without CoA in their hippocampus.Epilepsy is the most prevalent chronic neurological disorder and is a major public health concern, directly affecting an estimated 50 million people worldwide and involving an additional 500 million people as family members and caregivers of patients. Despite 4sistance.7 The exp results. The receepilepsy.–10 In adepilepsy.12 Hence,ma cells. The Ex-7ma cells. We hypotThe epilepsy patients were recruited through the Epilepsy Clinic at R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Sree Chitra Tirunal Institute of Medical Sciences and Technology at Trivandrum, India. Phenotypic definition of drug resistance is a critical issue in epilepsy genetics. There is no consistent clinical definition of multidrug resistance in epilepsy, and agreement among the different definitions is strong but imperfect. This hasen bloc standard anterior temporal lobectomy with amygdalohippocampectomy.[en bloc along with the uncus and parahippocampal gyrus by subpial dissection using the operating microscope.For MTLE-HS, we performed an mpectomy. After a Four-micrometer-thick histological sections of the resected temporal lobe were generated from 10% formalin-fixed, paraffin-embedded tissue. In addition to the routine hematoxylin and eosin stain, we stained the hippocampal sections with Luxol fast blue–Periodic acid Schiff’s stain to highlight the presence of CoA in the hippocampus and in the adjoining temporal structures . We defiABCB1 Ex06+139C/T (rs1202168), Ex 12 C1236T (rs1128503), Ex 17-76T/A (rs1922242), Ex 21 G2677T/A (rs2032582) and Ex26 C3435T (rs1045642) [We augmented the reported polymorphism with the addition of four SNPs flanking the C3435T, which together capture the majority of the functional variations across 045642) . The gen045642) . PCR proP-value of ≤0.05 was considered as significant. The frequency distribution of allele and genotype frequencies of the five polymorphisms was analyzed in the MTLE-HS-CoA+ and MTLE-HS-CoA– patients in a case-control format using the statistical software UNPHASED (version 2.404). The method for case-control data is a standard unconditional logistic regression identical to the model-free method T5 of EHPLUS and the log-linear modelling of Mander.[P <0.05. All analyses were performed using SPSS statistical analysis software, Version 17.0 .We summarized the quantitative data as mean ± standard deviation (SD). Chi square-tests, Fisher’s exact tests and t-tests were used to evaluate the statistical significance of the difference in clinical characteristics between the MTLE-HS-CoA+ and MTLE-HS-CoA– patient groups. A f Mander. Binary lOf the 46  MTLE-HS patients who were included in the study, 24 (52.1%) were MTLE-HS-CoA+ and 22 (47.9%) were MTLE-HS-CoA–. The mean age at surgery was 32.3 years  and the mean duration of epilepsy prior to surgery was 22.8 years . Antecedent history of febrile seizures was present in 19 (41.3%) patients. In the MTLEHS-CoA+ group, there were 11 patients (45.9%) with grade 1, seven (29.1%) patients with grade 2 and six (25%) patients with grade 3 CoA accumulation. The distribution of variables among the MTLE-HS-CoA+ and the MTLE-HS-CoA– groups of patients is compared in P < 0.0005). The duration of epilepsy before surgery was also borderline significantly longer in the MTLE-HS-CoA+ patients compared with the MTLE-HS-CoA– patients . However, none of the other variables such as age at onset of habitual seizures, seizure frequency, seizure types, history of antecedent events, family history of seizures, presence of mental retardation or other co-morbid conditions and AED use profile differed significantly between the groups.The age at surgery was found to be significantly higher for the MTLE-HS-CoA+ patients compared with the MTLE-HS-CoA– patients  [P = 0.04). After adjustment of the odds ratios for age at surgery, sex, age at onset, duration of epilepsy and genotype frequency, there was a significant difference between the MTLE-HS-CoA+ and the MTLE-HS-CoA– groups  for the TA genotype. The genotype frequency of the 2677G>T/A ABCB1 polymorphism also differed significantly between the MTLE-HS-CoA+ and the MTLE-HS-CoA– groups . Significant differences were observed at the allele level also (P = 0.01). However, after adjustment of the ORs for age at surgery, sex, age at onset, duration of epilepsy and genotype frequency, there was no significant difference between the MTLE-HS-CoA+ and the MTLE-HS-CoA– groups. Similarly, genotype frequencies of the 1236C>T, +139C>T and C3435T ABCB1 polymorphism also did not differ significantly between the MTLE-HS-CoA+ and the MTLE-HS-CoA– groups. However, there was a significant difference at the allele level for the allele frequency of +139C>T (P = 0.03).Patients in the MTLE-HS-CoA+ group were more likely to have the TA genotype at 34-18.5) . SignifiABCB1 gene with the CoA deposition in MTLE-HS in a cohort of south Indian epilepsy patients. This is a novel association for the ABCB1 gene, but its role in CoA deposition can have a biologic plausibility. ABCB1 belongs to the broad group of transporters known as ATP-binding cassette (ABC) transporter of the MDR/TAP subfamily.[In this study, using a strict phenotypic definition, we found an association between the intronic polymorphic variation (TA genotype in Ex17-76) in the ubfamily. The locaABCB1 gene products at the site of tissue damage is a physiological phenomenon for tissue defense. Overexpression of ABCB1 in the epileptic tissue, both in animal and human tissue, was one of the key evidence to propose its role in drug resistance in epilepsy.[ABCB1 in the epileptic foci of drug-resistant epilepsy patients was shown to be elevated 10-fold.[ABCB1 and multidrug-associated protein (ABCC1/MRP1) have also been associated with pathologies associated with drug refractoriness, such as in tuberous sclerosis and also in epileptic tissue surrounding dysembryoplastic neuroepithelial tumors, focal cortical dysplasia and hippocampal sclerosis. The adjacent nonepileptic tissue from the same patients did not show elevated expression of the transporter.[et al.[ABCB1 gene as being associated with resistance to multiple AEDs, and leading to the suggestion, for the first time, that drug resistance in epilepsy might be genetically determined. Since then, several other genetic association studies have attempted to verify this result; however, taken overall, the role of P-gp in drug resistance in epilepsy still remains uncertain.[ABCB1 C3435T polymorphism confer significant risk to drug resistance in epilepsy. In the subgroup analysis for the Asian and the Caucasian populations, none of the genetic comparisons showed a significant association. Hence, the substitution of C to T at position 3435 of the exon 26 of the ABCB1 gene does not effect the response to AEDs in the epilepsy patients with different ethnicities. Even in subgroup meta-analyses based on the new definition of drug resistance by International League Against Epilepsy (ILAE)[ABCB1 gene in epilepsy and more importance must be attributed to its role in tissue defense in epileptic tissue. The role of CoA in sequestration of toxic cellular metabolites is being increasingly recognized and is supported by the presence of ubiquitin and heat shock proteins in CoA and its abundant accumulation in neurodegenerative diseases, where oxidative stress and mitochondrial dysfunction are common denominators compared with age-matched controls.[ABCB1 polymorphisms and CoA accumulation that we observed in our well-characterized MTLE-HS patients? We hypothesize a link through the tissue defense function of ABCB1-encoded P-gp. The Ex-76 T/A has been shown to be in linkage disequilibrium with G2677T and the alleles of Ex-76 T/A formed major haplotypes with G2677T and C3435T.[et al.[ABCB1 polymorphisms are associated with CoA deposition in MTLE-HS patients in south Indian patients, and further substantiate the need to revise its role in epilepsy genetics. However, the association found in our study is modest, most likely due to the small sample size. As the stringent selection criteria resulted in the small sample size, haplotype analysis was not possible. As the G2677T polymorphism  was also found to be associated with CoA deposition and the Ex-76 T/A has been shown to be in linkage disequilibrium with G2677T, the haplotypic analysis would be interesting. Hence, a further study with a larger sample size and P-glycoprotein functional expression studies will be required to establish the relationship between Ex-76 T/A polymorphism and CoA accumulation.Interestingly, in a situation of organ damage or disease, changes in the expression levels of ABC transporters have been observed, probably to compensate for the increased load of harmful products of oxidative stress formed during an insult or to compensate for the loss of efflux pumps in damaged tissue. In addit12epilepsy.22 The ex 10-fold. Elevatednsporter. In 2003,r.[et al. reportedncertain.–10 The fncertain. and the ncertain. Neither sy (ILAE) and ethnd C3435T. AlthoughT.[et al. found th


Understanding genetic factors that affect monoamine neurotransmitters flux in prefrontal cortex may help to further specify the complex neurobiological processes that underlie cognitive function and dysfunction in health and illness. The current study examined the associations between the polymorphisms of dopaminergic  and serotoninergic (5-HTTLPR) genes and the sequential pattern of responses in a motor random generation task providing well-established indexes for executive functioning in a large sample of 255 healthy women. Participants homozygous for the Met allele of the COMT polymorphism showed impaired inhibition of prepotent responses, whereas individuals homozygous for the s-allele of the 5-HTTLPR showed a restricted ability to update information in working memory. Taken together the results indicate differentiated influences of dopaminergic and serotonergic genes on important and definite executive sub-processes related to cognitive flexibility. Most psychiatric disorders including affective disorders, psychotic problems or addiction have been linked to executive dysfunction such as impairment in cognitive flexibility The Catechol-O-methyltransferase (COMT) enzyme plays an important role in modulating the dopamine levels in prefrontal cortex It is widely accepted that serotonin  plays a central role in the regulation of mood and emotion but emerging evidence also suggests a role of 5-HT in executive functions such as top-down attention and inhibitory control , which is a diffuse indicator of brain function comprising several cognitive components. Therefore, more sensitive neuropsychological tools that parse and segregate underlying cognitive processes are warranted to move the research on genetic individual differences in executive functioning forward. It has been posited that some executive functions are difficult to quantify experimentally, because they are rooted in the temporal domain The examination of the temporal organization of behavior requires a behavioral paradigm that enables the repeated measurement of many observations of behavior. Paulus and co-workers The generation of random sequences, also relying on the sequential pattern of responses, may be another promising tool in this context. Random motor generation tasks have proved to be a useful diagnostic tool for the identification of clinically relevant impairments of executive functions in psychiatric and neurological disorders such as schizophrenia The major advantage of random sequence generation tasks is that performance essentially relies on the two components of cognitive flexibility mentioned above It has been proposed that the sequential pattern of behavior in terms of interdependence of responding may be closely linked to the functional status of the dopamine system The purpose of this study was to assess the association between the polymorphisms of dopamine and serotonin systems’ genes and the generation of random sequences using the Mittenecker Pointing Test, which provides specific and well-established indexes of executive functioning and cognitive flexibility. We expected the Met allel of the COMT polymorphism, and the short allele of the 5-HTTLPR genotype, to be associated with relatively poorer performance on the inhibition and the memory updating component of cognitive flexibility, respectively.The study was performed in accordance with the 1964 Declaration of Helsinki and was approved by the Ethics Committee of the Karl-Franzens University, Graz. After complete description of the study, written informed consent was obtained from all participants.M = 22.7, SD = 4.8) were recruited from a larger screening sample (n = 624). All participants were Caucasian and native German speakers recruited at the local university. The students received course credit for their participation. No participant reported suffering from neuropsychiatric disease or was using psychoactive medication. They completed a screening questionnaire concerning demographic data and general information. Furthermore, all subjects were tested with the Mittenecker Pointing Test.A total of 255 healthy female students aged 18 to 59 years  = 1.50, ns.; 5-HTTLPR X2 = 0.62, ns.). Buccal swabs were taken to genotype all participants for the 5-HTTLPR and COMT Met158Val polymorphisms. Data of the total screening sample were in Hardy-Weinberg equilibrium (COMT XThe MPT The symbol redundancy (SR) refers to the inequality of the relative frequencies of chosen keys. The randomness of a series decreases with increasing deviation of the frequency distribution of chosen response alternatives from equality. A SR score of zero denotes maximal equality of the relative frequencies and thus minimal predictability, whereas a score of 1.000 denotes maximal redundancy and, thus, a lack of randomness. SR is related to the memory component (memory monitoring/updating) of random sequence generation The context redundancy (CR) is based on the sequential probability of each chosen key. In true random series all possible dyads (pairs of adjacent responses), but also all possible triples, quadruples etc. are approximately equiprobable, whereas the frequency distribution of dyads deviates from equality, if responses are continuously influenced by previously chosen alternatives. As in most studies of response series, in this paper, too, the CR measure (“second order CR”) is based only on the distribution of pairs of adjacent responses and of single responses as a sufficient measure of redundancy of response series.  and 200 µg/mL Proteinase K  were added to the saliva swab placed in a 1.5-ml microcentrifuge tube. The solution was incubated at 55°C for 30 min, vortexed, incubated at 90°C for 8 min, and finally centrifuged at 13,000×g for 5 min.GCAACCTCCCAGCAACTCCCTGTA, 100 nM primer HTTLPR_R: GAGGTGCAGGGGGATGCTGGAA , and 2 µl sample DNA. The thermal cycling protocol implied an initial denaturation step at 95°C for 10 min, 40 cycles of 96°C for 15 s and 62.5°C for 90 s, and a final extension step at 62.5°C for 30 min. Laser induced fluorescence capillary electrophoretic separation of the PCR products was performed on an ABI Prism 3100 Genetic Analyzer using POP6, 36 cm capillary arrays , and default instrument settings. Prior to electrophoresis, 2 µl PCR product were heat-denatured in 20 µl deionised formamide. Amplicon-length determination was based on the GeneScan-500 LIZ internal size standard (LT). Raw data were recorded and analyzed with the ABI Prism 3100 Genetic Analyzer data collection (v 1.1) and the Genotyper (v 3.6 NT) softwares (both LT). For the computer-assisted calling of the 5-HTTLPR s and l alleles, size bins of 131.2±0.5 nt and 175.2±0.5 nt, respectively, were used. Further, a peak height threshold of 250 rfu was defined .Polymerase chain reaction (PCR) amplification followed the protocol published by Hu et al. For the molecular genetic analysis of the human COMT Val158Met polymorphism the high resolution melting (HRM) curve profiles of short PCR amplicons were analysed.−44 (5′-CCGACTGTGCCGCCATCAC-3′), 250 nM primer COMT-R+27 . The amplification cocktail had a total volume of 20 µl and consisted of 1x Type-it HRM PCR master mix (Qiagen), 250 nM primer COMT-FThe cycler protocol used for amplification comprised an initial denaturation step at 95°C for 5 min followed by 40 cycles of 95°C for 15 s and 68°C for 45 s. The final extension step (68°C) was extended by 10 min. To identify samples featuring exceptionally low or high template molecule concentrations and/or aberrant amplification plots, PCR kinetics was determined by the on-line recording of the signal emitted by the bound double-stranded DNA specific EvaGreen fluorescent dye. Following amplification, the PCR products (71 bp) were subjected to a temperature ramp from 68°C to 95°C (0.1°C increments) without any prior manipulations. EvaGreen fluorescence was continuously recorded to monitor DNA strand dissociation kinetics. For the automated COMT Val158Met genotype calling from the HRM data of unknown samples, the Rotor-Gene ScreenClust HRM software  in the amplicon, a single sample was erroneously attributed by the ScreenClust software to the A/A (Met/Met) instead of the actual G/A  genotype. However, this particular rs4680 genotype was tagged potentially problematic, as it featured low class membership indices (data not shown).The relationships between the genotypes and the two MPT test scores were assessed using two two-way analyses of variance, using the COMT genotype and the 5-HTTLPR genotype as between-subjects factors, and either CR or SR as the dependent variable. The effects of the two genotypes were simultaneously analyzed in one analysis, in order to be able to test the effect of the COMT genotype independently of the 5-HTTLPR genotype and vice versa . In addition, analysis of covariance was conducted to test whether any observed associations for one of the MPT scores remained significant after adjusting for the other, that is, if the effects were either due to shared or unique variance of the two MPT measures.F2,246 = 4.4, p = .013, pη2 = .034). There was no significant main effect of 5-HTTLPR . By contrast, in the analysis with SR as the dependent variable, the main effect of 5-HTTLPR was significant , whereas no significant effect was observed for COMT . Means and standard deviations for the main effects of COMT and 5-HTTLPR are shown in The analysis with CR as the dependent variable yielded a significant main effect of COMT genotype  as compared to carriers of at least one Val allele . The significant main effect of 5-HTTLPR for SR showed impaired memory updating in homozygous s/s carriers  as compared to those carrying at least one long allele .Post-hoc tests (Tukey's HSD) indicated that homozygous Met carriers exhibited poorer performance in the inhibition component of the MPT (CR) than Val/Met carriers, whereas those homozygous for the Val allele did not show any further improvement, thus suggesting that the inhibition of developing routines is impaired in individuals homozygous for the Met allele compared with those carrying one or two copies of the Val allele. Similarly, individuals homozygous for the 5-HTTLPR s-allele showed poorer performance on the memory component of the MPT (CR) than s/l carriers, with no further improvement in l/l homozygotes, suggesting poorer memory monitoring and updating skills in individuals homozygous for the s-allele compared with carriers of the l-allele. To confirm these conclusions, the analyses were repeated testing the COMT Met/Met genotype against the combined Met/Val and Val/Val group, and testing the 5-HTTLPR s/s genotype against the combined s/l and l/l group. The patterns of findings were confirmed for both MPT measures. The significant main effect of COMT for CR showed impaired inhibition in individuals homozygous for the Met allele  and the effect of 5-HTTLPR on SR  remained significant after adjusting for the other MPT variable in analyses of covariance. The means for the main effects of these analyses (adjusted for the other MPT variable) are shown in Confirming the double dissociation pattern, both the effects of COMT on CR .Neither of the two dependent measures were correlated with age  than healthy controls In the current study, the analysis of the 5-HTTLPR genotype showed that individuals homozygous for the s-allele produced higher symbol redundancy in the MPT. Symbol redundancy refers to a balanced selection of single keys and is related to the memory-updating component of random sequence generation However, the role of serotonin in cognition is among the least understood of monoaminergic neurotransmission Again, one caveat in linking genes to cognitive functions is the use of diffuse indicators of brain functions such as many standard neuropsychological tests which measure several cognitive components at the same time. Tests such as the MPT may help to disentangle more specific processes as compared to the more classical tests. The MPT has also advantages compared to the more commonly used random number generation task, in which participants are instructed to say the numbers one to nine in a random fashion for a number of trials. Although there are great similarities, some features of the MPT allow more straightforward interpretations of the functionality of the inhibition and the memory components of random sequence generation A limitation of the study is that the statistical effects of the genetic variants are only small. However, specific genetic variants typically only account for very small amounts of variance in psychological traits. Even when all variants for which evidence suggests an effect are aggregated, the total variance explained typically does not exceed a few percent Further, in the present study, relatively poorer performance was observed in only one group of the COMT and 5-HTTLPR polymorphisms, respectively (Met/Met and s/s). Val/Val homozygotes and l/l homozygotes did not show any further performance improvements as compared to the respective heterozygous group. The literature on genetic effects on cognition is mixed regarding the most impaired groups, and demonstrated effects have rarely been linear. In the present study, a possible explanation for the failure to show more linear effects in the data may be ceiling effects in the relatively young and healthy sample, so that further improvement may have been hardly possible. Nevertheless, replication in further studies seems particularly important for the effect of 5-HTTLPR on memory updating, which is less obvious than the COMT effect on prepotent response inhibition.Taken together, the present results indicate that dopaminergic and serotonergic genes may differentially modulate important and definite executive sub-processes in healthy adult women. Whereas the Val-allele of the COMT polymorphism was associated with better performance on the inhibition component of cognitive flexibility, the l-allele of the 5-HTTLPR genotype was associated with better memory monitoring and updating.


CD226 or DNAM-1 is a type 1 membrane protein belonging to the Ig-superfamily and is involved in the adhesion and co-stimulation of T cells and NK cells. A trend towards association of this SNP with Juvenile Idiopathic Arthritis (JIA) was recently reported, but was not statistically significant (p=0.13) :194-8).Recent genetic studies have reported an association of the Gly307Ser single nucleotide polymorphism (SNP) in the CD226 gene with susceptibility to multiple autoimmune diseases. CD226 Gly307Ser is associated with susceptibility to JIA.We performed a case-control genetic association study to investigate whether CD226 Gly307Ser was genotyped in 667 JIA cases and 1320 healthy controls, both of North-West-European white origin. Allele frequencies were compared. Patients with oligoarticular (persistent and extended), polyarticular (rheumatoid factor negative and positive) and systemic JIA have been included and were analyzed separately as well as grouped together. A meta-analysis of our study combined with the previously published study was performed.CD226 Gly307Ser was significantly associated with susceptibility to JIA , particularly in the persistent oligoarticular subtype . The meta-analysis  confirmed the association with JIA .CD226 with persistent oligoarticular JIA has been identified. This finding is in line with the hypothesis that this oligoarticular subtype is not only phenotypically, but also genetically different from the polyarticular subtypes, including extended oligoarthritis.This study provides evidence for a novel JIA susceptibility locus. Additionally, a subtype-specific association of


Tardive dyskinesia (TD) is a human hyperkinetic movement disorder as a result of potentially irreversible long-term chronic first-generation antipsychotic medications. Unfortunately, mechanisms involved in the development of TD have been poorly understood. Previous studies have indicated that some genetic polymorphisms of immune system and dopamine beta-hydroxylase (DBH) genes may be involved in the pathogenesis of TD. Rs1800872 and rs72393728 are located on the promoter of interleukin-10 (IL10) and DBH gene, respectively. The genetic association between the rs1800872 and TD is unclear. Previous studies have indicated that genetic variations of IL 10 and DBH are implicated in the positive and negative symptoms in schizophrenia. However, the interaction of two variations with severity of TD and symptoms of schizophrenic patients with TD has not been reported. The present study investigated whether these variations and their interaction were associated with clinical phenotypes of TD with schizophrenia in a genetically homogeneous northern Chinese Han population.n = 372) and without TD . The Abnormal Involuntary Movement Scale (AIMS) and Positive and Negative Syndrome Scale (PANSS) were applied to assess the severity of TD and psychopathology of schizophrenia, respectively.Rs1800872 and rs72393728 were genotyped in schizophrenic patients with TD (p>0.05). No significant difference was found in the AIMS total score among the genotypes of two loci (p>0.05). Interestingly, the interaction of rs1800872 and rs72393728 showed a significant association with the PANSS general score (p = 0.011), and a trend toward to the PANSS total score (p = 0.055).The allele and genotype frequencies of rs1800872 and rs72393728 did not significantly differ between TD and NTD patients (These findings suggest that the interaction of rs1800872 and rs72393728 variants may play a role in psychopathology of the general symptoms on PANSS in schizophrenic patients with TD in a northern Chinese Han population. Tardive dyskinesia (TD) is an iatrogenic human hyperkinetic movement disorder and potentially irreversible long-term adverse effect of treatment associated with chronic first-generation antipsychotic medications Cytokines are key proteins involved in the immune system activation. Several studies have demonstrated alterations of the level of interleukins in schizophrenia del) allele is associated with the regulation of promoter activity leading to lower DBH enzyme levels and activity in plasma and cerebrospinal fluid Dopaminergic system abnormality in nature in schizophrenia is presynaptic involving in dopamine synthesis and baseline synaptic dopamine density The susceptibility of schizophrenia with degree of genetic relationship is too complex to be explained by a single gene or the sum of effects of several such genes, and schizophrenia might be an end result of a complex interaction between thousands of genes and multiple environmental factors. The overall genetic contribution to schizophrenia may be large, but none of them on their own could cause schizophrenia. Thus, the inheritance pattern of schizophrenia suggests that each of multiple genes with small effect interacts with one another and with environmental factors nonlinearly to influence susceptibility In this current study, we discussed whether the two vitiations, rs1800872 and rs72393728 on IL10 and DBH genes and their interaction contributed to the susceptibility and the development of TD and the schizophrenic patients’ psychopathology measured by the Positive and Negative Syndrome Scale (PANSS) in a group of northern Chinese Han schizophrenic patients.This project was approved by the Institutional Review Board of Beijing Hui-Long-Guan Hospital. Informed written consent was obtained from all participants before taking part in this study after given a verbal and written complete and detail description of the study. The clinical staff explained the nature of the subjects, risks, benefits of this study. Meanwhile, the participants were informed to opt not to join the study without any influencing on the treatment in the hospital. If a subject could not understand these issues due to the status of mental health impaired, he/she was not asked to take part in this study. If the participant had a possible compromised capacity to consent, his/her next of kin, care takers or guardians consented on the behalf of the participant signed the additional written informed consent.n = 664 males, n = 120 females) took part in this study. Participants were all northern Chinese Han population from Beijing Hui-Long-Guan Psychiatric Hospital and Rong-Jun Hospital in Hebei province. Diagnoses met the criteria for chronic schizophrenia of Diagnostic and Statistical Manual of Mental Disorders, 4th edition. All of them received ongoing stable dose of oral antipsychotic drugs at least one year, when they were recruited. Antipsychotic drug treatment was composed mainly of monotherapy with clozapine (n = 364), risperidone (n = 164), perphenazine (n = 35), sulpiride (n = 42), chlorpromazine (n = 58), haloperidol (n = 27), aripiprizol (n = 24), quetiapine (n = 28) and other typicals and atypicals (n = 42). Mean antipsychotic dose being in chlorpromazine equivalents was 462±452 mg/day. The patients had been on their respective medication for 23.29±10.46 years at the time of the investigation. All patients were chronic type with mean duration of illness for 24.58±9.379 years and between 19 and 73 years old. Subjects without a history of drug abuse or dependence, with the exception of alcohol and nicotine using, took part in this study.Seven hundred eighty-four schizophrenic inpatients  The same four psychiatrists assessed the psychopathology of all participants using the PANSS at begin with all the subjects entering into this present study. The four psychiatrists simultaneously received training ahead of the study. All of the assessments were completed prior to the laboratory experiments.Five milliliter peripheral blood was used to extract genomic DNA with a salting-out method ins/del) genotypes were del homozygote (144 bp), and ins homozygote (163 bp) with 3% agarose gel stained with ethidium bromide The primers and PCR condition of rs1800872 and rs72393728 were applied as the reference t-test for continuous variables was analyzed for testing group differences. Independent variables, including genotype, sex, age, hospitalization time, and age of onset, were analyzed using regression analysis for TD and NTD patients as the dependent variables. Logistic regression was performed to adjust underlying interference factors for TD using TD as a dependent variable and genotype, sex, age, age at onset, antipsychotic type  and duration of antipsychotic treatments as independent and dose of drugs . GMDR project was used to calculate the interactions of polymorphisms and continuous variable, which is a platform of nonparametric and genetic model-free alternative to linear or logistic regression to detect and characterize nonlinear interactions among discrete genetic and environmental attributes p-values were at the significance level of 0.05. We calculated p-values for interaction models based on 1,000 permutations.The SHEsis project p = 0.752 and p = 0.751 for rs1800872, respectively in NTD and in TD group; p = 0.603 and p = 0.930 for rs72393728, respectively in NTD and in TD group). The AA, AC and CC genotypes of rs1800872 were found in 284 (39.78%), 337 (47.20%) and 93 (13.03%) of the 714 patients, respectively, and the genotype data of 70 samples were missing. The ins homozygote, ins/del and del homozygote of rs72393728 were found in 253 (33.64%), 370 (49.20%) and 129 (17.15%) of the 752 patients, respectively, and the genotypes of other 32 samples were not genotyped. There was no significant association found the between rs1800872, rs72393728 and TD .Patients did not show a departure from Hardy-Weinberg Equilibrium in TD group for two polymorphisms (p>0.05 for each locus). Continuous variables were analyzed using a one-way ANOVA for each genotype with respect to sex, age and age at onset for both variations (p>0.05). In addition, No interaction was found between gender and genotype  or between age and genotype in both two loci . Total AIMS scores were 2.66±3.08 for AA, 2.65±3.20 for AC and 2.38±2.48 for CC  in rs1800872. Total AIMS scores were 2.67±2.86 for ins/ins, 2.71±3.39 for ins/del and 2.33±2.95 for del/del  in rs72393728.Demographic variables and PANSS and AIMS scores in each genotype of rs1800872 and rs72393728 are shown in n = 372) and NTD group (n = 412) are shown in t = 3.480, p = 0.001) and hospitalization time  were found between TD and NTD groups. There were more male TD patients  than female TD patients in the whole population . However, no difference was found in age at onset between the two groups . The negative symptom scores on the PANSS were found that there was significant different between TD and NTD subjects (p<0.0001).The differences in demographic and clinical variables between TD , and PANSS negative symptom scores  were risk factors of TD on rs1800872 and rs72393728 respectively. No association was found between genotype and TD .Logistic regression analyses were calculated for some demographic variables, the clinical variables, and the genotypes of rs1800872 and rs72393728 to determine whether these variables were risk factors for TD. To judge the relative importance of the selected independent variables, rs1800872 and rs72393728 genotype was represented as 2 dummy variables, each coded with the number  of alleles, respectively, in each genotype. Sex  was 2.758  in this two-locus (rs1800872–rs72393728) model.To explore the interaction of two loci to the severity of TD and the psychopathology of schizophrenia, we analyzed the influence of rs1800872×rs72393728 to the score of AIMS and PANSS total scores and subscores with GMDR algorithms to detect the top potential interaction between the analyzed variations and distribution of high-risk and low-risk genotypes in the best two-locus model, dark gray and light gray boxes stood for the high- and low-risk factor combinations, respectively. Left bars within each box represented TD while the right bars represented NTD. We found that the interplay had effect on with general symptom scores on the PANSS, and the OR for the high-risk genotype combination (AC)- No significant association was found between TD and rs1800872 and rs72393728 on DBH gene. (2) Age (older age), sex , hospitalization time (longer) and PANSS negative symptoms were major risk factors for TD. (3) The model of rs1800872×rs72393728 may be a risk factor for general symptom scores on the PANSS and for a trend toward significance with total scores on the PANSS of TD patients.We did not detect significant association between rs1800872, rs72393728 and schizophrenia in our research. Older age, male, longer hospitalization time and PANSS negative symptoms were major risk factors for TD, which is consistent with our previous investigation del allele is associated with lowering DBH levels and enzyme activity in plasma and cerebrospinal fluid ins/del might be easy to regulate the patterns of genes expression could result in this specific interaction showing the significance, because of the heterozygote in two genes. The two variations that we genotyped gave us an interaction model of heterozygous, and IL10 and DBH have been identified to influence negative and positive symptoms of schizophrenia, respectively For further explanation for biological significance of interaction, we founded that information of location for the variations, which is noteworthy that rs1800872 and rs72393728 (both located on the promoter) might affect on the expression level of proteins There are several limitations needed to be mentioned in this current study. First, it is important to think about the sample size to detect the effect when initiating a genetic study, but our subjects were relatively large, and needs more participants generally. And the demographic factors were not well-matched, such as gender, age and hospitalization time between TD and NTD groups. Second, although the Chinese around Beijing and Hebei province might be ethnically relatively homogenous, minute differences still exist However, it is important to derive a reasonable biological interpretation of identified gene×gene. To strengthen the reliability of the interaction founded in our study, we conducted analysis by existing biological resources of bioinformatics to aid the biological interpretation of the identified gene×gene. In other words, the goal of this step is to determine known biological evidence that supports the identified gene×gene. A previous study suggested that if two genes are involved in generating the variability of a phenotype together, biological interaction between them or their products must be involved On one hand, there is a mass of interactions mechanisms and phenomena in organism, with feedback regulation at several levels, such as the nucleotide molecular, regulatory factor, signal transduction and metabolic and physiological processes. It seems that the biological system is a network of interplays. On the other hand, interactions might be a consequence of biological evolutionary processes Although the result in the current study may be of limited value for clarifying the underlying pathogeny, more interaction models that identify the potential loci of disorders should generate more power for detection of genetic effects. However, models of gene×gene/gene×environment given by statistical methods are likely to accelerate the discovery and identifying of genetic variants of biological system network, which might be feasible to help understand the real biological explanations for various physiological effects of the researched polymorphisms further. However, whether these polymorphisms are functional and all factors interplay need be confirmed further by experimental evidence finally.


GCK) is the key glucose phosphorylation enzyme which has attracted considerable attention as a candidate gene for type 2 diabetes (T2D) based on its enzyme function as the first rate-limiting step in the glycolysis pathway and regulates glucose-stimulated insulin secretion. In the past decade, the relationship between GCK and T2D has been reported in various ethnic groups. To derive a more precise estimation of the relationship and the effect of factors that might modify the risk, we performed this meta-analysis.Glucokinase  were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association.P<10−4) was found for the GCK −30G>A polymorphism. Significant results were also observed using dominant or recessive genetic models. In the subgroup analyses by ethnicity, significant results were found in Caucasians; whereas no significant associations were found among Asians. In addition, we found that the −30G>A polymorphism is a risk factor associated with increased impaired glucose regulation susceptibility. Besides, −30G>A homozygous was found to be significantly associated with increased fasting plasma glucose level with weighted mean difference (WMD) of 0.15  compared with G/G genotype.A total of 24 articles involving 88, 229 cases and 210, 239 controls were included. An overall random-effects per-allele OR of 1.06 (95% CI: 1.03–1.09; GCK is a risk factor associated with increased T2D susceptibility, but these associations vary in different ethnic populations.This meta-analysis demonstrated that the −30G>A polymorphism of  Type 2 diabetes (T2D) is a complex metabolic disease characterised by hyperglycemia, insulin resistance, impaired insulin secretion due to pancreatic β-cell defects and increased hepatic glucose production. Despite much investigation, the causes underlying the development and progression of T2D have not been fully elucidated, accumulated evidence suggests that multiple genetic and environmental factors, as well as the interplay between these factors, determine the phenotype. Although the genetic contribution to T2D is well recognized, the current set of 56 established susceptibility loci, identified primarily through large-scale genome-wide association studies (GWAS), captures at best 10% of familial aggregation of the disease GCK) is the key glucose phosphorylation enzyme responsible for the first rate-limiting step in the glycolysis pathway and regulates glucose-stimulated insulin secretion from pancreatic β-cells and glucose metabolism in the liver GCK mutations lead to maturity-onset diabetes of the young and neonatal diabetes GCK mutations cause persistent hyperinsulinaemic hypoglycaemia GCK has been shown to be associated with increased risk of type 2 diabetes, hyperglycaemia and impaired beta cell function Glucokinase  without language restrictions. Search term combinations were keywords relating to the glucokinase gene  in combination with words related to T2D  and polymorphism or variation. The search was supplemented by reviews of reference lists for all relevant studies and review articles. The major inclusion criteria were (a) original papers containing independent data, (b) case–control or cohort studies and (c) genotype distribution information or odds ratio (OR) with its 95% confidence interval (CI) and P-value. The major reasons for exclusion of studies were (a) overlapping data and (b) case-only studies, family-based studies and review articles.2 = 1) Data extraction was performed independently by two reviewers, and differences were resolved by further discussion among all authors. For each included study, the following information was extracted from each report according to a fixed protocol: first author’s surname, publication year, definition and numbers of cases and controls, diagnostic criterion, frequency of genotypes, source of controls, age, gender, body mass index (BMI), Hardy–Weinberg equilibrium status, ethnicity and genotyping method. Not all researchers use the same SNP, we report herein 2 common SNPs (rs1799884 and rs4607517), as these SNPs are in complete disequilibrium (rGCK and T2D risk was assessed by odds ratio (OR) with the corresponding 95% confidence interval (CI). We first used the chi square test to check if there was significant deviation from Hardy–Weinberg equilibrium among the control subjects in each study. The meta-analysis examined the association between each polymorphism and the risk of T2D for the: (i) allele contrast, (ii) dominant, and (iii) recessive model. For continuity variable, weighted mean difference (WMD) was used to pool results from studies.The strength of association between −30G>A polymorphism of Heterogeneity across individual studies was calculated using the Cochran chi-square Q test followed by subsidiary analysis or by random-effects regression models with restricted maximum likelihood estimation We assessed publication bias by using an ancillary procedure attributed to Egger et al. Study selection process was shown in GCK, our meta-analysis gave an overall OR of 1.06  and recessive genetic models . This analysis is based on pooling of data from a number of different ethnic populations. When stratifying for ethnicity, an OR of 1.08 , 1.01  and 1.13  resulted for the A allele, among Caucasian, Asian and other ethnic population, respectively. Similar results were also detected using dominant and recessive genetic models (P = 0.02), ADA criterion of 1.13  and for other criterion of 1.05 .For T2D risk and the −30G>A polymorphism of c models . When stP<0.05). In meta-regression analysis, mean age of cases (P = 0.31) and controls (P = 0.24) and genotyping method (P = 0.96) did not significantly explain such heterogeneity. By contrast, ethnicity (P = 0.02) and the sample size in cases (P = 0.01) was significantly correlated with the magnitude of the genetic effect, explaining 11% and 16% of the heterogeneity, respectively. Since significant between-study heterogeneity still maintained in Caucasian subgroup, hence studies on Caucasian populations is the main source of heterogeneity.Significant heterogeneity was present among the included studies  <10−5; P(Q) = 0.73; P(Z) <10−5; P(Q) = 0.56] and recessive  genetic model.To investigate how glucose metabolism was related to glucokinase, we analyzed individuals with impaired glucose regulation (impaired glucose tolerance and/or impaired fasting glucose). The data on genotypes of the −30G>A polymorphism among impaired glucose regulation cases and controls were available in 5 (including 3177 cases and 8970 controls) studies. In the overall analysis, the −30G>A polymorphism of P(Z) <10−5, P(Q) <10−5; P(Z) = 0.001, P(Q)<10−5], respectively.The data on fasting plasma glucose (FPG) level among subjects stratified by genotype of −30G>A polymorphism were available in 6 studies, including 31,616 subjects. Significant increases of fasting plasma glucose level were observed in A allele carriers compared with non-carriers. Using the random-effects model, compared with G/G genotype, the WMD for heterozygous were 0.07 [95%: 0.05–0.08, P = 0.60).Sensitivity analysis indicated that no single study influenced the pooled OR qualitatively, suggesting that the results of this meta-analysis are stable (data not shown). The shape of the funnel plots was symmetrical . The staGCK −30G>A polymorphism and the relationship to T2D risk. Its strength was based on the accumulation of published data giving greater information to detect significant differences. In total, the present meta-analysis combined 24 studies for T2D including 88, 229 cases and 210, 239 controls. Our results demonstrated that a modest association existed between the −30G>A variant of GCK and T2D risk.Large sample and unbiased epidemiological studies of predisposition genes polymorphisms could provide insight into the in vivo relationship between candidate genes and diseases. This is the most comprehensive meta-analysis examining the GCK −30G>A polymorphism may be in close linkage with different nearby causal variants in different populations. Moreover, clinical heterogeneity like age, sex ratio, dietary, years from onset and disease severity may also explain the discrepancy. Finally, such different results could also be explained by study design or sample size. As significant between-study heterogeneity was found among Caucasian subgroup, so the result must be interpreted with caution since the Caucasian population reports in the subgroup analysis include a mixture of populations from very distant countries.In meta-analysis, heterogeneity evaluation was always conducted in statistical analysis. Thus, several subgroup meta-analyses were performed. In the stratified analysis by ethnicity, significant associations were found in Caucasians for the polymorphism in all genetic models; while no associations were detected among Asians. There are several possible reasons for such differences. First, the distribution of the A allele varies extensively between different races, with a prevalence of ∼23% among Asians and ∼17% among Caucasians. Therefore, additional studies are warranted to further validate ethnic difference in the effect of this polymorphism on T2D risk. In addition, different populations usually have different linkage disequilibrium patterns. A polymorphism may be in close linkage with another nearby causal variant in one ethnic population but not in another. GCK influences susceptibility to phenotypes of impaired glucose regulation. In terms of genetic versus environmental influences on T2D susceptibility, this finding supports previous heritability studies, including a Danish twin study, generating considerably higher heritability estimates for the impaired glucose tolerance state compared with manifest T2D The present study also provides evidence that the −30G>A polymorphism of GCK (−30A) allele was previously shown to be associated with type 2 diabetes and increased risk for coronary heart diseases in both diabetic and nondiabetic samples GCK −30A allele causes hyperglycemia is uncertain, but its effect seems constant throughout the lifespan, although insulin secretion is known to decrease with age in the general population. This is in accordance with the constant effect of the GCK −30A allele on fasting glucose reported in several groups of normoglycemic subjects whose median age varied from 8 to 72 years We also observed a significant effect of the −30G>A variant on FPG levels. This confirms a recent observation in a French study GCKA number of factors predict T2D; however, detailed pathogenesis mechanisms of T2D remain a matter of speculation. GCK is a key regulatory enzyme in the pancreatic β-cell, and it plays a crucial role in determining the threshold for glucose-stimulated insulin secretion. Heterozygous inactivating mutations in GCK cause maturity-onset diabetes of the young subtype 2, in which hyperglycemia is present from birth. The decreased expression of functional GCK seems to be the cause of the observed hyperglycemia among maturity-onset diabetes of the young subtype 2 patients. The mechanism by which the −30G>A polymorphism causes hyperglycemia is uncertain. Previously studies suggested that the minor A allele or a genetic variant with which it is in linkage disequilibrium may alters the expression of In interpreting the results, some limitations of this meta-analysis should be addressed. Firstly, in the subgroup analyses, different ethnicities were pooled in the other ethnic group which may bring in some heterogeneity. As studies among the other ethnic group are currently limited, further studies including a wider spectrum of subjects should be carried to investigate the role of these variants in different populations. Secondly, our results were based on unadjusted estimates, while a more precise analysis should be conducted if all individual raw data were available, which would allow for the adjustment by other co-variants including age, drinking status, obesity, cigarette consumption, and other lifestyle. Thirdly, only published studies were included in this meta-analysis. Therefore, publication bias may have occurred, even though the use of a statistical test did not show it.GCK −30G>A polymorphism was significantly associated with increased risk of T2D, particularly in Caucasian population. In addition, GCK –30A allele is a true risk factor for the development of impaired glucose regulation, having a significant impact on FPG level.Despite these limitations, this meta-analysis suggests that Figure S1Study selection process.(TIF)Click here for additional data file.Figure S2GCK −30G>A polymorphism and T2D risk.Begg’s funnel plot of (TIF)Click here for additional data file.Checklist S1(DOC)Click here for additional data file.


VEGFA) gene has been suggested to play an important role in the pathogenesis of diabetic retinopathy (DR). However, the results have been inconsistent. In this study, we performed a meta-analysis to clarify the associations between VEGFA polymorphisms and DR risk.The vascular endothelial growth factor  with 95% confidence intervals (CIs) were calculated using fixed- or random-effects model.p = 0.040) and a dominant model , whereas the association between rs2010963 polymorphism and DR was not significant under all genetic models . In the subgroup analysis, the effect size for rs699947 polymorphism was only marginally significant among European populations under a dominant model , but not among East Asians. After exclusion of outliers which were the source of between-study heterogeneity, there was significant association between rs699947 polymorphism and DR under a homogeneous co-dominant model , even after multiple comparison correction.A total of eight studies (1204 cases and 1198 controls) for rs699947 polymorphism and ten studies (1666 cases and 1782 controls) for rs2010963 polymorphism were included in the meta-analysis. The results suggested that rs699947 polymorphism was marginally associated with DR under a homogeneous co-dominant model (AA vs. CC: OR = 1.69, 95% CI = 1.03-2.77, Our meta-analysis confirmed the significant association between rs699947 polymorphism and DR after exclusion of outliers, and rs2010963 polymorphism might be not associated with DR. Diabetic retinopathy (DR), a micro-vascular complication of diabetes, is a main cause of blindness in adults. It is wVEGFA gene is located on chromosome 6p21.3 and consists of 8 exons. The genetic variants in the VEGFA gene are suggested to influence levels of VEGFA protein expression. To date, many studies have investigated the associations between polymorphisms in the VEGFA gene and DR. -634G/C (+405G/C or rs2010963) polymorphism in the 5′-untranslated region and-2578C/A (−2549I/D (in high linkage disequilibrium with -2578C/A) or rs699947) polymorphism in the promoter region of the VEGFA gene are most frequently investigated. However, the results have been inconsistent[p value under allelic model and recessive model was 0.03. Most importantly, the recent meta-analysis by Qiu et al.[Vascular endothelial growth factor (VEGFA), an endothelial cellspecific mitogen, has been implicated as a major contributor to the development of DR. VEGFA cnsistent. To datensistent-19 have nsistent. Only 6 nsistent. Althougu et al. and inclVEGFA OR VEGF) and (variant OR variation OR polymorphism OR single nucleotide polymorphism OR SNP) and (diabetic retinopathy OR DR OR PDR). All related studies published in English language were included. The reference lists of retrieved articles were hand-searched. If more than one article were published using the same case series, only the study with the latest data was included. The literature search was updated on July 20, 2013.We searched PubMed, EMBASE, Web of Science and Google Scholar literature databases. The search strategy to identify all possible studies involved the use of the following key words:  with DR; (2) used case–control or cohort design; and (3) provided sufficient data for calculation of odds ratio (OR) with 95% confidence interval (CI). The following information was extracted from each study: (1) name of the first author; (2) year of publication; (3) origin of country; (4) sample sizes of cases and controls; (5) genotype distributions of cases and controls; and (6) whether the variant was in HWE in controls. Two authors independently searched articles, assessed the articles for compliance with the inclusion/exclusion criteria, resolved disagreements and reached a consistent decision.The studies included in the meta-analysis met all the following inclusion criteria: (1) evaluated the association of VEGFA polymorphism with DR was estimated by calculating pooled ORs and 95% CIs under a co-dominant, a dominant, and a recessive model, respectively. The significance of pooled OR was determined by Z test . Q test was performed to evaluate the between-study heterogeneity. A random- (DerSimonian-Laird method[p ≤ 0.10) or absence (p > 0.10) of heterogeneity, respectively. Subgroup analyses by ethnicity and type of DR were performed. Sensitivity analysis was performed after excluding one study at a time to test the stability of the result. Begg’s funnel plot, a scatter plot of effect against a measure of study size, was generated as a visual aid to detect bias or systematic heterogeneity[p < 0.05 was considered statistically significant). Data analysis was performed using STATA version 11 . In this meta-analysis, we used four genetic models for each of two polymorphisms, and Bonferroni method was used to correct for multiple comparisons (p = 0.05/8 = 0.00625).The association of d method or fixedd method effects ogeneity. Publicaogeneity . Further subgroup analysis suggested that the effect size was only significant among European populations under a dominant model , but not among East Asian populations under all genetic models .Using the Egger’s test, no publication bias was detected for the studies on rs699947 polymorphism and rs2010963 polymorphism under all genetic models , even after multiple comparison correction was applied.In the present meta-analysis, there was evidence of between-study heterogeneity for both rs699947 and rs2010963 polymorphisms. The meta-regression analysis was performed to explore source of heterogeneity. However, variables such as publication year, ethnicity, sample size in cases and controls can not account for the source heterogeneity. After exclusion of outliers, the heterogeneity for both rs699947 and rs2010963 polymorphisms was abolished. Interestingly, there was significant association between rs699947 polymorphism and DR under a homogeneous co-dominant model  were not controlled for. Second, the effects of gene–gene and gene–environment interactions were not addressed in this meta-analysis since the original publications did not provide the related data. Third, the results in the subgroups should be interpreted with caution because of limited sample size. Fourth, for rs699947 polymorphism, since majority of included studies did not report the association with type of DR, we are unable to perform the further analysis. Fifth, we only assessed two polymorphisms in the VEGFA rs699947 polymorphism and risk of DR after exclusion of outliers, whereas rs2010963 polymorphism might be not associated with risk of DR. Further well-designed large-scale studies with the consideration of gene–gene and gene–environment interactions should be conducted to investigate the association in future.In conclusions, the results of our meta-analysis indicated that there was a significantly association between The authors declare that they have no competing interests.Conceived and designed the study: ZH. Acquisition of data: YS JY. Analysis and interpretation of data: YL, YG, ZH. Drafting the manuscript: YL, YG. Revising the manuscript critically for important intellectual content: YL, YG, YS, JY, ZH. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2415/13/56/prepubVEGFA variants and diabetic retinopathy after exclusion of the outliers.Pooled ORs and 95% CIs of the association between Click here for file


P = 0.049, power = 94%, alpha = 0.05) after the study which deviated from Hardy-Weinberg Equilibrium was excluded, indicating that the ACE I/D gene polymorphism might be associated with HCM. The AGT M235T polymorphism did not significantly affect the risk of HCM. In addition, ACE I/D gene polymorphism did not significantly influence the interventricular septal thickness in HCM patients. In conclusion, the ACE I/D polymorphism might be associated with the risk of HCM.Some studies have reported that angiotensin converting enzyme (ACE) and angiotensinogen (AGT) genes have been associated with hypertrophic cardiomyopathy (HCM). However, there have been inconsonant results among different studies. To clarify the influence of ACE and AGT on HCM, a systemic review and meta-analysis of case-control studies were performed. The following databases were searched to indentify related studies: PubMed database, the Embase database, the Cochrane Central Register of Controlled Trials database, China National Knowledge Information database, and Chinese Scientific and Technological Journal database. Search terms included “hypertrophic cardiomyopathy”, “angiotensin converting enzyme” (ACE) or “ACE” and “polymorphism or mutation”. For the association of AGT M235T polymorphism and HCM, “angiotensin converting enzyme” or “ACE” was replaced with “angiotensinogen”. A total of seventeen studies were included in our review. For the association of ACE I/D polymorphism and HCM, eleven literatures were included in the meta-analysis on association of penetrance and genotype. Similarly, six case-control studies were included in the meta-analysis for AGT M235T. For ACE I/D polymorphism, the comparison of DI/II genotype vs DD genotype was performed in the present meta-analysis. The OR was 0.73 (95% CI: 0.527, 0.998,  Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy (LVH) with predominant involvement of the interventricular septum (IVS) in the absence of hypertension, valvular heart disease, or other evident cardiac or systemic cause HCM is frequently caused by mutations in genes encoding sarcomeric proteins The deletion/insertion (D/I) polymorphism in intron 16 of the gene encoding angiotensin converting enzyme (ACE) on chromosome 17q23 has been associated with several cardiovascular disorders including LVH in untreated hypertension, complications of atherosclerosis In addition, indices of cardiac hypertrophy, such as the mean interventricular septal thickness (IVST), the mean left ventricular mass index, were greater in HCM patients with the ACE DD genotype as compared with II genotype In spite of the above mentioned reports associating RAS and HCM, the studies from different populations have been conflicting and the role of the RAS system in modifying the phenotype in HCM remains controversial. As meta-analysis is a reliable way to combine information from many studies and thus may provide more conclusive answers, we decided to evaluate the influence of ACE and AGT polymorphisms on the HCM phenotype.The following database were searched: PubMed database, the Embase database, the Cochrane Central Register of Controlled Trials database, China National Knowledge Information database, and the Chinese Scientific and Technological Journal database were searched.For the association of ACE I/D and HCM, the following search term were used in searching the PubMed database: “hypertrophic cardiomyopathy”, “angiotensin converting enzyme” or “ACE” and “polymorphism or mutation”. Alternatively, “angiotensin converting enzyme” or “ACE” was replaced with “angiotensinogen” for the association of M235T genotype and HCM. The last search was up to July 2013. No language is limited. In addition, the references of retrieved articles were also screened to find the related papers.Two investigators independently reviewed all studies and extracted the data using a standard information extraction and reached consensus on all items. Only those articles that detected the genotype polymorphism and the patients were diagnosed as HCM were included. For the meta-analysis for the association of genotype and penetrance of HCM, only studies in which control group were healthy people were included. In the present study, we also performed a meta-analysis on the association of IVST/maximal left ventricle wall thickness (MWT) and ACE genotype polymorphism, which studies were all case-case studies.P value of Hardy-Weinberg equilibrium (HWE) in control, origin of control subjects, mean age in case and controls. With regard to risk of bias, each item was classified as yes, no, unclear, which refer to low risk, high risk, and unclear if insufficient information was available for assessment For the meta-analysis for the association of genotype polymorphism and penetrance of HCM, all studies were case-control studies. The quality of studies was independently assessed by two reviewers using a risk of bias assessment for genetic association studies 1 ; OR2 ; and OR3  were explored. The heterogeneity among different studies was tested by the chi-square-based Q statistic test and I square statistics. P<0.1 2<25% is considered low heterogeneity among studies; 25% to 50% moderate, and >50% as high level heterogeneity For the meta-analysis for the association of genotype and penetrance of HCM, the statistical analysis was performed according to the previous studies The most appropriate genetic models were selected as follows 1 = OR2≠1 and OR3 = 1;Dominant model if OR1 = OR3≠1 and OR2 = 1;Recessive model if OR2 = 1/OR3≠1 and OR1 = 1;Overdominant model if OR1>OR2>1 and OR1>OR3>1 (or OR1<OR2<1 and OR1<OR3<1).Codominant model if ORP<0.05 was considered statistically significant.Finally, once the appropriate genetic model was identified, results were pooled again under this genetic model. The significance of the pooled OR was determined using the Z-test. As for the meta-analysis for the association of thickness of IVST/MWT and genotype polymorphism, the combined standard mean difference was compared.Egger's test and the visual symmetry of funnel plot were assessed to examine publication bias of the related studies.http://ims.cochrane.org/revman/download) was used to performed the present meta-analysis. Furthermore, the PS software http://biostat.mc.vanderbilt.edu/wiki/Main/PowerSampleSize) was used to calculate the power of statistical test.In addition, meta-regression was used to explore the source of the heterogeneity by the Stata software. Sensitivity analysis was also performed to test the robustness of the results by excluding studies that deviated from HWE. The Stata software  and Review Manager software 5.2 , P<0.01) except for one study in which “I” allele frequency can not be calculated P<0.01).HWE in control were showed in P<0.01]. The OR1 (II vs DD) and OR2 (DI vs DD) was 0.631 , 0.695 , respectively. The ORs were significantly heterogeneous for OR1 . Neither the publishing year nor the region was the main origin of the heterogeneity. The meta-regression did not identify the source of heterogeneity. Therefore, the random effects model was used to pool these studies by logistic regression. The gene model was most likely to be dominant model. Then, the comparison of DI+II vs DD was performed in the present meta-analysis.For the association of genotype and penetrance, the eligible 11 studies included 916 cases and 1692 healthy people for ACE I/D were brought into the meta-analysis. The overall gene effect was significant As for the association of genotype and penetrance of AGT M235T, six studies consisted of 634 cases and 1096 healthy people were included. The overall gene effect was not significant .For the association of IVST/MWT and ACE I/D genotype in HCM patients, there were eight studies included in the present meta-analysis. The pooled standard mean difference was 0.05  after excluding the three studies which the left ventricular wall index was MWT rather than IVST. Similarly, there is no publication bias for the association of ACE I/D genotype and IVST/MWT because a symmetrical funnel plot.Sensitivity analysis indicated that the pooled IVST standard mean difference was not statistically significant Click here for additional data file.Appendix S1An appendix for Stata commands used in the present meta-analysis.(DOC)Click here for additional data file.


Oral and pharyngeal cancers are the sixth most common cancers internationally. In the United States, there are about 30,000 new cases of oral and pharyngeal cancers diagnosed each year. Furthermore, survival rates for oral and pharyngeal cancers have not significantly improved over the last three decades. This review examines the scientific literature surrounding the epidemiology of oral and pharyngeal cancers, including but not limited to risk factors, disparities, preventative factors, and the epidemiology in countries outside the United States. The literature review revealed that much of the research in this field has been focused on alcohol, tobacco, and their combined effects on oral and pharyngeal cancers. The literature on oral and pharyngeal cancer disparities among racial groups also appears to be growing. However, less literature is available on the influence of dietary factors on these cancers. Finally, effective interventions for the reduction of oral and pharyngeal cancers are discussed. Oral and pharyngeal cancers (OPC) are considered an important part of the global burden of cancer, mainly due to the widespread use of tobacco and alcohol. In the United States, cancers of the oral cavity account for nearly 2.3% of cancers and also have a relatively low five-year survival rate . There aThough much of the literature on OPC risk factors is dominated by tobacco studies, there have been several studies that have established the protective effects of a healthful diet. Certain protective factors against developing OPC include the consumption of coffee, vegetables, fruit, and dietary folate intake ,9. OtherThis review examines the scientific literature surrounding OPC, including but not limited to OPC risk factors, OPC disparities, OPC preventative factors, and OPC in countries outside the United States.PubMed [Google Scholar [The methods for the inclusion of scientific articles in this review are liberal in nature. This review does not aim to be wholly comprehensive of all the literature on OPC, rather, it highlights the most relevant articles in the literature, and discusses the most important finding in each study. No exclusion criteria were applied when deciding which scientific articles would be included in this review. The search engines PubMed , and Goo Scholar  were useAlso, unlike conditions such as the metabolic syndrome (MetS) where the definition is not wholly agreed upon or standardized , there wTobacco use is understood to be the most important risk factor for the development of OPC . Much ofA separate case-control study performed on Italian and Swiss men also found large risk increases for oral cancer (OR = 228) and pharyngeal cancer (OR = 100) for the highest level of drinking (≥ 77 drinks/week) and smoking (≥ 25 cigarettes/day) combined . The autIn addition, alcohol consumption has been shown to be associated with increased odds of OPC among never smokers. Fioretti et al (1999) examined 42 cases of OPC among never smokers and found that the major risk factor for OPC in never smokers was alcohol consumption, with an OR three-fold higher in drinkers than non-drinkers .Another case-control study that confirmed a multiplicative synergism between smoking and alcohol consumption on OPC examined 1,114 cases and 1,268 controls. Similar results were found as the above studies in that among those that smoked two or more packs of cigarettes and four or more drinks per day, there was an observed 35-fold increase in the risk of OPC. The authors estimate that smoking and drinking combined account for about 75% of all OPC in the United States . A similMoreover, a study examining the separate effects of alcohol in non-smokers and smoking in non-drinkers also found results similar to the above studies cited. This study was performed essentially to test the relative independence that smoking and alcohol consumption has on the development of OPC. The ORs were 1.5 for 14-55 versus 0-13 drinks per week, and 2.2 for 56 drinks or more in non-smokers. The ORs for non-drinkers who smoked were 3.8 for smokers of < 15 cigarettes per day and 12.9 for ≥ 15 cigarettes per day . This isInterestingly, two studies found that among male current smokers, those that used filter cigarettes had a reduced risk of oral cancer than those who used non-filter cigarettes ,24. HoweLess research has been focused on risk factors besides smoking and drinking and their relationship with OPC. However, there is some evidence that meat, vegetable, and vitamin intake may be related to OPC. A case-control study on meat consumption in Uruguay among nearly 4,000 cases showed a significant increase in the odds of having OPC  with a high intake of red meat . SeveralDietary vitamin C consumption of > 745 mg/week was also shown to protect subjects from developing OPC (OR = 0.39) . AnotherVitamin D intake was also found to have an inverse risk on OPC (OR = 0.76) . The samEven fewer studies have examined factors besides tobacco, alcohol, and diet and the relation to OPC development. A familial-based study found non-significant odds ratios associated with any cancer in the family. However, a slightly elevated OR of 1.6 (95%CI 1.1-2.2) for OPC was found among family members whose sisters developed cancers . This asThough much of the literature regarding the risk factors of OPC is slightly dated, this is not the case for OPC disparities research. This type of research in the literature seems relatively new in nature. Much of the literature shows there to be differences in mortality, incidence, and survival among black and white males in the United States. For example, Goodwin et al (2008) shows there to be an unequal burden or disparity among black and white Americans with respect to OPC incidence and survival . They arWithin a specific state, a study performed on OPC survival in Florida found that black Americans had higher hazard ratios (HR range: 1.20-1.53) than white Americans across all sites and stages . An inteIn addition, the impact of health insurance status on stage of diagnosis of OPC has been found to lead to a late-stage diagnosis. Schrage and Halpern (2007) found that patients with advanced OPC at diagnosis were more likely to be uninsured with an OR of 1.37 (95%CI 1.21-1.25) compared with patients who had private insurance. Similar results were found for patients who were covered by Medicaid, who presented with the largest tumors, and with the greatest degree of lymph node involvement. This study presents a diagnosis disparity based on insurance status. That is, being uninsured or on Medicaid increased the odds of presenting with more advanced and severe OPC, thus increasing the risk of lower survival   on the evidence in the literature on interventions for OPC concluded there was insufficient evidence on the effectiveness of population-based interventions for early detection of OPC . This stOne important social issue associated with OPC deals mainly with the disparity present between black and white Americans. Though this disparity may potentially be due to an unaccounted confounder, the burden of OPC mortality and lower survival is placed heavily on black Americans. Inability to pay for medical bills, increased rates of smoking and alcohol use, cultural beliefs, a late-stage diagnosis of OPC, etc, may be partly due to the lower survival rates and higher mortality rates experienced by black Americans with respect to OPC.Improving the incidence, mortality, and survival rates of OPC requires a multi-tier structural approach that targets society, dentists, communities, and the individual. Dentists should encourage their patients to quit smoking and abusing alcohol. In addition, dentists could also be compensated for reducing smoking rates among their patient population; this would be a clear incentive for dentists to engage in their patient population. Silverman 2001) argues that efforts should be maximized to increase the early detection of localized lesions and pre-cancers, coupled with "aggressive" counseling in tobacco cessation and alcohol use for OPC outcomes to improve [001 argueReducing smoking rates through the enactment of a nation-wide smoking ban would also reduce OPC, given the highly interrelatedness of smoking and OPC. Reducing alcohol consumption should also be targeted. The number of alcohol outlets can be mitigated by making it available only in pharmacies. This policy can also be applied to cigarettes.This review revealed interesting information about the literature on OPC. There were several noticeable biases within the literature, however. Many of the research articles cited included European study populations. Populations in non-European countries must be examined to ensure the relative generalizability of the results. Also, most of these studies were case-control studies, and not prospective cohort studies. This presents a limitation in the generalizablitiy and causal inference one can make from these studies. However, that most of the studies found similar results highlight the strength of the association of several of the risk factors  related to OPC. Future research study designs should be prospective cohorts with large sample sizes that firmly establish the risk factors associated with the development of OPC.OPC: oral and pharyngeal cancers; MetS: metabolic syndrome; ICD-10: International Classification of Diseases-tenth revision; OR: odds ratio; HR: hazard ratio.The author declares that he has no competing interests.DMS conceived the manuscript and wrote the entirety of the manuscript. All authors read and approved the final manuscript.