And susceptibility to inflammatory bowel diseases and colorectal drehdphones cancer Relationship between the polymorphism of tumor necrosis factor g and susceptibility to inflammatory bowel diseases and colorectal cancer:A metaanalysis Wang fan1, wang maoqing2, chen wangyang3, hu fulan1, li dandan1, ren jiaojiao1, dong xinshu4, cui binbin4 and zhao yashuang1 1Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, Heilongjiang Province, PR China2Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, Heilongjiang Province, PR China3Department of Epidemiology, Institute of Cancer Prevention and Treatment, Harbin Medical University, Harbin, Heilongjiang Province, PR China4Department of Abdominal Surgery, Tumor Hospital, Harbin Medical University, Harbin, Heilongjiang Province, PR ChinaCorrespondence:Dr z yashuang, department of epidemiology, school of public health, harbin medical university, harbin, heilongjiang province, pr china. Top of pageabstractinflammatory bowel disease(Ibd)And colorectal cancer(Crc)Are common health problems worldwide.Tumor necrosis factor(Tnf)Is a type of cytokine that indUces inflammation and inhibits tumorigenesis.Several studies have assessed the relationship between the polymorphism of tnf g and the susceptibility to ibdAnd crc;However, the results have been controversial.In addition, the hypothesis whether the increased risk of crc in ibd patients could be partly ascribed to the polymorphism of tnf g was unclear.Therefore, we condUcted this metaanalysis to confirm these associations.Pooled odd ratios(Ors)And 95 confidence intervals(95 CIs)Were calculated on the basis of data from 14, 18, and 7 studies from a total of 27 studies for the associations between the polymorphism of tnf g and ulcerative colitis, crohn's disease(Cd)And crc.In europeans, the aa genotype increased the risk of ulcerative colitis(Uc) (Or, 2.041;95 CI, 1.261 and CD(Or, 1.730;95 CI, 1.168 significantly, without obvious heterogeneity and publication bias.Meanwhile, the ga genotype increased the risk of uc in asians(Or, 2.360;95 CI, 1.269 significantly.However, no significant association was observed for crc in any ethnic population.The results of this metaanalysis suggested that the polymorphism of tnf g participates in modifying the susceptibility to uc and cd in europeans and asians.The increased risk of crc in ibd patients should be clarified as the combined effects of polymorphisms in tnf and other cytokines, and the interaction with environmental factors, in future studies. Keywords:Tumor necrosis factor crohn's disease;Ulcerative colitis;Inflammatory bowel disease;Colorectal cancer Top of pageintrodUctioninflammatory bowel disease(Ibd)Refers to two chronic diseases caused by an inflammatory condition of the intestine:Ulcerative colitis(Uc)And crohn's disease(Cd).Extensive studies have suggested that ibd is a multifactorial disease that has arisen from both environmental risk factors and genetic susceptibility.5, 6 Previous genetic association studies mainly focused on the relationship between IBD and the genetic variants in HLA genes instead of on genes involved in immune regulation and inflammatory response.Recent identification of polymorphisms in the tumor necrosis factor(Tnf gene gave suggestions on understanding the genetic predisposition of these two diseases.7, 8 The human tnf gene was first cloned in 1985.It maps to chromosome 6p21.3 and encodes a multifunctional proinflammatory cytokine that belongs to the TNF superfamily.Tnf has several actions, such as stimulating the acute phase response, leading to an increase in the level of creactive protein, and producing Il1 oxidant and inflammatory lipid prostaglandin e2.Large amounts of tnf are released in response to lipopolysaccharides, other bacterial products, and interleukin1(Il1). Studies have highlighted that small differences at cytokine levels as a result of genetic variants may have an important effect on inflammatory response and may influence the pathophysiology.Two snps located at nucleotides and have been extensively researched on the susceptibility to a range of autoimmune disorders, including rheumatoid arthritis, 9 exfoliation glaucoma, 10 and many kinds of cancers.11, 12, 13 The hypothesis that TNF G may have important roles in the development of UC, CD, and CRC has been debated.The results of previous association studies were inconsistent.Moreover, whether the increased risk of crc in ibd patients could be partly ascribed to the polymorphism of tnf remains unclear.Therefore, to further explore the relationship between the promoter g polymorphism in tnf and the risk of uc, cd, and crc, we conducted a systematical review and a metaanalysis. Top of pagematerials and methods Search strategypubmed, cochrane and embase were retrieved for the association studies focused on the relationship between the polymorphism of tnf g and the risk of ibd and crc primarily.Only the fulltext papers published in english were included. Criteria of inclusionAndexclusionany human association study, regardless of sample size, was eligible(1)If it pertained to1 the relationship between the polymorphism of tnf gAndthe risk of ibd or crc; (2)The genetic information of included studies was from unrelated populations; (3)Controls of included studies were from a healthy population or were subjects without diseases related to ibd or crc; (4)The genotype distribution of the control population was in hardy equilibrium;And(5) for the articles with overlap data of the same population resource, only the latestAndlargest report was included. Baseline informationAnddata were extracted by two reviewers independently using the same standard. In addition, the quality of studies was assessed by these two reviewers adopting the quality assessment score method, which was based on traditional epidemiological considerationsAndgenetic issues.14 Another reviewer adjudicated the differences between them. Statistical analysisvariant allele frequencies were compared between cases and controls in different ethnic populations.Compared with wildtype homozygote gg, ors, and 95 cis for the heterozygote ga and the variant homozygote aa were calculated, respectively.The relationship between the polymorphism of tnf g and the risk of uc, cd, and crc was further analyzed by categorizing into different ethnic populations.The associations with p were considered as being statistically significant.Homogeneity among the included studies was assessed using the cochrane q value and i2.When obvious heterogeneity was detected, a randomeffects model was used;Otherwise, a fixedeffects model was adopted.Publication bias was investigated using graphical evaluation of funnel plots.In addition, the possible presence of publication bias was assessed by rank correlation and linear regression.If significant publication bias was detected, ors and 95 cis would be adjusted by trim and fill. Analyses were performed with the software spss(13.015, Permanent licence, Stats Data Mining Co., Ltd, Beijing, China).Ors and 95 cis were generated by cma(Comprehensive meta analysis v2(2005)Biostat, inc., Englewood, NJ, USA). ToPof pageresultsmain characteristics of included studiesdetails beats by dre uk for literature search were shown in figure 1.Finally, 27 studies were included in this metaanalysis.Six of them were on asians, and the others were conducted on a european population.In all, 25 of the 27 studies were populationbased case studies, except for two hospitalbased case studies.Data were obtained from 14, 18, and 7 studies for the association between the polymorphism of tnf g and uc, cd, and crc, respectively.Genotype and variant allele frequencies were presented in table 1in these included studies, ibd patients were diagnosed with conventional pathological examination or selected from definite cases in the hospital.Crc patients were confirmed by histological diagnosis.All cases were matched with unrelated healthy individuals or volunteers recruited from the same ethnic population.In these 27 studies, pcrrflPor pcrsscPwas chosen for genotyping in 18 studies, and realtime pcr assays with(Taqman, life technologies corporation, carlsbad, ca, usa)Primers and probes were used in the others.No statistically significant differences in variant allele frequencies between cases and controls were found in either europeans(Por asians(P(Table 2).Compared with asian controls(Mean 0.052 European controls carried a higher frequency(Mean 0. 174 Pof the allele (Table 2).There were no significant associations for the comparisons of ga vs gg and ga vs gg in these two ethnic populations.As only one study carried out in asians was included, onesample ttest was used to compare the differences of allele frequencies between european and asian controls(PNo significant association was observed between the polymorphism of TNF G and the risk of CRC.Most ors and 95 cis adjusted by the trim and fill method were listed in table 3. As shown in figures 2a and b, the graphics of funnel plot revealed that no publication bias in the dominant genetic model was observed in the total analysis of uc and cd.Only the funnel plot of crc was asymmetrical and adjusted by the trim and fill method(Figure 2c).Rank correlation and the linear regression approach have also been used to evaluate potential publication bias.Detailed results are listed in table 3.
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