Association of IL-12β rs3212227 and Psoriasis

connective of IL-12 rs3212227 and PsoriasisTitle Associations between IL-12 rs3212227 polymorphism and susceptibility to psoriasis a meta-analysisRunning title Association of IL-12 rs3212227 and psoriasisHighlightsWe performed a Meta-analysis to assess the necktie ofIL-12 rs3212227 and psoriasis.Association between IL-12 rs3212227 and psoriasis was proved.IL-12 rs3212227 is the susceptibility ingredient of psoriasis in Asian and European.AbstractPurpose The aim of this meta-analysis was to explore whether IL-12 rs3212227 polymorphism chit-chat susceptibility to psoriasis.Methods We performed a computerized literature search before December 2013. Review Manger 5.2 was employ to perform meta-analysis. The meta-analysis was conducted on the associations between IL-12 rs3212227 polymorphism and the risk of psoriasis.Results society studies involving 17,620 subjects were include in this meta-analysis. Significant association was found between psoriasis and IL-12 rs3212227 allele in all study subjects (C vs. A OR=0.68, 95%CI =0.64-0.72, PConclusions This meta-analysis demonstrated that the IL-12 rs3212227 polymorphism is associated with the risk of psoriasis.Keywords IL-12, polymorphism, psoriasis, Meta-analysis, susceptibility geneIntroductionPsoriasis is an immune-mediated chronic inflammatory skin disease, characterized by epidermal hyperplasia and infiltration of leukocytes into the dermis and epidermis 1. An youthful systematic review 2 describe that the prevalence in children ranged from 0% (Taiwan) to 2.1% (Italy), and in adults it varied from 0.91%(United States) to 8.5% (Norway). In children, the incidence estimate reported (United States) was 40.8/100,000person-years. In adults, it varied from 78.9/100,000 person-years (United States) to 230/100,000 person-years (Italy).It reported that psoriasis occurred by the interaction between genetic and environmental factors 3 and the immune mechanism plays an essential role in the chronic development and pr ogression of psoriasis 4. However, until now the use up etiology and pathogenesis of psoriasis remain unclear 5. menstruumly, the study of psoriasis susceptibility genes is a hot research direction.IL-12 is a kind of list cytokines involved in T cellular ph nonpareil immune 6. It confirmed thatIL -12 is closely related to the pathogenesis of psoriasis . rs3212227 is a SNP in 3 untranslated region 7. Tsunemi et al. 8 reported the association of rs3212227 with risk of psoriasis. Capon et al. reported that there was significant association between rs3212227 and psoriasis. It showd that IL-12 rs3212227 may be one of the psoriasis susceptibility genes. The aim of this meta-analysis was to determine whether IL-12 rs3212227 polymorphisms confer susceptibility to psoriasis.MethodsLiterature searchA literature search was conducted use PubMed, Medline and Embase up to December 2013. We screened all fields by combining the term psoriasis or psoriatic, interleukin-12 or IL-12 and genetic polymorphism or genetic variant. infusion criteriaLiteratures were include in this meta-analysis if they met each of the following criteria (1) case-control studies between patients with psoriasis (experimental group) and hospital-based or population-based individuals (control group), (2) published English literatures involving studies of association between IL-12 genetic polymorphism and psoriasis, and (3) having the entropy of genotype and relative frequency of allele in the experimental and control group or obtaining by computing. Studies were excluded when genotype distribution in the control group did not meet the evidence of hardy-weinberg equilibrium.Data extraction and feeling assessmentData extraction was conducted by two reviewers independently. Disagreements between reviewers were resolved by discussion with a third investigator. From the include studies, the following data were abstracted the first author name, year of publication, country or race, genotype distribut ion inthe experimental and control group, gender ratio and stringent age of the subjects in the experimental and control group. In this meta-analysis, we applied the criteria based on Clark et al 9 to assess the quality of include studies. On the basis of their ca-cas, the included studies were classified into three levels low quality (0-4), moderate quality (5-7)and high quality (8-10).Statistical analysisTest of hardy-weinberg equilibrium 10 was conducted to ensure the quality of the included literatures before running meta-analysis. Review Manger 5.2 was used to perform meta-analysis. Odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated under five genetic frameworks the allele model (C vs. A), the dominant model (CC+AC vs. AA), the recessive model (CC vs. AA+AC), the homozygous/additive model (CC vs. AA) and the heterozygous model (CC vs. AC). Heterogeneity was evaluated using by the chi-square-based Q statistic ladder 11 and I2 test with 12. Subgroup analys is was performed by the difference of ethnicity. The sensitivity analysis was conducted to see the stability of pooled results by sequential omission of individual studies 13. Funnel plots were used to assess the theory of publication bias.ResultsLiterature searchIn total, 114 potentially relevant studies were identified and screened after an initial search. Among them, 98 articles were excluded after screening based on abstracts or titles. Five out of these 16 remaining literatures were excluded because of duplicate publication. Then 2 studies were removing because there was no available data. As a result, 9 literatures were included in this meta-analysis. A flow diagram of the search process is shown in Fig.1.Characteristics of included studiesThe characteristics of 9 included studies 8, 14-21 were summarized in circumvent 1. The publication years of these studies ranged from year 2002 to 2013. A total of 17,620 subjects were involved in this meta-analysis, including 6,520 psori asis patients and 11,150 healthy controls. The race of these subjects was Caucasian or Asian except one study in which mix racial subjects were studied. no(prenominal) of the SNPs had genotype frequencies that deviated significantly from HardyWeinberg equilibrium in these included studies. All quality scores of included studies were from 5 to 8. It showed that the included studies were moderatehigh quality literatures in this meta-analysis.Meta-analysis of the association between IL-12 rs3212227 polymorphism and psoriasisSummary results of this meta-analysis for the association between IL-12 rs3212227 polymorphism and psoriasis were shown in Table 2. For the genotype model of CC+AC vs. A, no heterogeneity (I2=57%, P=0.02) existed in the included literatures, so the random effects model was used. For the other genotype model, fixed effects model was used because of significant heterogeneity among studies.The meta-analysis results showed the highly significant association of these al leles with psoriasis (C vs. A OR=0.68, 95%CI =0.64-0.72, PC vs. A OR= 0.66, 95%CI =0.61-0.70, PSensitivity analysis and publication biasSensitivity analysis by dropping one study at a time did not indicate the dominant influence of any single study. The funnel plot showed that there was no obvious publication bias was shown in the result.DiscussionIn this meta-analysis, we feature data from published studies to evaluate genetic associations between polymorphisms of IL-12 rs3212227 and psoriasis. Our meta-analysis of IL-12 rs3212227 showed significant association of the IL-12 rs3212227 polymorphisms with the risk of psoriasis. Another meta-analysis 22 reported the association of IL-12 rs3212227 and psoriasis. Compared with that one, there were three the advantages of this meta-analysis. The first one was that this meta-analysis had been more recently (2013) conducted to synthesize evidence concerning the association of IL-12 rs3212227 and psoriasis. Second, furthermore subgroup anal ysis by ethnicity was performed and showed that the results did not varies with the difference of ethnicity. Third, the publication meta-analysis reported no heterogeneity among the included studies. Nevertheless, in this meta-analysis, heterogeneity was found among the included studies in the genotype model of CC+AC vs. AA. Exploring the sources of heterogeneity was useful to study the association of IL-12 rs3212227 and psoriasis. Thus, further well-designed studies postulate to focus on exploring the sources of heterogeneity.In the publication studies, it demonstrated that IL-12 was closely related to the pathogenesis of psoriasis. It reported that the mRNA 23and protein expression 24 of IL-12 p40 was increased in the psoriatic skin. Efficacy was obtained by the dose therapy on immunization targets 25. The SNP, rs3212227, is located in IL-12 gene 26. The expression of IL-12 p40 was changed after import homozygous gene fragment into cell 27. It indicated that the change of allele office cause change in the expression of IL-12p40 and affect the function of IL-12p40. Then a series of immune responses were triggered. Finally, these events would lead to the onset of psoriasis. These findings prove that IL-12 rs3212227 may be the susceptibility gene of psoriasis. The result of this meta-analysis provided further evidence of the association betweenthe polymorphisms of IL-12 rs3212227 and psoriasis.It reported that the occurrence of psoriasis varied according to geographic region 2. And the family genes are difference in each region. In this meta-analysis, subgroup analysis was performed by the difference of ethnicity. However, the subjects did not contain all the population. Thus, it proved that rs3212227 is the susceptibility gene of psoriasis in Asian and European. Further studies accept to be done to study the influence of ethnicity.Present study has some limitations that require specific consideration. The first one is that there is no enough data of age an d sex to concern the influence of these confounding factors for the result of this meta-analysis. Second limitation is that the type of psoriasis cannot be analyzed because of the limited information. Furthermore, there are more other possible susceptibility genes, but only one of them was selected to do this meta-analysis.ConclusionsIn conclusion, we determined that there was significant association between the polymorphisms of IL-12 rs3212227 and psoriasis. IL-12 rs3212227 has a frigid role in the pathogenesis of psoriasis. For researching the pathogenesis of psoriasis, all the susceptibility genes as well as the interaction among them need to be studied in the future.References1. Bromley SK, Larson RP, Ziegler SF, Luster AD IL-23 Induces Atopic Dermatitis-Like turmoil Instead of Psoriasis-Like Inflammation in CCR2-Deficient Mice. PloS one 2013, 8(3)e58196.2. Parisi R, Symmons DP, Griffiths CE, Ashcroft DM Global epidemiology of psoriasis a systematic review of incidence and pr evalence. Journal of Investigative Dermatology 2012.3. Naldi L Risk Factors for Psoriasis. Current Dermatology Reports 2013, 2(1)58-65.4. 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Nature genetics 2001, 27(2)218-221.Table 1 Characteristics of included studies.AuthorsYearCountrypopulationExperimental group/control groupscorePHWEmare%age (years)nCapon F12007UKEuropean65.4/5052.1/-318/28880.05Capon F22007UKEuropean42.4/5044.1/49519/52880.05Cargill M12007USAEuropean45.528467/50070.5876Cargill M22007USAEuropean45.529498/49870.9129Eiris N2012SpainEuropean54/5547/47304/42260.1045Hffmeier U2009GermanyEuropean62/5848.2/31.61114/93760.05Nair RP12008GermanyEuropean360/109770.05Nair RP22008USAEuropean1450/142570.05Nair RP32010ThailandAsian58/4234/45206/11470.8488Oka A2013JapaneseAsian560/5608Smith RL2008UKMixed581/468160.5815Tsunemi Y2002JapaneseAsian143/10050.3177PHWEthe result of the test of hardy-weinberg equilibriumTable 2 Meta-analysis of the associations between IL-12 rs3212227 polymorphisms and psoriasisPolymorphismpopulationTest of associationTest of heterogeneityOR (95%CI)pPI2C vs. AOverall0.68 (0.64, 0.72)0.1827%European0.66 (0.61, 0.70)Asian0.71 (0.62, 0.82)CC+AC vs. AAOverall0.61 (0.53, 0.71)0.0257%European0.62 (0.52, 0.73)Asian0.45 (0.25, 0.82)CC vs. AC+AAOverall0.53 (0.43, 0.66)0.850%European0.48 (0.36, 0.64)Asian0.56 (0.36, 0.85)CC vs. AAOverall0.46 (0.36, 0.57)0.780%European0.42 (0.31, 0.56)Asian0.43 (0.26, 0.70)AC vs. AAOverall0.65 (0.59, 0.71)0.1633%European0.62(0.56, 0.69)Asian0.66 (0.44, 0.98)Figure legendsFig.1 Selection of relevant publications, reasons for exclusion.Fig.2 Forest plot displaying the results of the meta-analysis on the genotype of C vs. AFig.3 Funnel plot analysis of publication bias.________________________________________________________________________