Association of IL-12β rs3212227 and Psoriasis

Association of IL-12ÃŽ ² rs3212227 and Psoriasis Title: Associations between IL-12ÃŽ ² rs3212227 polymorphism and susceptibility to psoriasis: a meta-analysis Running title: Association of IL-12ÃŽ ² rs3212227 and psoriasis Highlights: We performed a Meta-analysis to assess the association ofIL-12ÃŽ ² rs3212227 and psoriasis. Association between IL-12ÃŽ ² rs3212227 and psoriasis was proved. IL-12ÃŽ ² rs3212227 is the susceptibility gene of psoriasis in Asian and European. Abstract Purpose The aim of this meta-analysis was to explore whether IL-12ÃŽ ² rs3212227 polymorphism confer susceptibility to psoriasis. Methods We performed a computerized literature search before December 2013. Review Manger 5.2 was used to perform meta-analysis. The meta-analysis was conducted on the associations between IL-12ÃŽ ² rs3212227 polymorphism and the risk of psoriasis. Results Nine studies involving 17,620 subjects were included in this meta-analysis. Significant association was found between psoriasis and IL-12ÃŽ ² rs3212227 allele in all study subjects (C vs. A: OR=0.68, 95%CI =0.64-0.72, P Conclusions This meta-analysis demonstrated that the IL-12ÃŽ ² rs3212227 polymorphism is associated with the risk of psoriasis. Keywords IL-12ÃŽ ², polymorphism, psoriasis, Meta-analysis, susceptibility gene Introduction Psoriasis is an immune-mediated chronic inflammatory skin disease, characterized by epidermal hyperplasia and infiltration of leukocytes into the dermis and epidermis [1]. An recent systematic review [2] reported 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 progression of psoriasis [4]. However, until now the exact etiology and pathogenesis of psoriasis remain unclear [5]. Currently, the study of psoriasis susceptibility genes is a hot research direction. IL-12 is a kind of key cytokines involved in T cell 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 indicated that IL-12ÃŽ ² rs3212227 may be one of the psoriasis susceptibility genes. The aim of this meta-analysis was to determine whether IL-12ÃŽ ² rs3212227 polymorphisms confer susceptibility to psoriasis. Methods Literature search A literature search was conducted using PubMed, Medline and Embase up to December 2013. We screened all fields by combining the term â€Å"psoriasis† or â€Å"psoriatic†, â€Å"interleukin-12ÃŽ ²Ã¢â‚¬  or â€Å"IL-12ÃŽ ²Ã¢â‚¬  and â€Å"genetic polymorphism† or â€Å"genetic variant†. Selection criteria Literatures were included 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-12ÃŽ ² genetic polymorphism and psoriasis, and (3) having the data of genotype and 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 test of hardy-weinberg equilibrium. Data extraction and quality assessment Data extraction was conducted by two reviewers independently. Disagreements between reviewers were resolved by discussion with a third investigator. From the included studies, the following data were abstracted: the first author name, year of publication, country or race, genotype distribution inthe experimental and control group, gender ratio and mean 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 included studies. On the basis of their scores, the included studies were classified into three levels: low quality (0-4), moderate quality (5-7)and high quality (8-10). Statistical analysis Test 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 models: 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 test [11] and I2 test with ÃŽ ±12]. Subgroup analysis 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 possibility of publication bias. Results Literature search In 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 studies The characteristics of 9 included studies [8, 14-21] were summarized in Table 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 psoriasis 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. None of the SNPs had genotype frequencies that deviated significantly from Hardy–Weinberg equilibrium in these included studies. All quality scores of included studies were from 5 to 8. It showed that the included studies were moderate–high quality literatures in this meta-analysis. Meta-analysis of the association between IL-12ÃŽ ² rs3212227 polymorphism and psoriasis Summary results of this meta-analysis for the association between IL-12ÃŽ ² 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 alleles 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, P Sensitivity analysis and publication bias Sensitivity 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. Discussion In this meta-analysis, we combined data from published studies to evaluate genetic associations between polymorphisms of IL-12ÃŽ ² rs3212227 and psoriasis. Our meta-analysis of IL-12ÃŽ ² rs3212227 showed significant association of the IL-12ÃŽ ² rs3212227 polymorphisms with the risk of psoriasis. Another meta-analysis [22] reported the association of IL-12ÃŽ ² 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-12ÃŽ ² rs3212227 and psoriasis. Second, furthermore subgroup analysis 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. Ex ploring the sources of heterogeneity was useful to study the association of IL-12ÃŽ ² rs3212227 and psoriasis. Thus, further well-designed studies need 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 [23]and protein expression [24] of IL-12 p40 was increased in the psoriatic skin. Efficacy was obtained by the drug therapy on immunization targets [25]. The SNP, rs3212227, is located in IL-12ÃŽ ² 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 might 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-12ÃŽ ² rs3212227 may be the susceptibility gene of psoriasis. The result of this meta-analysis provided further evidence of the association betweenthe polymorphisms of IL-12ÃŽ ² 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 need 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 and 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 many other possible susceptibility genes, but only one of them was selected to do this meta-analysis. Conclusions In conclusion, we determined that there was significant association between the polymorphisms of IL-12ÃŽ ² rs3212227 and psoriasis. IL-12ÃŽ ² rs3212227 has a pivotal 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. References 1. Bromley SK, Larson RP, Ziegler SF, Luster AD: IL-23 Induces Atopic Dermatitis-Like Inflammation 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 prevalence. Journal of Investigative Dermatology 2012. 3. 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Journal of dermatological science 2002, 30(2):161-166. 9. Clark MF, Baudouin SV: A systematic review of the quality of genetic association studies in human sepsis. Intensive care medicine 2006, 32(11):1706-1712. 10. Ledwina T, Gnot S: Testing for Hardy-Weinberg equilibrium. Biometrics 1980:161-165. 11. Lau J, Ioannidis JP, Schmid CH: Quantitative synthesis in systematic reviews. Annals of internal medicine 1997, 127(9):820-826. 12. Feng R-N, Zhao C, Sun C-H, Li Y: Meta-analysis of TNF 308 G/A polymorphism and type 2 diabetes mellitus. PloS one 2011, 6(4):e18480. 13. Liu ZH DY, Xiu LC, Pan HY, Liang Y, Zhong SQ, Liu WW, Rao SQ, Kong DL: A meta-analysis of the association between TNF-alpha -308G>A polymorphism and type 2 diabetes mellitus in Han Chinese population. PloS one 2013, 8(3):e59421. 14. 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Smith RL, Warren RB, Eyre S, Ho P, Ke X, Young HS, Griffiths CEM, Worthington J: Polymorphisms in the IL-12ÃŽ ² and IL-23R Genes Are Associated with Psoriasis of Early Onset in a UK Cohort. Journal of Investigative Dermatology 2007, 128(5):1325-1327. 22. Zhu KJ, Zhu CY, Shi G, Fan YM: Meta-analysis of IL12B polymorphisms (rs3212227, rs6887695) with psoriasis and psoriatic arthritis. Rheumatology international 2013, 33(7):1785-1790. 23. Jiqun C, Yating T, Jiawen L, Changzheng H, Zhixiang L, Daofan L: A study on the expression of interleukin (IL)-10 and IL-12 P35, P40 mRNA in the psoriatic lesions. Journal of Tongji Medical University 2001, 21(1):86-88. 24. Yawalkar N, Karlen S, Hunger R, Brand CU, Braathen LR: Expression of interleukin-12 is increased in psoriatic skin. Journal of investigative dermatology 1998, 111(6):1053-1057. 25. O’Neill JL, Kalb RE: Ustekinumab in the therapy of chronic plaque psoriasis. Biologics: targets therapy 2009, 3:159. 26. Smith RL, Warren RB, Eyre S, Ho P, Ke X, Young HS, Griffiths CE, Worthington J: Polymorphisms in the IL-12ÃŽ ² and IL-23R genes are associated with psoriasis of early onset in a UK cohort. Journal of Investigative Dermatology 2007, 128(5):1325-1327. 27. Morahan G, Huang D, Ymer SI, Cancilla MR, Stephen K, Dabadghao P, Werther G, Tait BD, Harrison LC, Colman PG: Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele. Nature genetics 2001, 27(2):218-221. Table 1 Characteristics of included studies. Authors Year Country population Experimental group/control group score PHWE mareà ¯Ã‚ ¼Ã‹â€ %à ¯Ã‚ ¼Ã¢â‚¬ ° age (years) n Capon F1 2007 UK European 65.4/50 52.1/- 318/288 8 >0.05 Capon F2 2007 UK European 42.4/50 44.1/49 519/528 8 >0.05 Cargill M1 2007 USA European 45.5 28 467/500 7 0.5876 Cargill M2 2007 USA European 45.5 29 498/498 7 0.9129 Eiris N 2012 Spain European 54/55 47/47 304/422 6 0.1045 Hà ¼ffmeier U 2009 Germany European 62/58 48.2/31.6 1114/937 6 >0.05 Nair RP1 2008 Germany European 360/1097 7 >0.05 Nair RP2 2008 USA European 1450/1425 7 >0.05 Nair RP3 2010 Thailand Asian 58/42 34/45 206/114 7 0.8488 Oka A 2013 Japanese Asian 560/560 8 Smith RL 2008 UK Mixed 581/4681 6 0.5815 Tsunemi Y 2002 Japanese Asian 143/100 5 0.3177 PHWEà ¯Ã‚ ¼Ã…’the result of the test of hardy-weinberg equilibrium Table 2 Meta-analysis of the associations between IL-12ÃŽ ² rs3212227 polymorphisms and psoriasis Polymorphism population Test of association Test of heterogeneity OR (95%CI) p P I2 C vs. A Overall 0.68 (0.64, 0.72) 0.18 27% European 0.66 (0.61, 0.70) Asian 0.71 (0.62, 0.82) CC+AC vs. AA Overall 0.61 (0.53, 0.71) 0.02 57% European 0.62 (0.52, 0.73) Asian 0.45 (0.25, 0.82) CC vs. AC+AA Overall 0.53 (0.43, 0.66) 0.85 0% European 0.48 (0.36, 0.64) Asian 0.56 (0.36, 0.85) CC vs. AA Overall 0.46 (0.36, 0.57) 0.78 0% European 0.42 (0.31, 0.56) Asian 0.43 (0.26, 0.70) AC vs. AA Overall 0.65 (0.59, 0.71) 0.16 33% European 0.62(0.56, 0.69) Asian 0.66 (0.44, 0.98) Figure legends Fig.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. A Fig.3 Funnel plot analysis of publication bias. ________________________________________________________________________