Abstract:
Background: Psoriasis is a common immune-mediated hyperproliferative skin dysfunction with known genetic predisposition. Gene-gene interaction (e.g., between HLA-C and ERAP1) in the psoriasis context has been reported in various populations. As ERAP1 has been recognized as a psoriasis susceptibility gene and plays a critical role in antigen presentation, we performed this study to identify interactions between ERAP1 and other psoriasis susceptibility gene variants. Methods: We validated psoriasis susceptibility gene variants in an independent cohort of 5,414 patients with psoriasis and 5,556 controls. Multifactor dimensionality reduction (MDR) analysis was performed to identify the interaction between variants significantly associated with psoriasis in the validation cohort and ERAP1 variants. We then conducted a meta-analysis of those variants with datasets from exome sequencing, target sequencing, and validation analyses and used MDR to identify the best gene-gene interaction model, including variants that were significant in the meta-analysis and ERAP1 variants. Results: We found that 19 of the replicated variants were identified with p < 0.05 and detected six single-nucleotide polymorphisms of psoriasis susceptibility genes in the meta-analysis. MDR analysis revealed that the best predictive model was that between the rs27044 polymorphism of ERAP1 and the rs7590692 polymorphism of IFIH1 (cross-validation consistency = 9/10, test accuracy = 0.53, odds ratio = 1.32 (95% CI, 1.09-1.59), p < 0.01). Conclusion: Our findings suggest that the interaction between ERAP1 and IFIH1 affects the development of psoriasis. This hypothesis needs to be tested in basic biological studies.
摘要:
背景:银屑病是一种常见的免疫介导的过度增生性皮肤功能障碍,具有已知的遗传易感性。基因-基因相互作用(例如,HLA-C和ERAP1)在银屑病背景下已在不同人群中报道。由于ERAP1已被认为是银屑病易感基因,并且在抗原呈递中起关键作用,我们进行这项研究是为了确定ERAP1与其他银屑病易感基因变异体之间的相互作用.方法:我们在5,414例银屑病患者和5,556例对照的独立队列中验证了银屑病易感基因变异。进行多因素降维(MDR)分析以鉴定验证队列中与银屑病显著相关的变体与ERAP1变体之间的相互作用。然后,我们用外显子组测序的数据集对这些变异进行了荟萃分析,目标测序,和验证分析,并使用MDR来确定最佳的基因-基因相互作用模型,包括在荟萃分析中显著的变异体和ERAP1变异体.结果:在meta分析中,我们发现19个重复变异体被鉴定为p<0.05,并检测到6个银屑病易感基因的单核苷酸多态性。MDR分析显示,最佳预测模型是ERAP1的rs27044多态性和IFIH1的rs7590692多态性之间(交叉验证一致性=9/10,检验准确性=0.53,比值比=1.32(95%CI,1.09-1.59),p<0.01)。结论:我们的发现表明,ERAP1和IFIH1之间的相互作用影响银屑病的发展。这一假设需要在基础生物学研究中进行检验。