| Background:Psoriasis is a chronic immune-mediated inflammatory skin disease characterized by excessive proliferation of keratinocytes.It is manifested as erythema papula damage overlying white scales clinically,and it can damage joints.It has a strong genetic predisposition,genome-wide association analysis（GWAS）studies have identified a large number of susceptibility genes previously,with complex genetic heterogeneity,gene interactions study between susceptibility genes are also important parts of genetics.Gene interaction plays an important role in many autoimmune diseases,such as systemic lupus erythematosus,rheumatoid arthritis and multiple sclerosis.There are also studies on the interaction of susceptibility genes in psoriasis,but the study only involves a little part of genes.This study aims to explore more gene interactions of psoriasis.Objective:In this study,we aimed to find significant gene-gene interactions based on the genome-wide association analysis of psoriasis,which further explained the etiology and pathogenesis of psoriasis and enriched the genetic pattern of psoriasis in Chinese Han population.Method:Based on our previous GWAS data,using case-control studies,including exome-sequencing（781 psoriasis cases and 676 controls）,targeted sequencing 1326related genes and HLA regions sequencing（9946 cases and 10,689 controls）,then to explore gene interactions between them.We replicated 49 variants in an independent cohort of 5414 cases and 5556 controls,those variants are reported loci in the exome and targeted sequencing previously.Next,we analyzed gene interactions between variants with p<0.05.All samples were Chinese Han people.The P value,odds ratio（OR）and 95%confidence interval（95%CI）of association studies were obtained by PLINK 1.07.The multifactor dimensionality reduction（MDR,V2.0 Beta 2）was used to calculate the interactions between variants.Results:In this 3 datasets（exome,targeted and HLA regions sequencing data）,the strongest interactions were between HLA-C*06:02 and rs118179173(P=8.21×10-20,OR=0.22)and between HLA-C*06:02 and HLA-B:AA67(P=1.22×10-12,OR=0.45),which were reached the standard of Bonferroni correction.Forty-nine variants were available for replication stage after quality control,of which 29 variants were nominally significant（P<0.05）.Among those variants,ERAP1 showed the strongest association with psoriasis(chr5＿96118852,P=9.92×10-9,OR=0.85;chr5＿96117300,P=1.28×10-8,OR=0.86;chr5＿96125910,P=1.49×10-8,OR=0.86;chr5＿96121715,P=7.12×10-8,OR=0.86;chr5＿96121994,P=1.56×10-7,OR=0.86;chr5＿96124447,P=2.73×10-6,OR=0.88),further,we analyzed the haplotypes of the ERAP1 using this 6 variants with the most significant associations.Eleven haplotypes showed associations with psoriasis,in which 5 were only found in psoriatic cases,did not exist in healthy controls,the most 2 significant haplotypes were GCCACT(P=7.09×10-23)and AGTGGC(P=3.95×10-22).Meanwhile,there are two haplotypes found both in cases and control,ACTGCT(P=9.64×10-10,OR=0.84)showed protective effect,GGCAGC showed risk effect(P=1.38×10-3,OR=1.10).Next,we analyzed gene interaction between variants with p<0.05,while the most interaction was between ERAP1 and ERAP2(chr5＿96118852×chr5＿96222183,P=2.43×10-4,OR=0.85),and this reached the standard of Bonferroni correction.Interactions between IL18R1 and ERAP1 were also suggestive in this stage.Conclusion:In this study,we found significant gene–gene interactions of psoriasis.We have identified significant genetic interacting signals within the HLA complex,in no-MHC region,we find gene interaction between ERAP1 and ERAP2,previously reported interactions have also been confirmed,including interactions between HLA and ERAP1,HLA and IL12B.Moreover,we also replicated variants that were reported in the previously study,ERAP1 showed the strongest association with psoriasis,we futher analyzed haplotypes in ERAP1,it plays an important part in prediction of psoriasis risk. |
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