An Association Study Between ERAP1, ERAP2, SLC9B1, AARS2, EXOC4 Gene Indel Variant And Psoriasis

Background Psoriasis is a common immune-mediated, papulosquamous disease typically characterized by red plaques covered by white or silvery scales,the plaques are well-delineated from surrounding normal skin., usually distributed symmetrically,and occur most commonly on the extensor aspects of elbows and knees. The age, race, geographical environment and other factors are involved in the incidence of psoriasis. The highest incidence is in Nordic, accounting for 3%, while Asian countries are lo w, less than 0.5%. Until now the pathogenesis of psoriasis is still not clear, the genetic factor plays a crucial role in the pathogenesis of psoriasis. Our previous whole-genome targetd sequence found ERAP1（chr5₉6145335_A/ACT, chr5₉6126822_T/TA）, ERAP2（chr5₉6258006_G/GAAA, chr5₉6258101_CAT/C）, SLC9B1（chr4₁04025745_C/CTA）, AARS2（chr6₄4382119_GAGA/G） and EXOC4（chr7₁33399868_C/CT） acted as the candidate indel（insertion/deletion） of psoriasis. Then we carried out a validation experiment in independent samples to further confirm the correlation between the indel and psoriasis.Objective The correlation between ERAP1, ERAP2, SLC9B1, AARS2 and EXOC4 gene indel and psoriasis will be further confirmed through validation experiment. Then we perform a combined statistical analysis of the two stages. Then we explore the association among ERAP1（chr5₉6145335） indel and psoriasis by the stratified analysis of psoriasis phenotype.Methods A validation test was performed to analyze the candidate indel variant in independent samples（2208 cases vs 2208 controls）. Then we performed the statistical analysis of combined data with Plink1.07. Regression analysis was conducted to identify whether ERAP1（chr5₉6145335, chr5₉6126822）, ERAP2（chr5₉6258006, chr5₉6258101） in a same chromosome belong to the same signal. We arranged the clinical information of 12154 cases and 12114 controls, including targeted sequence and verification data. The indel variant information was from target sequencing studies and validation. With a series of data collection, induction and creating an excel table, we carried out a statistic analysis about genotype- phenotype of indel variant significant in validation test with Plink1.07 software, obtaining the P-value, OR value and 95% CI（95 % confidence interval）.Result 1. ERAP1（chr5₉6145335, chr5₉6126822） and ERAP2（chr5₉6258006, chr5₉6258101） indel variant were significantly associated with psoriasis（P96145335 = 8.24 × 10-08, OR = 0.794; P96126882 = 1.3 × 10-04, OR = 1.181; P96258006 = 1.41 × 10-05, OR = 0.825; P96258101 = 4.51 × 10-05, OR = 0.834）. There was no si gnificant correlation between SLC9B1（chr4₁04025745）, AARS2（chr6₄4382119）, EXOC4（chr7₁33399868） indel variant and psoriasis(PSLC9B1 = 0.25, OR = 1.051; PAARS2 = 0.99, OR = 0.999; PEXOC4 = 0.44, OR = 0.951. 2. Two-phase combining analysis revealed four indel reached a significant level of the whole genome :ERAP1（chr5₉6145335, Pcombined = 3.98×10-20,OR = 0.8462; chr5₉6126822, Pcombined = 6.67 × 10-12, OR = 1.135）, ERAP2（chr5₉6258006, Pcombined = 1.40×10-09, OR = 0.8931; chr5₉6258101, Pcombined = 1.87×10-09, OR = 0.8939）. SLC9B1（Pcombined = 3.76×10-04, OR = 1.067）, AARS2（Pcombined =1.11×10-04, OR = 0.902） and EXOC4（P = 0.02, OR = 1.067）could not reach a significant level of the whole genome.3. Regression analysis of ERAP1（chr5₉6145335, chr5₉6126822） and ERAP2（chr5₉6258006, chr5₉6258101） confirmed they belonged to the same signal. 4. There was no statistical significance in the study between ERAP1（chr5₉6145335） and the four phenotypes.Conclusion In the validation phase, we found ERAP1 and ERAP2 gene indel variant significantly associated with psoriasis. Combined analysis of two phases showed ERAP1, ERAP2 gene indel variant reached a significant level of the whole genome, further confirmed ERAP1 and ERAP2 gene indel variant might be associated with genetic susceptibility to psoriasis. While ERAP1（chr5₉6145335） indel variant was not relevant with specific phenotype of disease.