Genetic Variants Of The Long Non-coding RNA With Susceptibility To Behcet’s Disease And Its Mechanism Research

Background:Behcet’s disease（BD）,which is often characterized by various symptoms such as recurrent oral ulcers,genital ulcers,ocular inflammation,and skin lesions,is an inflammatory and immune-related uveitis disorder.Although the exact pathogenesis of BD has not been well elucidated,it is generally believed that environmental factors and genetic risk variants may play a pivotal role in an individual’s predisposition to BD.Long noncoding RNAs（lnc RNA）play a crucial role in the process of immune-mediated diseases.However,the defined involvement of lnc RNA on Behcet’s disease（BD）is not well known.Objective:The aim of this study was to investigate the effects of lnc RNA-related single nucleotide polymorphisms（SNPs）on BD susceptibility in Chinese populations.Methods:We selected the candidate SNPs based on the multi-omics approach.A two-stage case-control association study was conducted in a cohort of 1152 BD individuals and 1152 healthy controls.Genotyping was performed using the TYPER software in the Mass ARRAY System.Quantified expression of lnc RNA-mi RNA-m RNA molecular axis were detected by real-time PCR and western blot.The cell proliferation was measured by CCK-8 assay.SPSS V.17.0 software and Graph Pad Prism V.8.0 were employed for all statistical analyses.A two-tailed Student’s t-test was used to compare between two groups and ANOVA was employed for comparison of multiple groups.Results:Two-stage association analysis showed a significantly decreased frequency of A allele of SNP rs7130280 in BD patients compared with healthy controls(OR=0.72,95%CI=0.64-0.81,P_c=1.15×10^-6).Similarly,subjects with AA genotype were at decreased risk of BD compared with those having the GG/GA genotype(OR=0.68,95%CI=0.58–0.81,P_c=5.10×10^-4).Besides,no significant differences were observed regarding the distribution of age of onset and patients carrying A allele showed similar age of onset with GG genotype carriers（P>0.05）.Functionally,SNP rs7130280 could influence the secondary structure and relative expression of NONHSAT159216.1 in human THP-1/U937macrophages and in peripheral blood mononuclear cells from healthy volunteers.In vitro,overexpression of the rs7130280 A allele also suppressed cell proliferation.Mechanistically,rs7130280 A allele could inhibit the expression of mi R-6778-5p,thus enhanced its downstream molecular RPS6KA4/IL10 in a ce RNA sponge manner.Conclusion:Our findings suggest that NONHSAT159216.1rs7130280 G>A might be associated with low risk of BD and participates in a potential lnc RNA-mi RNA-m RNA regulatory network.