Association Study Of Long Noncoding RNAs Expression Levels And Their Gene Polymorphisms With Systemic Lupus Erythematosus

Background Systemic lupus erythematosus(SLE)is a chronic multisystem autoimmune disease which is characterized by multiple autoantibody production,formation of immune complexes that result in multiple tissue or organ damage.To date,the exact pathogenic mechanism of SLE is still unknown.Over the past decades,experimental and clinical studies indicated that the interaction of genetic,environmental,and immunoregulatory factors may be involved in the initiation and promotion of SLE.Many genes associated with susceptibility to SLE have been identified through the genome-wide association studies(GWASs).Previous studies of SLE were mainly focused on coding genes,and the report of noncoding genes was rarely.Besides many widely studied classes of short noncoding RNA(nc RNA),such as micro RNAs(mi RNA),long noncoding RNA(lnc RNA)is a class of nc RNA longer than 200 nucleotides,which have emerged as important regulators of diverse biological functions.Although the accurate functions of lnc RNAs remains largely unclear,a number of studies have revealed that lnc RNAs can participate in various critical biological processes,such as chromatin remodeling,gene transcription,RNA splicing,and protein transport diverse mechanisms,implicating their impact on a wide range of complex human diseases.Recently,a number of lnc RNAs have been considered as an important role in the regulation of human immune system and been reported to be involved in the pathogenesis of immune-mediated inflammatory diseases.So we hypothesized thatlnc RNAs may play a critical role in the pathogenesis of SLE.Objective In the present study,we aimed to investigate the expression levels of several lnc RNAs(GAS5,lnc-DC,linc0597 and linc0949)in peripheral blood mononuclear cells(PBMCs)from SLE patients and healthy controls,as well as the relationship between these lnc RNAs gene polymorphisms and susceptibility to SLE.Methods A two stage case-control design was applied.85 SLE patients and 71 healthy controls were enrolled to investigate the lnc RNAs expression levels in PBMCs in stage one.Then,860 SLE patients and 831 healthy controls were included to detect the single nucleotide polymorphisms(SNPs)in the differentially expressed lnc RNAs in stage two.Expression levels of lnc RNAs were detected by quantitative real-time reverse transcription polymerase chain reaction(q RT-PCR).Genotyping was performed using the Taq Man SNP genotyping assays by a Fluidigm EP1 platform.?=0.0125(0.05/4)when Bonferroni correction was used to do the 4 expression levels of lnc RNAs and 4 SNP analysis,? was 0.05 in the other analysis.Results(1)The expression levels of linc0597,lnc-DC and GAS5 were significantly lower in SLE patients than healthy controls(Z=-5.984,P<0.001;Z=-3.703,P<0.001;Z=-2.995,P=0.003 respectively).No significant differences in linc0949 expression level was found between SLE patients and healthy controls(Z=-0.254,P=0.799).(2)The expression levels of linc0597 was significantly decreased in lupus nephritis(LN)compared with SLE patients without nephritis(Z=-2.411,P=0.016),moreover,the expression levels of linc0597 were significantly decreased in positive proteinuria(Z=-2.865,P=0.004)compared with the negtive.The expression levels of linc0949,lnc-DC and GAS5 did not shown any differences between LN and non-LN(all P>0.05).(3)The expression level of linc0597 was negative correlated with systemic lupus erythematosus disease activity index 2000(SLEDAI-2K)(rs=-0.267,P=0.013).There were no association between the expression levels of of linc0949,lnc-DC and GAS5 with SLEDAI-2K(all P>0.05).(4)Four SNPs(rs10515177 for lnc-DC;rs2070107,rs2632516,rs2877877 for linc0597)with SLE risk were analyzed.Significant association was observed between the distribution of genotype(CC vs.GG)at SNP rs2070107 and susceptibility to SLE(?2=7.164,P=0.007),but there was no significant association after adjustment for gender and age(?2=5.000,P=0.025).An increased risk was also found in the recessive model(CC vs.CG+GG)(?2=7.244,P=0.007),however,after adjustment for gender and age there were no significant association(?2=5.220,P=0.022).There were no significant association between susceptibility to SLE and polymorphisms of the other SNPs(rs10515177,rs2632516,rs2877877)(all P>0.0125).(5)Linc0597 expression level in PBMCs may be associated with the genotype(CC+CG vs.GG)of rs2070107 in the exploration of 34 patients(Z=-2.236,P=0.025).Conclusions The expression levels of linc0597,lnc-DC and GAS5 in SLE patients were significantly down-regulated than those in the healthy controls,but there was no significant difference in the expression level of linc0949 in SLE cases and healthy controls.Further analysis showed that the expression level of linc0597 in SLE with LN was lower than that in non LN cases,and the expression level of linc0597 may be negatively correlated with SLE disease activity.The results of genotyping showed that rs2070107 gene polymorphism was associated with susceptibility to SLE,but the association between rs2070107 and SLE was disappeared after adjustment by gender and age whenBonferroni correction was taken into consideration.