Expression Of CREBL2,CDKN1B,and GPR19 In Peripheral Blood Mononuclear Cells In Systemic Lupus Erythematosus

Background Systemic lupus erythematosus(SLE)is a kind of chronic autoimmune connective tissue disease involving multiple systems,it is characterized by the production of diverse autoantibodis and the incompetent clearence of immune complexes.It has diverse clinical manifestations with obvious individual differences in the treatment effects and prognosis.It is known that the incidence of SLE is related to the genetic background,environmental factors,estrogen levels,etc,and the genetic factors is crucial to SLE.With the development of the research methods of human genomics and genetics,the research on the genetic mechanism of SLE is increasingly deepened.At present,we found more than 60 susceptibility loci in different populations though linkageassociation analysis and genome-wide association study(GWAS).In 2013 a metaanalysis of published studies among different races of SLE found that the adjacent genes CREBL2,CDKN1 B,GPR19 were associated with SLE and had minimum linkage disequilibrium(LD)with each other,and the associations of SLE with the SNP rs12822507,rs34330,rs10845606 reached genomewide significance(3.83×10-17?Pcombined ? 2.23 ×10-8).CREBL2(c AMP responsive binding protein like 2)contains a 48-residue segment showing 41% identity to the b ZIP domain of DNA-binding proteins,and involves in the regulation of cell cycle.GPR19 is highly expressed in human embryonic stem cells and encodes an orphan receptor which contains the 7 transmembrane domains characteristic of GPCRs.It is closely associated with members of the D2 dopamine receptor family and the neuropeptide Y receptors.CDKN1B(cyclin-dependent kinase inhibitor 1B)encodes the cyclin dependent kinase inhibitor,which regulates the cell cycle from G1 phase to S phase through the inhibition of CDK2(cyclin dependent-kinase 2)/cyclin E and CDK2/cyclin A complex.And P27CDKN1 Bis essential to the induction of T cells tolerance through adjusting the CD4+T memory response and the homeostasis of CD8+T cells.It has been reported that many genes(such as NKG2,CD4,C1s/r,CD163,AID)in the 12p13 region are associated with autoimmune diseases including SLE,while the explicit mechanisms by which the three genes might be related to the pathogenesis of SLE remain unclear.The study used the real-time PCR to detect CREBL2,CDKN1 B,GPR19 m RNA in the SLE cases and normal controls in order to investigate the possible role of them in the pathogenesis of SLE.Objective To investigate the expression of CREBL2,CDKN1 B,GPR19 in peripheral blood mononuclear cells(PBMCs),as well as the relationship with the SNP rs12822507,rs34330,rs10845606,and the SLE phenotype,and the SLEDAI scores.Method 119 unrelated female patients and 129 unrelated female controls were enrolled in the study.The m RNA was extracted from the PBMCs and then complementary DNA(c DNA)was generated by reverse transcription of RNA.Fluorescent quantitative reverse transcription polymerase chain reaction(RT-PCR)was applicated to detect the expression levels of CREBL2,CDKN1 B,GPR19 in PBMCs.ABI3730 XL Sequencer was used to genotype SNP rs12822507,rs34330,rs10845606 in these individuals.Then using the SPSS17.0(Statistical Package for the Social Science 17.0)software for statistical analysis.Results We found that the relative m RNA expression levels of CREBL2 and CDKN1 B were significantly decreased in SLE patients compared with those normal controls(P <0.001).However,no remarkable difference was found for gene GPR19(P > 0.05).We did not observe any statistically significant e QTL effect for the reported SNP rs12822507,rs34330,and rs10845606 on genes CREBL2,CDKN1 B,and GPR19 in both normal controls or SLE patients(P > 0.05).We discovered that the CREBL2 expression levels were decreased in SLE patients with high CRP levels,or positive anti-SSA/Ro antibodies,or negative photosensitivity(P < 0.05);and the CDKN1 B expression levels were decreased in SLE patients with high C3 levels,or positive anti-SSA/Ro antibodies,or SLEDAI < 10(P < 0.05).No statistically significant correlations were detected between any of the three genes expression levels and SLEDAI scores(P > 0.05).Conclusion It suggestes that CREBL2 and CDKN1 B may be involved in the pathogenesis of SLE and contribute to the complex sub-phenotypes.So far we did not observe any statistically significant e QTL effect for the reported SNP rs12822507,rs34330,and rs10845606 on gene CREBL2,CDKN1 B,and GPR19 in both normal controls or SLE patients.