The Polymorphisms Of KIR3DL1 Alleles In Yunnan China And The Correlation With Autoimmune Disease

Autoimmune disease is a kind of disease,which is caused by the destruction of the immune tolerance and the abnormal activation of the immune system was attacking autoantigen,and finally it will lead to tissue(organ)damage.The etiology and pathogenesis of autoimmune disease is not very clear.An extremely complicated and multifactorial interaction among various genetic,virus infections,environmental factors is involved.Among those factors,genetic factors play an important role in the pathogenesis of autoimmune diseases.Rheumatoid arthritis(RA)and systemic lupus erythematosus(SLE)are the two of most common autoimmune disease;the similar pathological response of both of them is the disorder of immune system regulation.the genetic mechanism of the immune system disorder depends on the interaction of multiple genes.Among those genes,HLA system is an important part of the immune system,and its high genetic polymorphism is closely related to the susceptibility of autoimmune diseases.A genome-wide association analysis(GWAS)demonstrated that the risk of RA and SLE related to the polymorphism of exon in HLA-DRB1 and HLA-B gene.In recent studies,as the HLA antigen receptor,KIRs(Killer cell immunoglobulin-like receptors,KIR)was involved in the occurence and development of autoimmune diseases through regulate the function of damaged cell of NK by interaction with human leukocyte antigen class I.It was report that the frequency of KIR3DL1 gene in RA patients is lower than that in normal individuals and KIR3DL1 may inhibit the process of autoimmune diseases by inhibiting the activity of NK cells by interacting with HLA-Bw4.KIR3DL1 gene has very rich polymorphism,and the distribution and frequency of KIR3DL1 alleles in different regions and different populations have different characteristics.However,the correlation between autoimmune disease and susceptibility genes are often show differences in population and area,since the genetic heterogeneity of RA.The polymerphism of KIR3DL1 and HLA-B genes in different regions of China and the relation-ship between KIR3DL1 and HLA-B genes and the susceptibility to RA are need to be further explored.This study analysed the correlation between the RA and SLE with KIR3DL1 gene in Yunnan population by case-control study,expect to find the susceptible genes or site associated with autoimmune disease,provide more information for understand the pathogenesis of autoimmune diseases.Objective:The purpose of this study was to detect polymorphism of KIR3DL1 gene and investigate the association between the polymorphism of KIR3DL1 gene and autoimmune diseases.Method:PCR-SSP was used for detect KIR3DL1 functional allele distribution in 360 Chinese and 108 Mongolian in Yunnan,48 Mongolian in Inner Mongolia.PCR amplified KIR3DL1 gene and then DNA sequencing was used to detect polymorphism of KIR3DL1 gene sequence in Pumi,Achang,Jingpo,Dai,Mongolian and Han in Yunnan.After obtaining the data of KIR3DL1 gene polymorphism in Yunnan region,the KIR3DL1 functional alleles were analyzed by PCR-SSP in 270 patients with RA,271 patients with SLE and 360 normal individuals in Yunnan.Results:Our results show that in Han Chinese and Mongolian individuals from Yunnan,the frequency of low-expression KIR3DL1*007 were 30.55%and 45.54%,the frequency of activating KIR3DS1*013 were 23.89%and 3.70%,respectively,the differences are statistically significant.In Mongolians from Yunnan and Inner,the frequency of null-expression KIR3DL1*004 were 7.14%and 56.25%,the frequency of low-expression KIR3DL1*005 were 2.86%and 25.00%,with significant difference;We find 4 novel KIR3DL1 alleles in different ethnic groups in Yunnan by detected the polymorphism of KIR3DL1 gene.The frequency of carrying 4bp deletion in KIR3DL1 gene were detected in 7.94%in Pumi,5.19%in Achang,2.33%in Mongolian,2.38%in Jingpo,6.32%in Dai(N=94)and 8.24%in Han Chinese(N=61).After test,the frequency of 4bp gene deletion in Mongolian(Yunnan),Jinpo and Han are consistent with Hardy-Weinberg balance(P>0.05).Moreover,in the RA patients,the frequency of low-expression KIR3DL1*005 allele(46.44%)was significantly higher than that in controls(18,43%),the frequency of low-expression KIR3DL1*007 allele(22.03%)was significantly lower than that in controls(30.56%),respectively,The difference are statistically significant.there were no significant difference on frequency of high-expression KIR3DL1*002 alleles group and KIR3DL1*013 allele between RA individuals and controls.In addition,in the female individuals,the frequency of HLA-B*40(8.84%)allele in the RA patients was significantly lower than that in controls(18.33%),HLA-B*51(9.53%)allele was significantly higher than that in controls(2.83%),HLA-B*48(0.23%)allele was significantly lower than that in the controls(2.33%).Though in the male individuals,the frequency of HLA-B*40,B*51 and B*48 have no significant difference between RA patients and controls.In addition,individuals that carrying HLA-B*40 gene in RA patients and controls,the rate of carrying KIR3DL1*005 gene were higher in RA patients(82.50%)than controls(16.98%),individuals that carrying HLA-B*51 gene in RA patients and controls,the rate of carrying KIR3DL1*007 and KIR3DL1*002 group gene were lower in RA patients(11.80%)than controls(50.00%).Conclusion:Our data suggestion that the distribution of KIR3DL1 alleles were significant different between different ethnics and between areas.The highly polymorphic of KIR3DL1 gene relates to the origin and evolution of the ethnic.And balancing selection might maintain the diversity of KIR3DL1 alleles.The polymorphism of KIR3DL1 allele is associated with RA and SLE,KIR3DL1*005 may increase the risk of RA and SLE,though KIR3DL1*007 might be is a protective alleles against RA.It is revealed that RA and SLE have similar pathogenic factors as autoimmune diseases;KIR3DL1*004 may be is a protective allele of RA,which is not associated with SLE,suggesting that RA and SLE have different pathogenic mechanisms.HLA-B*51 gene may be a predisposing factor of RA,HLA-B*40,HLA-B*48 may be a protective factor of RA.HLA-B*40 and KIR3DL1*005 may be the risk factors of RA,indicated that diversity of combinations of KIR3DL1 and HLA-B subtypes make complex effect on the pathogenesis of RA.And analysis of KIR3DL1 receptor binding with HLA-B ligand could better reflect the influence of HLA-B and KIR3DL1 on RA susceptibility than analysis correlation between KIR3DL1 or HLA-B gene with RA alone.