Association Of Adiponectin And Adiponectin Receptor Gene Single Nucleotide Polymorphisms And Plasma Adiponectin Levels With Rheumatoid Arthritis

BackgroundRheumatoid arthritis(RA)is a chronic systemic autoimmune disease,which is predominantly characterized by progressive joint damage,synovial hyperplasia,the production of auto-antibodies and onsets in the small joints such as hand,foot,etc.It contributes to pain and swelling of the joints,severely articular deformities and disability,which causes a huge economic burden and strongly affects people's life quality.RA usually occurs in women and the elderly,and is distributed around the world,affecting 0.5%to 1%of the world's population.The prevalence of adults in developed countries is 5 to 50/100 000.The prevalence of RA is 0.41%in China,0.28%after adjustment,and increases with age.However,the pathogenesis of RA is complicated and has not been fully elucidated.At present,it is considered that the pathogenesis of RA may be related to genetic factors,environmental factors and immune disorders.Genetic factors play an important role in the occurrence and development of RA.Adiponectin is a kind of cytokine secreted by adipocytes and has many biological functions.Adiponectinbindstoitsreceptors,andparticipatesinthe immunomodulatory process through a variety of pathways,such as p38mitogen-activated protein kinase(p38 MAPK),c-Jun N-terminal kinase(JNK),phosphatidylinositol 3-kinase(PI3K),extracellular signal-regulated kinase 1/2(ERK1/2),AMP-activated protein kinase(AMPK),etc.Genome-wide association studies(GWAS)have found that adiponectin gene is a kind of susceptible gene of RA.Adiponectin gene and adiponectin receptor gene polymorphism may involve in the pathogenesis of RA by affecting the expression of adiponectin and adiponectin receptor,but the current report on this aspect has not yet been appeared.ObjectiveThe study was to explore the association between single-nucleotide polymorphisms(SNP)of adiponectin and adiponectin receptor genes and genetic susceptibility to RA,and to analyze the association between single-nucleotide polymorphisms(SNP)of adiponectin and adiponectin receptor genes and disease activity by the collected data.At the same time,the expression of plasma adiponectin in some patients was detected,and the relationship between adiponectin and the polymorphism of each gene locus was analyzed.MethodsIn this case-control study,a total of 617 RA patients and 639 healthy controls were genotyped by Fluidigm 192.24 TaqMan technique and enzyme-linked immunosorbent assay(ELISA)was performed in 95 RA patients and 95 age-and sex-matched controls to test plasma adiponectin levels.Statistical analysis was performed using Chi-square test,logistic regression analysis,and nonparametric test,etc.The detection level?was0.05.Results(1)Association of adiponectin and adiponectin receptor gene polymorphisms with RA susceptibility:The genotype frequencies and allele frequencies of rs266729,rs2241766,rs2082940,rs1063539 in adiponectin gene and rs7539542,rs12342 in adiponectin receptor gene were not different between RA patients and healthy controls(all P>0.05).At the same time,there was no significant difference in the distribution of dominant model and recessive model between RA patients and healthy controls(all P>0.05).There was no significant difference in distribution after further adjustment of age and sex(all P>0.05).(2)The relationship between the polymorphism of adiponectin,adiponectin receptor gene and the clinical characteristics and laboratory indexes of RA patients:The frequency of adiponectin gene rs1063539 GG genotype was higher in RA female patients with positive anti-citrullinated protein antibodies(ACPA)than those with negative RF(?~2=6.416,P=0.040).(3)Haplotype analysis of adiponectin gene polymorphism:There were no significant differences in the distribution of three major adiponectin gene haplotypes between CTGC,CTGG and TGCC in the adiponectin gene locus between RA patients and healthy controls(all P>0.05).(4)The expression level of adiponectin in plasma of RA patients and normal subjects:the expression level of plasma adiponectin in the case group was lower than that in the control group(12.83±5.50 vs.16.72±10.87?g/ml),the difference was statistically significant(t=3.116,P=0.002).There were no significant differences in plasma adiponectin levels between ACPA positive group and ACPA negative group,similarly between rheumatoid factor(RF)positive group and RF negative group,high activity group and relatively inactive group(all P>0.05).The correlation between plasma adiponectin levels and complements 3(C3),complements 4(C4),erythrocyte sedimentation rate(ESR),C-reactive protein(CRP),body mass index(BMI)and disease duration in RA patients was further analyzed,and results showed that adiponectin was not associated with the above clinical parameters(all P>0.05).(5)Association between adiponectin gene polymorphism and the expression level of adiponectin in plasma:There was no significant correlation between adiponectin gene rs266729,rs2241766,rs2082940,rs1063539 and adiponectin receptor gene rs7539542,rs12342 SNPs and plasma adiponectin levels in RA patients(all P>0.05).Conclusionsrs266729,rs2241766,rs2082940,rs1063539 in adiponectin gene and rs7539542,rs12342 in adiponectin receptor gene are possibly not associated with genetic susceptibility to RA,but adiponectin gene rs1063539 locus was possibly associated with ACPA in RA female patients.The expression level of adiponectin in plasma of RA patients was down-regulated,and the above six gene loci SNPs were possibly not related to plasma expression levels.