Association Between Single Nucleotide Polymorphism Of RANKL And OPG Gene And Patients With Rheumatoid Arthritis

BackgroundRheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronicinflammation of the joints, which may lead to invasion of synovial tissue into theadjacent cartilage matrix with degradation of cartilage as a consequence. In addition,RA may have negative effect on bone metabolism, leading to a low bone mineraldensity. Cumulative studies indicate that RANKL, the ligand of nuclear factor-kB(RANK), is an essential factor for osteoclast formation by cells in the rheumatic jointsand that OPG, the decoy receptor of RANK, may prevent the bone erosion seen in RAjoints. Several single-nucleotide polymorphisms (SNPs) in RANKL and OPG gene,which may affect the binding of transcription factors, have recently beendemonstrated a significant association with bone metabolism and susceptibility tomultiple autoimmune diseases including RA.ObjectiveTo investigate the association between single-nuclear polymorphism(SNP) inReceptor of Activator of Nuclear Factor kappa B Ligand (RANKL) andOsteoprotegerin (OPG) gene and rheumatoid arthritis(RA).MethodsTwo hundred RA patients (28males and172females) and201matched controls (30males and101females) were analyzed from Han Chinese populations by case–controldesign, and their samples were genotyped using a panel of two SNP markers(rs2073618+1181G/C, rs3102735+163A/G) within the OPG gene(TNFRSF11B) andone SNP marker (rs2277438+401A/G) within the RANKL gene(TNFRSF11) byligase detection reactions (LDRs). Bone mineral density (BMD) values at femur and lumbar spine were assessed using dual-energy X-ray absorptiometry. Joint counts fortenderness and swelling, Health Assessment Questionnaire(HAQ) score, VisualAssessment Score(VAS) of overall pain, erythrocyte sedimentation rate(ESR),C-reactive protein(CRP), rheumatic factor(RF) anti-cyclic citrullinepolypeptide(anti-CCP) values were measured in detail by rhumatologuessimultaneously.ResultsNo significant differences in the distribution frequency of the alleles and genotypes ofTNFRSF11B (rs2073618and rs3102735) and TNFRSF11(rs2277438) were observedbetween RA and control(P＞0.05).The haplotype analyses for TNFRSF11B and TNFRSF11SNPs showed thers2073618/rs2277438/rs3102735GGG haplotype reduced the risk of RA(1.5%vs6.0%)(P=0.008, OR0.216,95%CI:0.081to0.575) and thers2073618/rs2277438/rs3102735GAG haplotype increased the risk of RA（14.5%vs8.4%）(P=0.007; OR1.862,95%CI:1.179to2.943).Patients with TNFRSF11(rs2277438) AA or GG genotypes(n=62) had significantlyhigher BMD values compared to those with AG genotypes (n=39) at lumbar spine3(1.05±0.22vs0.93±0.26, t=2.314， P=0.023）, lumbar spine4(1.06±0.24vs0.94±0.28, t=2.27，P=0.030）, lumbar spine2-4(1.04±0.21vs0.89±0.28, t=2.788，P=0.007). There existed no obvious discrepancies in BMD at all detected positionsamong different genotype groups of TNFRSF11B(rs2073618or rs3102735)(P>0.05).Analysis of logistic regression showed genotypes of TNFRSF11(rs2277438) was therisk factor for the occurrence of osteoporosis in RA（OR=2.932，P=0.048，95%CI：1.008-8.529）. The tender joint counts (4.60±5.52vs6.64±5.46, t=2.154，P=0.034), tender jointindex(4.89±5.70vs7.14±5.71, t=2.318，P=0.023) and VAS score (3.57±2.46vs4.52±2.39, t=2.481， P=0.015) differed significantly between patients withTNFRSF11B (rs2073618) AA or GG genotypes (n=60) and AG genotypes(n=40).There were no apparent dissimilarities in clinical and laboratorial factors amongdifferent genotype groups of TNFRSF11B (rs3102735) or TNFRSF11(rs2277438)(P>0.05).ConclusionThe rs2073618/rs2277438/rs3102735GGG haplotype may be a protective factoragainst RA, while GAG haplotype probably increases susceptibility to RA.SNP of TNFRSF11(rs2277438) may affect BMD value at lumbar spine in patientswith RA, and genotypes of TNFRSF11(rs2277438) was the unique risk factor for theoccurrence of osteoporosis in RA, while SNP of TNFRSF11B (rs2073618) may havean influence on disease activity of RA.