Fcrl3 Gene Polymorphism And Association Study Of Rheumatoid Arthritis By The Chinese Population And Its Correlation Study Of Autoimmune Diseases Meta-analysis

Rheumatoid arthritis (RA) is a multifactorial disease that affects up to 1% of the adult population worldwide. It is associated with a complex mode of inheritance, with many genes being involved in the development and progression of the disease. The etiopathogenisis of RA, which has been unclear so far, is generally known to relate to genetic factors, infection and destruction of autoimmune tolerance. RA was observed to have a tendency towards family aggregation, as the morbidity of RA was up to 30% in monovular twins,5% in non-identical twins, which demonstrated the occurrence of RA associated to genetic factors. Recently, four polymorphisms in FCRL3 gene have been reported to be associated with rheumatoid arthritis and other autoimmune diseases in Japanese populations. The FCRL3 gene was mapped to chromosome 1q21.2-q22. It is predominantly expressed in lymphoid organs, it exhibit high structural homology with classical FcRy. The FCRL3 gene is a very promising candidate encoding the immune modulatory molecule that could contribute to the pathogenesis of common autoimmune disorders. Among those, the -169T/C polymorphism was only functionally relevant affecting the sequence of the putative site for binding transcription factor NF-κB. The predisposing allele -169C was associated with higher transcriptional activity of the FCRL3 promoter and severe disease phenotype. The CC genotype of the -169 locus was associated with a higher expression in B lymphoid. Although the precise function of gene is unknown, the presence of both ITAM and ITIM in the FCRL3 molecule assumes its functional relevance to signal transduction through regulatory mechanisms of the activation/inactivation by signaling tyrosine protein kinases. The finding of expression of FCRL3 in nonmature B lymphocytes could suggest a unique role for this protein in the early stages of B-cell maturation and then activation. FCRL3 may play a pivotal role in autoimmune disorders in general. The association of FCRL3 with RA and other autoimmune diseases has been replicated in several populations. Conversely, inconsistent results have been observed in populations among European ancestry and Asians. Since RA is a kind of polygene disease with genetic predisposition, the different degree mutation of hereditary feature could result from different ethnic group and region even individuals. So, in the present study, we would carry out a case-control study to observe the distributions of variations in FCRL3 and to evaluate the genetic associations of them with increased risk of Rheumatoid Arthritis in population from Northwest China. We detected the -169T/C,-110G/A,+358G/C, and +1381G/A polymorphisms in 229 RA patients and 252 normal controls by PCR-denaturing high-performance liquid chromatography (DHPLC) or PCR-restriction fragment length polymorphism (RFLP), respectively. The samples of DNA were extracted from the peripheral blood of all subjects. All patients with RA were dignosed by ACR criteria. To estimated the associations between different genotypes or haplotypes and the risk of RA. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated according to Woolfs method. The potential interaction between different locus and locus-environmental interactions on RA risk was evaluated using MDR software.The genotype and allele distributions of four polymorphisms were significantly different in RA patients compared to controls (P= 0.017 and P= 0.031; 0.041 and 0.008; 0.036 and 0.042; 0.033 and 0.029, respectively). The FCRL3-169 C allele was also significantly associated with rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) positive RA, but no association was detected for RF and anti-CCP negative RA. Furthermore, the frequency of the -169C allele was increased disproportionately in female patients (46.9% compared to 38.6% in male patients, P= 0.12), and the resulting odds ratio for female homozygote was increased to 2.375(95% CI 1.267-4.451, p=0.006). Haplotype analysis showed that the most common haplotype TGGG (formed by the common alleles of the 4 SNPs) was associated with decreased risk of RA (P= 0.001, OR = 0.656,95% CI 0.506-0.851). But the second most common haplotype CACA, which is formed by the minor alleles of the four SNPs, appeared to be a risk haplotype for RA cases (P=0.031, OR=1.398,95% CI 1.031-1.897). Similar trends were found when the haplotypes were analyzed according to their RF, anti-CCP status and gender. With MDR analysis, a significant interaction between four loci model was identified. The best single site model is FCRL3-110G/A.2 sites model is -169T/C and -110G/A.3 sites model is-169T/C,-110G/A and +1381G/A,4 sites model is contains all of loci and the combination of gender and genetic factors barely increased the accuracy. Above all, the best model is 4 sites model (FCRL3-169T/C,-110G/A,+358G/C and+1381G/A), it has highest CV value 10/10 with 58.07% testing accuracy. Interaction tree by Hierarchical Clustering methods show-110G/A locus and+1381G/A site in the same branch, but the information is redundancy. It suggested that-110G/A polymorphism had an independent effect. While-169T/C is at a different lonely branch. We construct the interaction graph with 4 SNPs and gender.-110G/A site get maximum stand-alone IG value. Although +1381G/A gets the lower IG value, it shows the highest interaction IG in 5 factor model. It also shows a synergy effect with-169 T/C locus and+358 G/C site. Gender may also shown additive effect with genetic factors or more complex effect. These results suggest that FCRL3 polymorphisms/haplotypes may contribute to genetic susceptibility to RA in Chinese population. Moreover, the SNP (-169T/C) is closely related to RF, anti-CCP status and gender in RA patients.In the second part of our study, we tested the association between FCRL3 polymorphisms and autoimmune disorders by Meta-analysis. The FCRL3 gene is a very promising candidate encoding the immune modulatory molecule that could contribute to the pathogenesis of common autoimmune disorders. Association studies on the FCRL3 polymorphisms in AIDs had shown conflicting results. We performed a meta-analysis from all eligible case-control studies to assess the purported associations. Sixteen data sets were extracted from 12 case-control studies for FCRL3-169T/C polymorphism and RA (contain our study). In combined analysis, the overall ORs for C-allele, C/C and C/C+C/T genotypes were significantly increased in RA, but decreased in MS and AAD. But there was substantial heterogeneity amongst these data sets. There was no association of the FCRL3-169 C allele and susceptibility of SLE, T1D, UC, CD and GD. We also found that there was no association between FCRL3-169T/C polymorphism and other AIDs which investigated only once. We could find no evidence to support disease association with-110 G/A polymorphism in AIDs except for AAD and AIP in combined analysis, the per-allele odds ratio of this variant for AAD was 0.61 (95% CI 0.46-0.80, P = 0.0004), with corresponding results under recessive and dominant genetic models of 0-46 and 0.57. Therefore, the -110 A allele presented a significant protective effect in AAD. On the contrary, the -110 A variant yielded a opposing effect under the recessive model and the genotype contrast of the homozygotes (AA vs. GG), The OR was 7.45(95% CI 1.52-36.41) and 7.27(95% CI 1.46,36.26) in AIP, respectively. The relationship between the -110G/A SNP and RA risk was further evaluated by ethnicity stratification. The result shows a very significant association of the FCRL3 -110A allele with RA in Asians, but no in Caucasians. The +358G/C variation and +1381 G/A polymorphism contribute to genetic susceptibility to RA in Asians but no White. Under both comparisons, the +358C allele was still associated with protection from AAD. An elevated but not significant protective effect between CG genotype and GD was found under heterozygote-homozygote (CG vs. GG) comparison (P= 0.04, OR= 0.83,95% CI 0.69-0.99, Phetero= 0.53).The accumulated evidence indicated FCRL3 polymorphisms may confer susceptibility to several AIDs. But FCRL3 may play different roles in different diseases, both quantitatively and qualitatively. Other genetic factors and environmental factors may be involved in this complexity effect model. More studies based on larger, stratified case-control population should be required to further evaluate the role of FCRL3 polymorphisms in different AIDs and populations.