Association Of STAT4 Gene Polymorphisms With RA Susceptibility In Northwestern Chinese Han Population And A Meta-analysis Of STAT4 Gene With Autoimmune Diseases

Autoimmune diseases (AID) occurred when the immune system losses "self tolerance" to itself. To date, AID has been considered to be a complex disease which is caused by the interrelationship from both genetic and environmental factors, and genetics have been documented to be the most important susceptibility factor, thus, findings on genetic susceptibility factors to AID will be helpful to provide methods for early diagnose or cure them on molecular levels. STAT4 (Signal transducer and activator of transcription 4) is found to be important in the course of the activatition and proliferation of both Th1 (T helper cell, Th) and Th17 cells which are the major proinflammation cells in AID. This study aimed to investigate the relationship between STAT4 gene single neucleotide polymorphisms and RA in Northwestern Chinese Han population based on the most frequently studied susceptibility locus to RA and other AID diseases, and a meta-analysis was also conducted in order to make it clear whether STAT4 is a susceptibility gene to all AID patients across the major populations.Part I:Association of STAT4 gene polymorphisms with RA susceptibility in Northwestern Chinese Han populationAims:Signal transducer and activator of transcription 4 (STAT4) encodes a transcriptional factor that transmits signals induced by several key cytokines which play important roles in the development of autoimmune diseases. Recently, several single nucleotide polymorphisms (SNPs) in STAT4 gene have been reported to be significantly associated with Rheumatoid arthritis (RA) in different ethnic populations. We undertook this study to investigate whether the association of STAT4 genetic polymorphisms with RA is present in Northwestern Chinese Han population.Main methods:A case-control association study in individuals with RA (n=208) and healthy controls (n= 312) was conducted. Four SNPs (rs7574865, rs8179673, rs10181656, rs11889341) in STAT4 gene were genotyped by using polymerase chain reaction followed by denaturing high-performance liquid chromatography (PCR-DHPLC) and DNA sequencing. significant association with Northwestern Chinese Han RA patients (P= 4×10-4,0.036,0.016, respectively), with SNP rs7574865 T allele and T/T genotype showing the most significant association with susceptibility to RA (OR= 1.645 and 3.111, respectively). Stratification studies showed that STAT4 gene polymorphisms were significantly associated with anti-cyclic citrullinated peptide (anti-CCP) positive subgroup in the Northwestern Chinese Han population. Linkage analysis showed that the four SNPs were in moderate linkage disequilibrium, and the haplotype formed by rs7574865G rs8179673Trs10181656Crs11889341C showed protective effect against RA patients while the rs7574865T rs8179673Trs10181656Crs11889341C haplotype seemed a risk haplotype for Northwestern Chinese Han RA patients.Conclusions:These findings strongly suggested that STAT4 genetic polymorphisms are associated with RA in Northwestern Chinese Han population, and provided further evidence on STAT4 gene polymorphisms influencing RA susceptibility across major populations.PartⅡ:Association of STAT4 gene rs7574865 G>T single neucleotide polymorphism with autoimmune diseases --- a Meta analysisObjectives:This study aimed to investigate whether combined evidence shows the association between STAT4 rs7574865 polymorphism and autoimmune diseases, and to summarize the effect size of the polymorphism associated with susceptibility of autoimmune diseases.Methods:Comprehensive Medline search and review of the references were used to study the STAT4 rs7574865 polymorphism and autoimmune diseases. A meta-analysis was conducted for genotypes T/T (recessive effect), T/T+C/T (dominant effect) and T allele in random effects models.Results:39 studies with 80 comparisons including 31 systemic lupus erythematosus (SLE),18 rheumatoid arthritis (RA),4 type 1 diabetes (T1D),12 Systemeric Sclerosisi (SSc),4 inflammatory bowed diseases (IBD),3 Primary Sjogren's syndrome (pSS),2 juvenile idiopathic arthritis (JIA),2 Primary antiphospholipid syndrome (APS),1 multiple sclerosis (MS),1 Psoriasis (Ps),1 Wegener's granulomatosis (WG), and 1 giant cell arteritis (GCA) disease were available for this meta-analysis. The overall odds ratios (ORS) for rs7574865 T-allele, T/T and G/T+T/T genotypes were significantly increased in SLE, RA, SSc, T1D, and APS (OR for T-allele in SLE, RA, SSc, and APS patients was 1.57,1.24,1.30,2.15, respectively, P< 0.00001; OR for T-allele in T1D patients was 1.27, P= 0.01). And this meta-analysis also showed association of T-allele and GT+TT genotype with IBD-UC, pSS, and JIA (OR for T allele= 1.11,1.33, and 1.23, respectively).Conclusion:This mata-analysis is the first to demonstrate that the STAT4 rs7574865 T allele confers susceptibility to SLE, RA, SSc, T1D, IBD-UC, pSS, JIA, and APS patients, supporting the hypothesis of association between STAT4 gene polymorphism and subgroup of autoimmune diseases.