Although these markers didn’t reach the stringent significance level, the current results suggest that ACPA-negative RA shares susceptibility loci beyond ethnicity. Although we did not find ACPA-negative RA-associated genes with a GWAS-significance level due to Shanzhiside methylester the limited power of case subjects, the current results suggested that the majority of non-HLA susceptibility loci are shared between ACPA-positive and ACPA-negative RA. GWAS meta-analysis for either ACPA-positive RA or ACPA-negative RA to address the question whether weakly-associated genes were also shared. The correlations between ACPA-positive RA and the subpopulations of ACPA-negative RA (rheumatoid factor (RF)-positive and RF-negative subsets) were also addressed. Results Rs6904716 in of Shanzhiside methylester the human leukocyte antigen (HLA) locus showed a borderline association with ACPA-negative RA (overall p?=?5.7??10?8), followed by rs6986423 in (p?=?2.4??10?6) and rs17727339 in (p?=?1.4??10?5). ACPA-negative RA showed Shanzhiside methylester significant correlations of ORs with ACPA-positive RA for the 21 susceptibility SNPs and non-HLA SNPs with p-values far from significance. These significant correlations with ACPA-positive RA were true for ACPA-negative RF-positive and ACPA-negative RF-negative RA. On the contrary, positive correlations were not observed between the ACPA-negative two subpopulations. Conclusion Many of the susceptibility loci were shared between ACPA-positive and -unfavorable RA. Electronic supplementary material The online version of this article (doi:10.1186/s13075-015-0623-4) contains supplementary material, which is available to authorized users. Introduction Shanzhiside methylester Rheumatoid arthritis (RA) is the most common autoimmune arthritis worldwide with prevalence of around 1%. Genetic factors as well as environmental factors are involved in the development of RA . 0.01) (Additional file 3). This ratio was significantly higher than the ratio obtained by chance based on 20,000 permutations (permutation 1.0??10?4; for detail see Methods). An independent set of 916 patients with ACPA-negative RA and 3,764 controls were utilized for the replication study using the Taqman Assay. As a result, 3 out of the 35 SNPs, namely, rs6904716 in (((0.039). In the combined study using the inverse-variance method, rs6904716, which is usually contained in the HLA locus, experienced borderline association (-value based on 0.001) with ACPA-positive RA also had strong correlation with ACPA-negative RF-positive RA ( 0.001) (Physique?3C). These results suggest that ACPA-positive RA is usually genetically much like ACPA-negative RF-positive RA rather than ACPA-negative RF-negative RA. Open in a separate window Physique 3 Correlations of odds ratios (ORs) in units of non-human leukocyte antigen (HLA) single nucleotide polymorphisms (SNPs) among anti-citrullinated peptide/protein antibody (ACPA)-positive rheumatoid arthritis (RA) and the two subsets of ACPA-negative RA. Correlation coefficient of ORs between ACPA-positive RA and ACPA-negative RF-positive RA (A), between ACPA-positive RA and ACPA-negative RF-negative RA (B), and between ACPA-negative RF-positive RA and ACPA-negative RF-negative RA (C), in terms of SNPs stratified by p-values of ACPA-positive RA (A, B) or each study (C). *Positive correlation with on chromosome 1 and on chromosome 8. We did not find heterogeneity among the studies, indicating that these associations were not obtained by one or two studies with extreme association. While the female ratio was different between cases and controls, we did not adjust for sex. This is because most of the previous GWAS, including our previous meta-analysis, did not adjust for sex to analyze autosomal SNPs. Because rs6904716 in was not very strongly associated with ACPA-positive RA in the RA meta-analysis , these results suggest that associated HLA alleles are different between ACPA-positive and ACPA-negative RA. Low effect sizes of the HLA locus to ACPA-negative RA may explain the lack of significant association of the HLA locus in the meta-analysis of GWAS. has been reported to be associated with RA, especially in the Japanese populace . Rs7528684 is considered Rabbit polyclonal to ARHGAP20 to be the causative variant of the region to which NFB binds and activates B cells to produce antibody by augmenting BCR-mediating signals . Rs17727339 is in moderate linkage disequilibrium (LD) with rs7528684 (D:0.80 and with ACPA-negative RA. Thus, it is likely that the region, possibly as a consequence of association of rs7528684, is usually associated with both ACPA-positive and -unfavorable RA. is usually a tumor-suppressor gene associated with psoriasis, Kawasaki disease and schizophrenia [39-41]. expresses mainly in epithelial cells and exhibits anti-tumor activity through activation of the Smad pathway [42,43]. also functions as a match regulatory gene, especially of the classical pathway . Thus, the role of on match or other genes nearby may have an important role around the development of ACPA-negative RA. This chromosome 8 region was not associated with ACPA-positive RA in the RA meta-analysis ( em P /em ?=?0.87), therefore, this region may.