Individuals with rheumatoid arthritis frequently have autoantibodies to citrullinated peptides, suggesting the involvement of the peptidylarginine deiminases citrullinating enzymes (encoded by PADI genes) in rheumatoid arthritis. Previous linkage studies have shown that a susceptibility locus for rheumatoid arthritis includes four PADI genes but did not establish which PADI gene confers susceptibility to rheumatoid arthritis. We used a case-control linkage disequilibrium study to show that PADI type 4 is a susceptibility locus for rheumatoid arthritis (P = 0.000008). PADI4 was expressed in hematological and rheumatoid arthritis synovial tissues. We also identified a haplotype of PADI4 associated with susceptibility to rheumatoid arthritis that affected stability of transcripts and was associated with levels of antibody to citrullinated peptide in sera from individuals with rheumatoid arthritis. Our results imply that the PADI4 haplotype associated with susceptibility to rheumatoid arthritis increases production of citrullinated peptides acting as autoantigens, resulting in heightened risk of developing the disease.

Rheumatoid arthritis is a common inflammatory disease with complex genetic components. We investigated the genetic contribution of the cytokine gene cluster in chromosome 5q31 to susceptibility to rheumatoid arthritis in the Japanese population by case-control linkage disequilibrium (LD) mapping using single nucleotide polymorphisms (SNPs). Here we report that there is significant association between rheumatoid arthritis and the organic cation transporter gene SLC22A4 (P = 0.000034). We show that expression of SLC22A4 is specific to hematological and immunological tissues and that SLC22A4 is also highly expressed in the inflammatory joints of mice with collagen-induced arthritis. A SNP affects the transcriptional efficiency of SLC22A4 in vitro, owing to an allelic difference in affinity to Runt-related transcription factor 1 (RUNX1), a transcriptional regulator in the hematopoietic system. A SNP in RUNX1 is also strongly associated with rheumatoid arthritis (P = 0.00035). Our data indicate that the regulation of SLC22A4 expression by RUNX1 is associated with susceptibility to rheumatoid arthritis, which may represent an example of an epistatic effect of two genes on this disorder.

Rheumatoid arthritis (RA) is a common autoimmune disease with a complex genetic etiology. Herein we identify a single-nucleotide polymorphism (SNP) in the promoter region of FcRH3, a member of the Fc receptor homolog family, that is associated with RA susceptibility (OR=2. 15, P=0.00000085). This polymorphism alters the binding affinity of nuclear factor-κB and regulates NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptFcRH3 expression. High FcRH3 expression on B-cells and augmented autoantibody production were observed in individuals with the disease-susceptible genotype. Associations were also found between the SNP and susceptibility to autoimmune thyroid disease and systemic lupus erythematosus. FcRH3 may thus play a pivotal role in autoimmunity.Rheumatoid arthritis represents one of the most common autoimmune diseases, and is characterized by inflammation of synovial tissue and joint destruction. Although the disease is believed to result from a combination of genetic and environmental factors, the complete etiology of RA has not yet been clarified 1 . While specific haplotypes of human leukocyte antigen (HLA)-DRB1, usually referred to as shared-epitope (SE) sequences 2 , have been repeatedly reported as conferring RA-susceptibility 3,4 , other genetic components are also involved in the pathogenesis of RA 5 . This combination of HLA haplotypes and non-HLA genes accounting for disease susceptibility is also seen in other autoimmune diseases 6-8 . In autoimmune thyroid disease (AITD), for instance, studies have consistently shown that the HLA-DR3 haplotype is associated with disease risk, in addition to a functional haplotype of a non-HLA gene, CTLA4, that has recently been associated with AITD susceptibility 9 .Identification of non-HLA genes associated with RA susceptibility and other autoimmunities seems difficult, due to the low relative risk of disease resulting from these non-HLA genes compared with the strong relative risk from disease-associated HLA haplotypes. In a search for non-HLA determinants of disease susceptibility, whole genome studies have been conducted for both human autoimmune diseases and experimental animal models. These studies have revealed non-random clustering of susceptibility loci for clinically distinct diseases 8,10 . This overlapping of susceptibility loci for multiple autoimmunities suggests the existence of common susceptibility genes in those regions. Intense studies of loci-clustering regions has revealed genes commonly associated with multiple autoimmune diseases, such as CTLA4 on 2q33 (ref. and Idd17 (ref. 25)). Although 1q21-23 is a strong candidate region for RA susceptible genes, as above mentioned, the association of classical FcγRs with disease susceptibility remains controvertial 26,27 . The present study focused on the 1q21-23 region to identify RA-associated genes in Japanese subjects using linkage disequilibrium (LD) mapping. RESULTS Case-control study by SNP-based LD-mapping in 1q21-23To evaluate the extent of association, we a...

The expression of VEGF may be a good prognostic indicator for patients with gastric carcinoma and may also be useful as a predictor of the mode of recurrence in patients with gastric carcinoma.

Rheumatoid arthritis is a common autoimmune disease characterized by chronic inflammation. We report a meta-analysis of genome-wide association studies (GWAS) in a Japanese population including 4,074 individuals with rheumatoid arthritis (cases) and 16,891 controls, followed by a replication in 5,277 rheumatoid arthritis cases and 21,684 controls. Our study identified nine loci newly associated with rheumatoid arthritis at a threshold of P < 5.0 × 10(-8), including B3GNT2, ANXA3, CSF2, CD83, NFKBIE, ARID5B, PDE2A-ARAP1, PLD4 and PTPN2. ANXA3 was also associated with susceptibility to systemic lupus erythematosus (P = 0.0040), and B3GNT2 and ARID5B were associated with Graves' disease (P = 3.5 × 10(-4) and 2.9 × 10(-4), respectively). We conducted a multi-ancestry comparative analysis with a previous meta-analysis in individuals of European descent (5,539 rheumatoid arthritis cases and 20,169 controls). This provided evidence of shared genetic risks of rheumatoid arthritis between the populations.