Demographic, clinical and therapeutic data at the time of an enrollment in IORRA.

<p>*Maximum value of RF measured in the cohort project during 2000–2010 for each individual was used.</p>†<p>Cut-off  = 4.5 IU/ml.</p><p>IORRA, Institute of Rheumatology Rheumatoid Arthritis cohort study; BMI, body mass index; DAS28, disease activity score in 28 joints; J-HAQ, the Japanese version of Health Assessment Questionnaire; RF, rheumatoid factor; ACPA, anti-citrullinated peptide antibody; TKR, total knee replacement; DMARDs, disease modifying antirheumatic drugs.</p

Multivariate Cox proportional hazards model of each SNP associated with the occurrence of hip fracture.

<p>All analyses were adjusted for independent non-genetic factors: age, body mass index, Japanese version of Health Assessment Questionnaire disability score, and history of total knee replacement. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104587#pone.0104587-Furuya1" target="_blank">[7]</a>.</p><p>*Alleles are listed as major allele/minor allele.</p><p>SNP, single nucleotide polymorphism; MAF, minor allele frequency; HR, hazard ratio; CI, confidence interval; <i>OPG</i>, osteoprotegerin; <i>ZBTB40</i>, zinc finger and BTB domain containing 40; <i>MHC</i>, major histocompatibility complex; <i>RANK</i>, receptor activator of the nuclear factor-κB; <i>SPTBN1</i>, spectrin β nonerythrocytic 1; <i>LRP4</i>, low-density lipoprotein receptor-related protein 4.</p

Boxplots representing the distribution of Sharp/van der Heijde score (SHS) of the hands according to the number of the risk factors.

<p>Risk factors; SE allele carrier, PADI4 risk allele carrier, ACPA positive, female and age at onset under 50. Each box represents the interquartile range of values, with the bold line showing the median value. The vertical lines show maximum and minimum value that fall within 1.5 box lengths, the open circles show extreme values >1.5 box plot lengths. PADI4, peptidyl arginine deiminase type IV ACPA, anti-citrullinated peptide antibody.</p

Univariate linear regression analysis on putative risk factors for radiographic progression: non-genetic and genetic factors.

*<p>Alleles shown as major allele/minor allele.</p>†<p>P<0.05.</p><p>ACPA, anti-citrullinated peptide antibody; RF, rheumatoid factor. MAF; Minor allele frequency in the tested population, SE, shared epitope; <i>PADI4</i>, peptidyl arginine deiminase type IV; <i>TNFAIP3</i>, tumor necrosis factor, alpha-induced protein 3; <i>CCR6</i>, C-C chemokine receptor type 6; <i>B3GNT2</i>, UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 2; <i>ANXA3</i>, annexin A3; <i>CSF2</i>, colony stimulating factor 2; <i>CD83</i>, CD83 molecule; <i>NFKBIE</i>, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, epsilon; <i>ARID5B</i>, AT rich interactive domain 5B [MRF1-like]; <i>PDE2A</i>, phosphodiesterase 2A, cGMP-stimulated; <i>ARAP1</i>, ArfGAP with RhoGAP domain, ankyrin repeat and PH domain 1; <i>PLD4</i>, phospholipase D family, member 4; <i>PTPN2</i>, protein tyrosine phosphatase, non-receptor type 2.</p

Stepwise multiple regression analysis on risk factors for radiographic progression (n = 830).

<p>Multiple R squared value = 0.055.</p><p>95% CI, 95% confidence interval; ACPA, anti-citrullinated peptide antibody; SE, shared epitope; <i>PADI4</i>, peptidyl arginine deiminase type IV.</p

Boxplots representing the distribution of Sharp/van der Heijde score (SHS) of the hands in each category of independent risk factors for joint destruction.

<p>Risk factors; the number of HLA-DRB1 shared epitope, the number of PADI4 risk alleles, ACPA status (negative [<4.5 IU/ml] and positive), gender (female and male) and age at onset (categorized as “age under 30”, “30 s”, “40 s”, “50 s”, “60 s” and “age over 70”). Each box represents the interquartile range of values, with the bold line showing the median value. The vertical lines show maximum and minimum value that fall within 1.5 box lengths, the open circles show extreme values >1.5 box plot lengths. The P values were given by the univariate linear regression analyses (a log-transformed SHS was used as the dependent variable). PADI4, peptidyl arginine deiminase type IV ACPA, anti-citrullinated peptide antibody.</p

Histogram of distribution of the log-transformed SHS (hands).

<p>Histogram of distribution of the log-transformed SHS (hands).</p

Demographic and clinical characteristics of patients at 5 years from onset.

<p>Data are presented as median (interquartile range) or n (%).</p>*<p>Cut-off = 4.5 IU/ml.</p>†<p>Maximum value in the first 5-year period of the disease was used, cut-off = 15.0 IU/ml.</p><p>SHS, Sharp/van der Heijde score; ACPA, anti-citrullinated peptide antibody; RF, rheumatoid factor; DMARDs, disease-modifying anti-rheumatic drugs.</p

Probability plot of Sharp/van der Heijde score of the hands at the 5-year disease duration.

<p>Each point on the plot represents the Sharp/van der Heijde score (SHS) of the hands at the 5-year disease duration, which representing approximate value of the radiographic progression in the first 5 years after onset of RA, in an individual patient. A zero value represents a patient without any radiographic progression, and the right-side tail represents patients with the most progression.</p

Functional Variants in <em>NFKBIE</em> and <em>RTKN2</em> Involved in Activation of the NF-κB Pathway Are Associated with Rheumatoid Arthritis in Japanese

<div><p>Rheumatoid arthritis is an autoimmune disease with a complex etiology, leading to inflammation of synovial tissue and joint destruction. Through a genome-wide association study (GWAS) and two replication studies in the Japanese population (7,907 cases and 35,362 controls), we identified two gene loci associated with rheumatoid arthritis susceptibility (<em>NFKBIE</em> at 6p21.1, rs2233434, odds ratio (OR) = 1.20, <em>P</em> = 1.3×10⁻¹⁵; <em>RTKN2</em> at 10q21.2, rs3125734, OR = 1.20, <em>P</em> = 4.6×10⁻⁹). In addition to two functional non-synonymous SNPs in <em>NFKBIE</em>, we identified candidate causal SNPs with regulatory potential in <em>NFKBIE</em> and <em>RTKN2</em> gene regions by integrating <em>in silico</em> analysis using public genome databases and subsequent <em>in vitro</em> analysis. Both of these genes are known to regulate the NF-κB pathway, and the risk alleles of the genes were implicated in the enhancement of NF-κB activity in our analyses. These results suggest that the NF-κB pathway plays a role in pathogenesis and would be a rational target for treatment of rheumatoid arthritis.</p> </div