ACPA-negative RA consists of two genetically distinct subsets based on RF positivity in Japanese.

HLA-DRB1, especially the shared epitope (SE), is strongly associated with rheumatoid arthritis (RA). However, recent studies have shown that SE is at most weakly associated with RA without anti-citrullinated peptide/protein antibody (ACPA). We have recently reported that ACPA-negative RA is associated with specific HLA-DRB1 alleles and diplotypes. Here, we attempted to detect genetically different subsets of ACPA-negative RA by classifying ACPA-negative RA patients into two groups based on their positivity for rheumatoid factor (RF). HLA-DRB1 genotyping data for totally 954 ACPA-negative RA patients and 2,008 healthy individuals in two independent sets were used. HLA-DRB1 allele and diplotype frequencies were compared among the ACPA-negative RF-positive RA patients, ACPA-negative RF-negative RA patients, and controls in each set. Combined results were also analyzed. A similar analysis was performed in 685 ACPA-positive RA patients classified according to their RF positivity. As a result, HLA-DRB1*04:05 and *09:01 showed strong associations with ACPA-negative RF-positive RA in the combined analysis (p = 8.8×10(-6) and 0.0011, OR: 1.57 (1.28-1.91) and 1.37 (1.13-1.65), respectively). We also found that HLA-DR14 and the HLA-DR8 homozygote were associated with ACPA-negative RF-negative RA (p = 0.00022 and 0.00013, OR: 1.52 (1.21-1.89) and 3.08 (1.68-5.64), respectively). These association tendencies were found in each set. On the contrary, we could not detect any significant differences between ACPA-positive RA subsets. As a conclusion, ACPA-negative RA includes two genetically distinct subsets according to RF positivity in Japan, which display different associations with HLA-DRB1. ACPA-negative RF-positive RA is strongly associated with HLA-DRB1*04:05 and *09:01. ACPA-negative RF-negative RA is associated with DR14 and the HLA-DR8 homozygote

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Effect of Boron Doping on Cellular Discontinuous Precipitation for Age-Hardenable Cu–Ti Alloys

The effects of boron doping on the microstructural evolution and mechanical and electrical properties of age-hardenable Cu–4Ti (at.%) alloys are investigated. In the quenched Cu–4Ti–0.03B (at.%) alloy, elemental B (boron) is preferentially segregated at the grain boundaries of the supersaturated solid-solution phase. The aging behavior of the B-doped alloy is mostly similar to that of conventional age-hardenable Cu–Ti alloys. In the early stage of aging at 450 °C, metastable β′-Cu4Ti with fine needle-shaped precipitates continuously form in the matrix phase. Cellular discontinuous precipitates composed of the stable β-Cu4Ti and solid-solution laminates are then formed and grown at the grain boundaries. However, the volume fraction of the discontinuous precipitates is lower in the Cu–4Ti–0.03B alloy than the Cu–4Ti alloy, particularly in the over-aging period of 72–120 h. The suppression of the formation of discontinuous precipitates eventually results in improvement of the hardness and tensile strength. It should be noted that minor B doping of Cu–Ti alloys also effectively enhances the elongation to fracture, which should be attributed to segregation of B at the grain boundaries

A large-scale association study identified multiple HLA-DRB1 alleles associated with ACPA-negative rheumatoid arthritis in Japanese subjects.

[Background] HLA-DRB1 is associated with rheumatoid arthritis (RA). However, it has recently been suggested that HLA-DRB1 is only associated with patients with RA who have anticitrullinated peptide/protein antibodies (ACPA), which are specific to RA. [Objective] To elucidate whether specific HLA-DR alleles are associated with ACPA-negative RA development. [Methods] HLA-DRB1 typing was carried out in 368 Japanese ACPA-negative patients with RA and 1508 healthy volunteers as the first set, followed by HLA-DRB1 typing of 501 cases and 500 controls as the second set. The HLA-DRB1 allele frequency and diplotype frequency were compared in each group, and the results of the two studies were combined to detect HLA-DRB1 alleles or diplotypes associated with ACPA-negative RA. [Results] HLA-DRB1*12:01 was identified as a novel susceptibility allele for ACPA-negative RA (p=0.000088, OR=1.72, 95% CI 1.31 to 2.26). HLA-DRB1*04:05 and *14:03 showed moderate associations with ACPA-negative RA (p=0.0063, OR=1.26, 95% CI 1.07 to 1.49 and p=0.0043, OR=1.81, 95% CI 1.20 to 2.73, respectively). The shared epitope was weakly associated with ACPA-negative RA, but no dosage effect was detected (p=0.016, OR=1.17, 95% CI 1.03 to 1.34). A combination of HLA-DRB1*12:01 and DRB1*09:01 showed a strong association with susceptibility to ACPA-negative RA (p=0.00013, OR=3.62, 95% CI 1.79 to 7.30). Homozygosity for HLA-DR8 was significantly associated with ACPA-negative RA (p=0.0070, OR=2.16, 95% CI 1.22 to 3.82). It was also found that HLA-DRB1*15:02 and *13:02 were protective against ACPA-negative RA (p=0.00010, OR=0.68, 95% CI 0.56 to 0.83 and p=0.00059, OR=0.66, 95% CI 0.52 to 0.84, respectively). [Conclusions] In this large-scale association study multiple alleles and diplotypes were found to be associated with susceptibility to, or protection against, ACPA-negative RA

インターロイキン1の胃粘膜防御作用

雑誌掲載

Logistic regression analysis of HLA-DRB1 alleles with ACPA-positive RF-positive RA and ACPA-positive RF-negative RA.

*<p><i>p</i>-values and odds ratios in logistic regression analysis using SE and HLA-DRB1*09:01.</p