Search

Assay for Transposase‐Accessible Chromatin using high‐throughput sequencing (ATAC‐seq) is the popular technique using next‐generation sequencing to measure chromatin accessibility and identify open chromatin regions. While read alignment shape information of next‐generation sequencing data with intensity information has been used in various bioinformatics methods, few studies have focused on pure shape information alone. In this study, we investigated what types of ATAC‐seq read alignment shapes are observed for the promoter region and whether the pure shape information was related or unrelated to other gene features. We introduced a novel concept and pipeline for handling the pure shape information of NGS data as probability distributions and quantifying their dissimilarities by information theory. Based on this concept, we demonstrate that the pure shape information of ATAC‐seq data is correlated with chromatin openness and some gene characteristics. On the other hand, it is suggested that the pure information of ATAC‐seq read alignment shape is unlikely to contain additional information to explain differences in RNA expression. Our study suggests that viewing the read alignment shape of NGS data as probability distributions enables us to capture the characteristics of the genome‐wide landscape of such data in a non‐parametric manner. [ABSTRACT FROM AUTHOR]

Proximal gastrectomy (PG) in combination with jejunal pouch interposition is a technique aimed at improving the postoperative dietary outcomes; however, some cases are reported to require surgical intervention owing to difficulty of food intake caused by pouch dysfunction. Herein, we present a case of robot‐assisted surgery for interposed jejunal pouch (IJP) dysfunction in a 79‐year‐old male, occurring 25 years after the initial PG for gastric cancer. The patient had chronic anorexia for 2 years and was treated with medications and dietary guidance; however, 3 months prior to admission his quality of life had reduced, owing to worsening symptoms. The patient was diagnosed with pouch dysfunction due to extremely dilated IJP identified using computed tomography and underwent robot‐assisted total remnant gastrectomy (RATRG) with IJP resection. After an uneventful course of intraoperative and postoperative treatment, he was discharged with sufficient food intake on postoperative day 9. RATRG can, thus, be considered in patients with IJP dysfunction after PG. [ABSTRACT FROM AUTHOR]

Background: There have been several reports about the prognosis of teeth adjacent to edentulous spaces for implant‐supported fixed prostheses (ISFPs) and removable partial dentures (RPDs). However, there are few reports about the prognosis of the other remaining teeth comparing ISFPs with RPDs. Purpose: The aim of this study was to evaluate and compare the prognosis of the remaining teeth for ISFPs and RPDs in terms of survival and complication‐free rates. Methods: Subjects were partially edentulous patients with ISFPs or RPDs inserted in 2003–2016. Teeth adjacent to edentulous spaces (A‐teeth), teeth not adjacent to edentulous spaces (R‐teeth), and teeth opposing edentulous spaces (O‐teeth) were investigated. The endpoints were tooth extraction and complications. A multivariate cox regression model was used to estimate the risk factors for survival of the investigated teeth. Results: A total of 233 (ISFP: 89, RPD: 144) patients were included in the statistical analyses. An IFSP prosthesis, when compared to an RPD prosthesis did not significantly decrease the tooth loss rate for A‐teeth (hazard ratio [HR]: 0.76; 95% confidence interval [CI]: 0.30–1.92), for R‐teeth (HR: 0.54; 95% CI: 0.28–1.05), or for O‐teeth (HR: 0.45; 95% CI: 0.10–2.09). Conclusions: In partially edentulous spaces, the difference between ISFPs and RPDs does not affect the prognosis of teeth adjacent to edentulous spaces, teeth not adjacent to edentulous spaces, and teeth opposing edentulous spaces. Namely, our findings suggest that it depends largely on the tooth type, jaw, endodontic therapy performed, not on the type of prostheses. [ABSTRACT FROM AUTHOR]

Genetic epidemiology is a rapidly advancing field due to the recent availability of large amounts of omics data. In recent years, it has become possible to obtain omics information at the single‐cell level, so genetic epidemiological models need to be updated to integrate with single‐cell expression data. In this perspective paper, we propose a cell population‐based framework for genetic epidemiology in the single‐cell era. In this framework, genetic diversity influences phenotypic diversity through the diversity of cell population profiles, which are defined as high‐dimensional probability distributions of the state spaces of biomolecules of each omics layer. We discuss how biomolecular experimental measurement data can capture the different properties of this distribution. In particular, single‐cell data constitute a sample from this population distribution where only some coordinate values are observable. From a data analysis standpoint, we introduce methodology for feature extraction from cell population profiles. Finally, we discuss how this framework can be applied not only to genetic epidemiology but also to systems biology. [ABSTRACT FROM AUTHOR]

A 50‐kW class three‐phase photovoltaic (PV) inverter typically applies a transformerless circuit configuration due to its high efficiency and small volume/size. On the other hand, the conventional PV inverter may suffer from the deterioration of solar panels due to a dc leakage current flowing through the stray capacitance of the solar panels. To solve this problem, this paper presents a transformerless three‐phase PV inverter consisting of multiple bidirectional choppers, which prevents the dc leakage current by maintaining a negative PV array voltage with respect to the ground potential to a dc voltage that is zero or higher. In addition, the size/volume of an ac filter can be reduced by applying the so‐called phase‐shifted PWM to the inverter. In this paper, the operating principles and control method of the inverter are discussed and the validity of the control method is verified by performing computer simulation using the "PSCAD/EMTDC" software package and conducting experiments using a 150‐V downscaled model. [ABSTRACT FROM AUTHOR]

Abstract: Single molecule conductance (SMC) of a series of porphyrin derivatives, whose porphyrin units are connected through a phenylene bridge that have one or two thiolate end groups, was measured by a scanning tunneling microscopic break junction (STM‐BJ) technique. The observed conductance values were analyzed by partial transmission probabilities (Ti) for the molecular parts using the equation G=G0 ∏ i N T i . Unique combination of Ti was obtained, which indicates the validity of this analysis. By the analysis, the free‐base porphyrin ring interacting with the gold electrode was found to show a greater transmission probability Tpor‐Au than that of the bridge between thiolate and the gold electrode (TS‐Au). [ABSTRACT FROM AUTHOR]

Epidemiological findings indicate that acute kidney injury (AKI) increases the risk for chronic kidney disease (CKD), although the molecular mechanism remains unclear. Genetic fate mapping demonstrated that nephrons, functional units in the kidney, are repaired by surviving nephrons after AKI. However, the cell population that repairs damaged nephrons and their repair capacity limitations remain controversial. To answer these questions, we generated a new transgenic mouse strain in which mature proximal tubules, the segment predominantly damaged during AKI, could be genetically labelled at desired time points. Using this strain, massive proliferation of mature proximal tubules is observed during repair, with no dilution of the genetic label after the repair process, demonstrating that proximal tubules are repaired mainly by their own proliferation. Furthermore, acute tubular injury caused significant shortening of proximal tubules associated with interstitial fibrosis, suggesting that proximal tubules have a limited capacity to repair. Understanding the mechanism of this limitation might clarify the mechanism of the AKI-to-CKD continuum. [ABSTRACT FROM AUTHOR]

Objective While antinuclear antibodies (ANAs) are observed in healthy populations as well as in patients with autoimmune diseases such as systemic lupus erythematosus (SLE), the detailed genetic background of ANAs has remained unclear. We undertook this study to identify the genetic determinants of ANAs in the general population in order to elucidate the underlying mechanisms of ANA production and to distinguish disease susceptibility genes from ANA production genes. Methods A total of 9,575 Japanese volunteers were registered, and their ANA levels were quantified using indirect immunofluorescence to analyze correlates of ANA positivity. Genetic studies were performed using 7,148 of the 9,575 subjects. We performed a genome-wide association study using 3,185 subjects genotyped for 303,506 single-nucleotide polymorphisms (SNPs), followed by a replication study of 3,963 subjects. HLA-DRB1 and HLA-DQB1 alleles were imputed, and associations between ANA positivity and the SNPs or the HLA alleles associated with SLE were analyzed. Results Female sex and old age were associated with ANA positivity, except for the nucleolar pattern. The T allele of rs2395185 in the HLA locus, which was in moderate linkage disequilibrium with HLA-DRB1*0405, was significantly associated with ANA positivity ( P = 1.3 × 10−11). The T allele of rs2395185 displayed increasing effects on the frequency of speckled and homogeneous patterns ( P = 7.5 × 10−12 and P = 2.2 × 10−11, respectively) but decreasing effects on the frequency of the nucleolar pattern ( P = 0.0045). The 7 SNPs and 4 HLA-DRB1 alleles associated with SLE did not display strong associations with ANA positivity. Conclusion SNP rs2395185 linked with HLA-DRB1*0405 is a genetic determinant of ANA production in the Japanese population. Overlapping of loci for susceptibility to SLE and to ANA positivity was limited. The nucleolar pattern showed different associations from other staining patterns, both with correlates of ANA positivity and with the HLA locus. [ABSTRACT FROM AUTHOR]

SUMMARY Tumor hypoxia is considered a potential therapeutic problem because it reduces the effects of radiation therapy. Clinical experience has shown that long-term tumor oxygenation cannot be achieved with oxygen inhalation, but the mechanisms behind this phenomenon remain unknown. In this study, we designed an optical system for evaluating spatiotemporal changes in tissue oxygen tension (pO2) by phosphorescence quenching. The system can measure continuous changes in pO2 at a fixed point and can also perform two-dimensional mapping of pO2 in any part of the tumor tissue. We implanted tumor tissue in a dorsal skinfold chamber (DSC) of C57BL/6 mice and observed tumor growth. The mice received oxygen inhalation and pO2 was measured. Tumor pO2 increased after inhalation but the oxygen level was not maintained despite continuous inhalation of pure oxygen; the tumor returned to a hypoxic state. These results mimic the clinical experience of oxygen inhalation treatment in radiation therapy. Our system reproduces the repeat hypoxic phenomenon in a murine tumor model and can be used to determine the mechanisms of oxygen metabolism in tumors. [ABSTRACT FROM AUTHOR]

Objective: The excessive consumption of confectionery might have adverse effects on human health. To screen genetic factors associated with confectionery-intake frequency, a genome-wide association study (GWAS) in Japan was conducted. Design and Methods: For the discovery phase (stage 1), we conducted a GWAS of 939 noncancer patients in a cancer hospital. Additive models were used to test associations between genotypes of approximately 500,000 single-nucleotide polymorphisms (SNPs) and the confectionery-intake score (based on intake frequency). We followed-up association signals with P < 1 × 10−5 and minor allele frequency >0.01 in stage 1 by genotyping the SNPs of 4,491 participants in a cross-sectional study within a cohort (replication phase [stage 2]). Results: We identified 12 SNPs in stage 1 that were potentially related to confectionery intake. In stage 2, this association was replicated for one SNP (rs822396; P = 0.049 for stage 2 and 4.2 × 10−5 for stage 1+2) in intron 1 of the ADIPOQ gene, which encodes the adipokine adiponectin. Conclusions: Given the biological plausibility and previous relevant findings, the association of an SNP in the ADIPOQ gene with a preference for confectionery is worthy of follow-up and provides a good working hypothesis for experimental testing. [ABSTRACT FROM AUTHOR]

Objective Systemic sclerosis (SSc) is an autoimmune disease for which multiple susceptibility genes have been reported. Genome-wide association studies have shown that large numbers of susceptibility genes are shared among autoimmune diseases. Recently, our group identified 9 novel susceptibility genes associated with rheumatoid arthritis (RA) in a Japanese population. The aim of this study was to elucidate whether the 18 genes that displayed associations or suggestive associations for RA in our previous study are associated with SSc in Japanese. Methods We performed an association study that included 415 patients with SSc and 16,891 control subjects, followed by a replication study that included 315 patients and 21,054 control subjects. The 18 markers reported to display association with RA were analyzed for their associations with SSc in the first study, and 5 markers were further analyzed in the replication study. The inverse variance method was used to evaluate the associations of these markers with SSc in a combined study. Results In the phospholipase D4 gene ( PLD4), rs2841277 displayed a significant association with SSc in Japanese patients ( P = 0.00017). We observed that rs2841280 in exon 2 of PLD4 was in strong linkage disequilibrium with rs2841277 and introduced an amino acid alteration. We also observed associations between SSc and rs6932056 in TNFAIP3 and rs2280381 in IRF8 ( P = 0.0000095 and P = 0.0030, respectively), both of which displayed associations with SSc in a European population. Conclusion We determined that PLD4 is a novel susceptibility gene for SSc in Japanese, thus confirming the involvement of PLD4 in autoimmunity. Associations between SSc and TNFAIP3 or IRF8 were also detected in our Japanese population. SSc and RA appear to share relatively large proportions of their genetic backgrounds. [ABSTRACT FROM AUTHOR]

Aims To investigate whether objective cardiovascular parameters have an independent association with nocturnal voiding in women. Methods Thirty-two parameters derived from questionnaires, and anthropometric, physiological and biochemical measures of 5,980 women were applied for analysis. Nocturnal voiding was assessed by the International Prostate Symptom Score and the Overactive Bladder Symptom Score. We measured variables including previously reported correlates of nocturnal voiding, such as age, a history of hypertension, and a history of diabetes, as well as those focusing on cardiovascular function, such as the cardio-ankle vascular index, the augmentation index, the ankle-brachial index, plasma B-type natriuretic peptide (BNP), and C-reactive protein (CRP). Results Age [odds ratio (OR): 1.058, P < 0.001], length of sleep (OR: 1.194, P < 0.001), sleeplessness (OR: 2.841, P < 0.001), urgency (OR: 1.528, P < 0.001), log(BNP) (OR: 2.031, P < 0.001), waist circumference (OR: 1.037, P = 0.002), body mass index (OR: 0.935, P = 0.007), menopause (OR: 1.503, P = 0.043), and history of hypertension (OR: 1.225, P = 0.029) were independently associated with nocturnal voiding ≥2 times. Age (β = 0.256, P < 0.001), urgency (β = 0.195, P < 0.001), sleeplessness (β = 0.181, P < 0.001), length of sleep (β = 0.088, P < 0.001), log(BNP) (β = 0.072, P < 0.001), waist circumference (β = 0.086, P < 0.001), and low-density lipoprotein-cholesterol (β = −0.038, P = 0.003) were significantly correlated with the severity of nocturnal voiding. Conclusions Plasma BNP, which represents cardiac load, is strongly associated with the prevalence and severity of nocturnal voiding in Japanese women, as well as previously known correlates including age, urgency, quality and quantity of sleep, and obesity. Neurourol. Urodynam. 31:1266-1271, 2012. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: In Drosophila, Eiger, a tumor necrosis factor α (TNFα) superfamily ligand, induces cell death by activating the c-Jun N-terminal kinase (JNK) pathway. Here, we report that overexpression of Plenty of SH3s (POSH) suppresses Eiger-induced cell death and produces highly deformed tissues. These results imply that high levels of POSH protect tissues from cell death. In humans, rheumatoid arthritis synovial fibroblasts (RASF) are generally resistant to apoptosis. We show that POSH is expressed at relatively high levels in RASF, and its reduction by RNAi sensitizes these cells to Fas-mediated apoptosis. Thus, we demonstrate that POSH promotes cell survival in Drosophila and in human RASF. [ABSTRACT FROM AUTHOR]

The article presents a study that assesses the role of tumor necrosis factor α (TNFα)-induced protein 3 gene (TNFAIP3) in the development of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Japanese population. The study examined two single-nucleotide polymorphisms (SNPs) obtained from earlier researches on genome-wide association (GWA). Results show the essential association between rs2230926 and a higher risk of RA and SLE among the Japanese subjects.

The article presents a study on the effects of haplotypes in the human leukocyte antigen (HLA) region of Japanese patients with rheumatoid arthritis (RA) to the anti-cyclic citrullinated peptide (anti-CCP) positivity. It is stated in the study that HLA regions demonstrate significant genetic factors in the RA pathogenesis. It notes that the study identified the risk heterogeneities among shared epitope (SE) alleles. It also mentions that the study confirmed anti-CCP antibody positivity risks.

Background: Typical exudative age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) are two of the major macular diseases found in Asians. Although genomic studies have shown a contribution by CFH and LOC387715/ HTRA1 polymorphisms to the development of these two diseases, the correlation of the clinical phenotypes to these genotypes has not been determined in Asian patients. Methods: The prevalence of the CFH Y402H and HTRA1 rs11200638 genotypes was determined in 116 patients with typical exudative AMD and in 204 patients with PCV. Potential correlations of these polymorphisms were tested retrospectively and cross-sectionally for bilaterality of the disease, final visual acuity and the greatest linear dimension of the choroidal neovascular (CNV) lesion. Results: There was no significant difference in the incidence of CFH Y402H ( P = 0.598) and HTRA1 rs11200638 ( P = 0.290) between eyes with typical exudative AMD and with PCV. There was a significant association between the lesion size and HTRA1 rs11200638. For eyes with typical AMD, the size of the lesion (6363 ± 2837 µm) was significantly larger in the high-risk homozygous group (AA), than in the low-risk homozygous group (GG) (3866 ± 1947 µm; P = 0.0003). The same tendency was observed for the size of the lesion in PCV cases (homozygous group: 6347 ± 2673 µm, non-risk homozygous group: 4405 ± 2066 µm, P = 1.3 × 10−5). Conclusions: A common genetic background may exist between typical exudative AMD and PCV patients. Among the patients with these two clinical entities, those with a homozygous HTRA1 rs11200638 risk allele had larger CNV lesions. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a complex, multifactorial disease with genetic and immunological aspects. Because RA is an autoimmune condition, dysregulation of the immune system is implied. Many linkage and association studies have also indicated that multiple genetic factors are associated with RA. Although the contribution of each genetic factor is small, the combination of these factors affects RA development. Previous studies have suggested that genetic changes affect the internal immunological environment, which results in autoimmune diseases. More recent genetic studies indicate that the HLA-DRB gene is the predominant cause of RA and that other non-HLA genes are also involved. We reported that peptidylarginine deiminase (gene name abbreviated to PADI, protein name abbreviated to PAD) type 4 is the one of the non-HLA genetic factors involved in RA via citrullination. Antibodies against citrullinated proteins/peptides are highly specific to RA, but the physiological roles of PADI gene, PAD proteins as their products and citrullinated proteins/peptides are obscure. However, levels of anticitrullinated protein antibodies are apparently also increased and were involved in the pathogenesis of autoimmune arthritis in mice with collagen-induced arthritis (CIA). These data suggested that citrullinated protein and anticitrullinated protein antibodies play important roles in the development of RA. This review summarizes the relationship between RA and citrullination, as well as the role of PADI4 genetics. [ABSTRACT FROM AUTHOR]

The physiological role of D-aspartate oxidase (ChDASPO) in the yeast Cryptococcus humicola was analysed through the growth characteristics of a ChDASPO gene-disrupted strain ( daspoΔ) and the expression profile of ChDASPO on various combinations of carbon and nitrogen sources. The daspoΔ strain, constructed by homologous integration of the yeast URA3 marker, grew as well as the wild-type strain on ammonium chloride, L-aspartate or D-alanine as the sole nitrogen source. In contrast, the daspoΔ strain did not grow at all on D-aspartate, not only as the sole nitrogen source but also as the sole carbon source or as the sole nitrogen and carbon source, and grew more slowly than the wild-type strain on D-glutamate as the sole nitrogen source. In the wild-type strain, the induction of ChDASPO activity strictly depended on the presence of D-aspartate and was little affected by the co-presence of ammonium chloride, but it was significantly reduced by the co-presence of both glucose and ammonium chloride, which, however, did not abolish the induction, allowing considerable expression of ChDASPO. This expression pattern was consistent with that shown by Northern blot analysis. The daspoΔ strain was more sensitive than the wild-type to the growth retardation by acidic D-amino acids, but not to that by the corresponding L-isomers or D-alanine. These results clearly show that in the yeast, DASPO plays an essential role in the assimilation of D-aspartate and acts as a detoxifying agent for D-aspartate. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The aim of this study was to prepare a DNA immunoadsorbent for the specific, extracorporeal removal of anti-DNA antibodies from the blood of patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Two kinds of cellulose beads were applied as a carrier. Calf thymus DNA was covalently coupled to the carrier using the epichlorohydrin method. Efforts were focused on optimization of conditions for activation and coupling, trying to couple as much DNA as possible to a certain amount of carrier. It was found that the activation level increased with the increase of NaOH concentration and the amount of epichlorohydrin used. The mole of epichlorohydrin must be in excess of that of NaOH because excess NaOH could react further with the epoxy groups in the beads resulting in a decrease of activation level. High activation level could be obtained in a medium of 3.0 M NaOH. The DNA coupling was found to be mainly temperature and pH dependent. Using 0.1 M Tris-HCl buffer, pH 8 at a temperature of 50–90°C, more than 3 mg of DNA could be coupled to 1 ml of wet beads. Prolonging the coupling reaction under 50°C to 72 h resulted in the same coupling capacity as that obtained under 90°C. To evaluate the adsorption ability for anti-DNA of this immunoadsorbent, batch and circulation tests were applied using SLE patient plasma. The immunoadsorbents showed excellent adsorption capacity, especially the cellulose with smaller size (200–300 μm). The incubation of 20 ml of patient's plasma with 1 ml of adsorbent resulted in an 80% decline in the anti-DNA antibody level. In the circulation tests, 30 ml of plasma was circulated through a column containing 3 ml of adsorbent. The maximum decline in anti-DNA level, 80%, was obtained after 60 min. Such high adsorption capacity and high adsorption rate suggest this immunoadsorbent may be used for treatment. For comparison, 1,4-butanediol diglycidyl ether activation method and other DNA... [ABSTRACT FROM AUTHOR]

The principle of a patient-specific immunoadsorber (PsIA) is demonstrated. Studies with model systems (HSA/anti-HSA) on immobilization, stability, and leakage form the basis for the presented fast-performance liquid chromatography (FPLC) and batch experiments, which were conducted using two different protein A adsorbers and autologous and heterologous PsIA systems. Experiments to determine the binding capacity of protein A adsorbers and PsIAs are described. In all experiments, the adsorption of plasma IgG, total protein, and C1q and C3d circulating immune complexes were measured. Plasma of patients with autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus) was investigated. Analysis was performed in both the initial plasma and the flow-through or supernatant. Results of the investigations using FPLC and batch experiments were compared. Autologous PsIA systems are suitable for the selective removal of elevated levels of circulating immune complexes in the plasma. [ABSTRACT FROM AUTHOR]

To remove anti-DNA antibodies from a patient's plasma with systemic lupus erythematosus (SLE), a DNA immunoadsorbent was developed by covalently coupling calf thymus DNA on activated Sepharose 4FF. Sepharose 4FF was activated with 5-norbornene-2,3-dicarboximido carbonochloridate (Cl-CO-ONB), which was proven to be a very effective method for preparation of affinity chromatographic adsorbents. The activation was carried out in dry acetone using 4-(dimethylamine)pyridine (DMAP) and triethylamine (TEA) as catalysts at 4°C or at room temperature. The coupling of DNA to the activated support was investigated as a function of pH, temperature, time, concentration of DNA, and activation level. It was found that the pH for optimal coupling is 3.0, and the amount of coupled DNA increases with an increase either in the concentration of DNA or the activation level. The maximum amount of coupled DNA could reach 1.0 mg DNA/ml support. The incubation of 5 to 20 ml of SLE plasma with 1.0 ml of adsorbent resulted in an 80 to 90% decline in the anti-DNA antibody level. Nonspecific adsorption for normal IgG and total protein is less than 15%. [ABSTRACT FROM AUTHOR]

The polymeric title compound, {[Mn(II) (2)W(IV)(CN)(8)(C(10)H(8)N(2))(2)(H(2)O)(4)]·6H(2)O}(n), has a one-dimensional cyanide-bridged Mn(II)-W(IV) bimetallic assembly. The coordination geometry of the W(IV) atom is eight-coordinate square-anti-prismatic and that of each of the Mn(II) atoms is six-coordinate distorted octa-hedral. Two pairs of CN ligands of W(CN)(8) are bridged to two Mn(II) atoms, the remaining CN ligands being terminal. Each Mn(II) atom is additionally coordinated by a bidentate 2,2'-bipyridyl ligand and two water mol-ecules. The crystal structure is stabilized by O-H⋯O and O-H⋯N hydrogen bonds.

Objective: To examine the entire HLA region for loci (other than the DRB1 locus) associated with rheumatoid arthritis (RA) susceptibility, by typing HLA-DRB1 alleles and multiple single-nucleotide polymorphisms (SNPs) in the Japanese population., Methods: The HLA-DRB1 alleles and 88 SNPs distributed over the HLA gene complex were genotyped, for 828 patients with RA and 1,032 control subjects. The data were evaluated for linkage disequilibrium, and case-control associations were analyzed in 2 ways, in the presence or absence of the disease-susceptibility DRB1 allele, to detect loci independent of the DRB1 allele., Results: HLA-DRB1 alleles *0405, *0401, *0901, *0101, *1401, *1602, *0403, and *1405 were significantly associated with RA in the Japanese population. The smallest P value (P = 1.4 x 10(-27)) was observed in association with an intronic SNP of the NOTCH4 gene, which was due to strong linkage disequilibrium with the HLA-DRB1 allele. A strong association that was independent of HLA-DRB1 shared epitope alleles was observed in 2 SNPs: one in the intron of the MICA gene, the other in the intron of the HLA-DQB2 gene. Their association with RA, independent of HLA-DRB1 shared epitope alleles, was suggestive (P = 0.0024 [corrected P (P(corr)) = 0.068, and P = 0.00037 [P(corr) = 0.012], respectively)., Conclusion: These findings suggest that 1 or more other loci besides the HLA-DRB1 or other DRB1 (non-shared epitope, non-*0901) alleles are involved in RA susceptibility/protection.