A Case of Adult-Onset Still's Disease With Hypocomplementemia.

Adult-onset Still's disease (AOSD) causes fever, rash, pharyngalgia, and arthralgia through autoinflammation. Its complement titer has not previously received attention because this usually increases during the inflammatory process. Our female patient in her 60s was admitted to the hospital with fever, rash, arthralgia, and pharyngalgia. Her white blood cell count was 19,130/µL, hemoglobin was 11.0 g/dL, platelet count was 26.0 × 104/µL, and ferritin titer was 6,175 ng/mL. Anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies were negative. The presence of infectious diseases and malignancies was excluded. She was diagnosed with hypocomplementemia at the onset of AOSD because of her low complement component 4 (C4) titer (<5.0 mg/dL). Her complement component 3 (C3) titer was 104.5 mg/dL, which was within normal limits. There was no sign of thrombotic microangiopathy (TMA) or hemophagocytosis. She was treated with high-dose corticosteroids, including pulse methylprednisolone therapy, cyclosporine, methotrexate, and intravenous immunoglobulin, but was resistant to these, and her disease repeatedly flared up. Treatment with intravenous cyclophosphamide eventually led to remission. Post-treatment, her C4 titer increased to within the normal range. Although hypocomplementemia with TMA or hemophagocytosis has been reported in AOSD patients, our patient showed no sign of either at disease onset. Hypocomplementemia of AOSD may be a sign of high disease activity and could be a predictive marker for resistance to standard therapy.

Pathogenetic associations of anti-ribosomal P protein antibody titres and its subclasses in patients with systemic lupus erythematosus.

OBJECTIVES: We evaluated the association between anti-ribosomal P antibody (anti-RibP) titres and disease activity in Japanese systemic lupus erythematosus (SLE) patients. METHODS: Eighty patients admitted and treated in Niigata University Hospital for new-onset or flare-up of SLE were included in this retrospective cross-sectional study. Clinical data were obtained from medical records at admission. Anti-RibP index, and cytokine and tryptophan metabolite levels were determined by ELISA. RESULTS: Of the 80 SLE patients, 30 had anti-RibP. Anti-RibP presence was associated with a greater prevalence of skin rash and more severe inflammatory responses, demonstrated by higher inflammatory cytokine levels, hypocomplementemia, and accelerated tryptophan metabolism, in younger patients. The serum anti-RibP index correlated with age at diagnosis, clinical indicators, initial prednisolone dose, and cytokines and tryptophan metabolite levels in univariate analysis. Multivariate analysis showed the anti-RibP index was independently associated with initial prednisolone dose and prevalence of skin rash. Anti-RibP IgG were mainly IgG2 and IgG3 subclasses, and anti-RibP IgG3 was associated with hypocomplementemia, higher disease activity score, accelerated kynurenine pathway activity, and higher proinflammatory cytokine production. The coexistence of anti-dsDNA IgG and anti-RibP IgG2 or IgG3 accompanied higher IL-10 and IFN-α2 levels; furthermore, anti-RibP IgG3 coexistence with anti-dsDNA antibody contributed to the requirement for higher initial prednisolone doses and accelerated kynurenine pathway activity. CONCLUSION: Anti-RibP was associated with clinical manifestations and parameters in SLE, and its index might be a useful indicator of disease severity. Anti-RibP IgG3 was the IgG subclass most strongly associated with the pathogenesis of SLE.

The Impact of Early Optimization of Infliximab Blood Concentrations >1 µg/mL on Therapeutic Effectiveness in Rheumatoid Arthritis.

BACKGROUND: Infliximab is a human-murine chimeric monoclonal IgG antibody against tumor necrosis factor that is used in combination with methotrexate for the treatment of moderate to severe rheumatoid arthritis (RA). The trough concentration of serum infliximab required to control disease activity in RA is ≥1 µg/mL, and we investigated whether this trough concentration can predict the effectiveness of RA treatment. METHODS: We retrospectively analyzed the cases of 76 patients with RA. The REMICHECK Q® (REMIQ) is a kit that can check for serum infliximab concentrations. Infliximab concentrations >1 µg/mL at 14 weeks after an initial infliximab induction is considered REMIQ-positive, otherwise considered REMIQ-negative. Here, we determined the retention rates and investigated the clinical and serologic features of REMIQ-positive and REMIQ-negative patients. RESULTS: At 14 weeks, significantly more of the REMIQ-positive patients (n = 46) were responders compared to the non-responders (n = 30). The retention rate at 54 weeks was also significantly higher in the REMIQ-positive group versus the negative group. After 14 weeks, more patients in the REMIQ-negative group were considered inadequate responders, and their infliximab doses were escalated. At baseline, the REMIQ-positive group had significantly lower C-reactive protein (CRP) levels compared to the negative group. Cox regression analysis with multiple variables showed that the positivity of REMIQ (hazard ratio [HR] 2.10 and 95% confidence interval [CI]: 1.55-5.71) at baseline was associated with the achievement of low disease activity. The positivities of rheumatoid factor and anti-CCP antibody at baseline were associated with the achievement of remission with infliximab treatment (HR 0.44, 95% CI: 0.09-0.82 and HR 0.35, 95% CI: 0.04-0.48, respectively). CONCLUSIONS: The results of this study suggest that the control of RA disease activity may be facilitated by using the REMIQ kit at 14 weeks to check whether it is necessary to increase a patient's infliximab dose to ensure a therapeutic blood concentration that will help the patient achieve low disease activity.

The Efficacy of Biological Disease-modifying Antirheumatic Drugs on Sarcopenia in Patients with Rheumatoid Arthritis.

Objective Sarcopenia is characterized by a loss of muscle mass and strength, which leads to frailty and mortality. Rheumatoid arthritis (RA) is considered to be a cause of sarcopenia. The present study assessed the effectiveness of biological disease-modifying antirheumatic drugs (bDMARDs) on sarcopenia. Methods This was a prospective cohort study including 48 patients [11 men, 37 women; 67.5 (57.0-74.8) years old] with RA who started bDMARDs in Niigata Rheumatic Center. We monitored the physical ability, nutritional status and body composition at the baseline, 6 months and 12 months. The physical activity was measured by the Health Assessment Questionnaire (HAQ) and 10-m walking test (10MWT). The nutritional status was assessed by the controlling nutrition status (CONUT) score. Results Among the 48 patients who started bDMARDs, 21 were classified as having sarcopenia. The physical activity and nutritional status were significantly ameliorated after 12 months of bDMARDs. The body composition analysis showed a significant increase in the body weight but no significant increase in the skeletal muscle mass index. The proportion of patients diagnosed with sarcopenia decreased significantly after 12 months of bDMARDs (43.8% vs. 27.1%, p=0.039). Among the 21 patients who were diagnosed with sarcopenia when starting bDMARDs, the skeletal muscle index was significantly increased after 12 months of bDMARDs. [5.22 (4.76-5.43) kg/m2 vs. 5.44 (4.84-5.77), p=0.039]. Conclusion Biologics may be useful in the treatment of sarcopenia through mechanisms such as improving the disease activity, physical activity and nutritional status.

Risks of femoral localized periosteal thickening in patients with autoimmune inflammatory rheumatic diseases.

OBJECTIVES: The incidence of femoral localized periosteal thickening (LPT), which can precede atypical femoral fracture (AFF), is not low (1-10%) in Japanese patients with autoimmune inflammatory rheumatic diseases (AIRDs). We explored the associations between underlying AIRDs and the prevalence of LPT. METHODS: We conducted post hoc analyses of two cohorts that included a total of 280 Japanese women, 105 of whom had AIRDs and had been taking bisphosphonate (BP) and prednisolone (PSL) and 175 of whom had rheumatoid arthritis (RA). RESULTS: LPT was detected in a total of 18 patients (6.4%) and 3 (1.1%) developed AFFs. RA was negatively correlated with LPT. A disease other than RA requiring glucocorticoid treatment, BP use ≥5 years, PSL use ≥7 years, and a PSL dose ≥5.5 mg/day were positively correlated with LPT. After adjusting for age, diabetes mellitus, and BP duration or daily PSL dose, RA was no longer associated with LPT. CONCLUSIONS: LPT in Japanese patients with AIRDs was associated with BP and glucocorticoid treatment rather than underlying AIRDs. When PSL dose ≥5.5 mg/day is required long-term [typically combined with long-term BP treatment (≥5 years)], clinicians need to pay particular attention in cases LPT and AFF as well as glucocorticoid-induced osteoporosis.

Acute heart failure due to left common iliac arteriovenous fistula: A case of VEXAS syndrome.

We describe the case of a 78-year-old man presenting with multiple oedematous erythemas, fever, and arthralgia who subsequently developed neutrophil infiltration into the cartilage of the bilateral auricularis, consistent with relapsing polychondritis. A skin biopsy of the erythema on his right arm showed dense neutrophilic infiltration into the dermis, while a bone marrow aspirate revealed myelodysplastic syndromes with characteristic vacuoles in myeloid precursor cells. Although the patient achieved remission with high-dose oral prednisolone, the inflammatory symptoms relapsed, and he was resistant to colchicine and cyclosporine. The patient spontaneously developed left leg oedema and high-output cardiac failure caused by an arteriovenous fistula with a common iliac artery aneurysm. We successfully performed a two-stage surgery using internal iliac artery coil embolisation and endovascular aortic repair of the iliac aneurysm. We assumed the patient was suffering from large-vessel vasculitis such as giant cell arteritis or Takayasu's arteritis. We treated him with tocilizumab in addition to prednisolone, and the febrile events and elevated C-reactive protein levels improved. One year later, sequencing of ubiquitylation-initiating E1 enzyme using peripheral blood leucocytes revealed somatic variants (c.121A>C p.Met41Leu), confirming the diagnosis of vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. This case suggests that arteriovenous fistula could be a complication of VEXAS syndrome with large-vessel vasculitis, and adequate surgical intervention and prompt diagnosis are essential for rescue. Although arteriovenous fistula is a rare complication of VEXAS syndrome, physicians should be aware of this complication to ensure prompt diagnosis and timely surgical intervention.

Giant Cell Arteritis That Presented with Buccal Skin Ulceration along the Facial Artery.

A 68-year-old man presented with right buccal ulceration along the facial artery, temporal pain, lagophthalmos, diplopia, and tongue deviation to the right. Contrast-enhanced computed tomography showed bilateral temporal artery and right maxillary artery wall thickening, and a diagnosis of giant cell arteritis (GCA) was made according to the American College of Rheumatology 1990 criteria. Treatment with corticosteroids ameliorated his symptoms. This is the first report of GCA with buccal skin ulceration along a facial artery. Because a delayed diagnosis can lead to irreversible damage, it is essential to notice rare symptoms, such as skin ulceration and multiple cranial neuropathy-like symptoms.

Effectiveness and Safety of Golimumab for Patients ≥75 Years Old with Rheumatoid Arthritis.

Objective Treatment of elderly patients with rheumatoid arthritis (RA) has been controversial because they often have serious comorbidities and cannot use methotrexate (MTX). In Japan, golimumab (GLM) 100 mg without MTX is approved. We investigated the effectiveness and safety of GLM in elderly patients with RA. Methods The GLM survival rate was evaluated using the Kaplan-Meier method. Disease activities, laboratory findings, and treatments were evaluated. Patients We enrolled 168 patients with RA in our hospital. Using age ≥75 years old to identify elderly patients, younger (n=111) and elderly (n=57) groups were established. Elderly patients were divided into 2 groups according to the MTX treatment status (with, n=27; without, n=25). Results The GLM survival rates were 80.8% and 82.3% in elderly and younger patients, respectively (p=0.762). At 52 weeks, the Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) was improved in elderly patients (4.26 vs. 3.31, p<0.001); the Health Assessment Questionnaire Disability Index (HAQ-DI) was unchanged (1.12 vs. 0.88, p=0.694). When elderly patients were compared according to the MTX treatment status, the DAS28-ESR had improved in both groups (with MTX: 3.82 vs. 2.68, p<0.001; without MTX: 4.76 vs. 4.25, p=0.026); however, the HAQ-DI had not. The GLM survival rates at 52 weeks were 85% and 76% in patients with and without MTX, respectively. Conclusion In elderly patients with RA, GLM was effective, regardless of MTX treatment status, but it did not affect the HAQ-DI. GLM survival rates were comparable between elderly and younger patients. GLM may be a suitable option for elderly patients with RA who cannot use MTX.

Lower trabecular bone score is associated with an increased incidence of localized femoral periosteal thickening.

INTRODUCTION: Femoral localized periosteal thickening (LPT, also termed "beaking") of the lateral cortex often precedes an atypical femoral fracture (AFF). Bisphosphonate (BP) use, glucocorticoid use, and Asian race are major risk factors for developing such fractures. The aim of this study was to determine whether the trabecular bone score (TBS) reflecting the lumbar trabecular microarchitecture was related to LPT in glucocorticoid-treated Japanese patients with autoimmune diseases. MATERIALS AND METHODS: We retrospectively investigated 111 women with autoimmune diseases treated with prednisolone (PSL) who had undergone both femoral X-ray and dual-energy X-ray absorptiometry of the L1 - L4 lumbar vertebrae and for whom TBS could be evaluated for two or more of these. RESULTS: Femoral LPT was evident in the X-rays of 18 of 111 patients (16.2%). Higher body mass index (BMI), longer duration of PSL use and longer duration of BP use were significant in patients with LPT compared to those without. The TBS was significantly lower in patients with LPT than in those without (1.314 ± 0.092 vs. 1.365 ± 0.100, p = 0.044); however, the lumbar bone mineral density did not differ significantly (0.892 ± 0.141 vs. 0.897 ± 0.154 g/cm2, p = 0.897). TBS was significantly associated with LPT (odds ratio, 0.004; 95% CI, 0 - 0.96; p = 0.048), but not in the multivariate analysis including BMI, duration of PSL use and duration of BP use. CONCLUSIONS: The TBS was lower in glucocorticoid-treated Japanese women with autoimmune diseases with LPT than in those without LPT, and deteriorated trabecular microarchitecture influenced by longer use of BP and glucocorticoid might be associated with the development of LPT.

Association of coexisting anti-ribosomal P and anti-dsDNA antibodies with histology and renal prognosis in lupus nephritis patients.

OBJECTIVES: Anti-ribosomal P protein autoantibodies (anti-P) specifically develop in patients with systemic lupus erythematosus. Associations of anti-P with lupus nephritis (LN) histological subclass and renal outcome remain inconclusive. We sought to determine the association of anti-P and anti-double-stranded DNA antibody (anti-dsDNA) with renal histology and prognosis in LN patients. METHODS: Thirty-four patients with LN, having undergone kidney biopsy, were included. The 2018 revised ISN/RPS classification system was used for pathophysiological evaluation. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2 for > 3 months. RESULTS: Six patients (17.6%) were positive for anti-P and 26 (76.5%) for anti-dsDNA. Among the six patients with anti-P, one did not have anti-dsDNA, but did have anti-Sm antibody, and showed a histological subtype of class V. This patient maintained good renal function for over 14 years. The remaining five patients, who had both anti-P and anti-dsDNA, exhibited proliferative nephritis and were associated with prolonged hypocomplementemia, and the incidence of CKD did not differ from patients without anti-P. CONCLUSION: Although this study included a small number of patients, the results indicated that histology class and renal prognosis associated with anti-P depend on the coexistence of anti-dsDNA. Further studies with a large number of patients are required to confirm this conclusion.

False-positive semiquantitative immunochromatography assays for procalcitonin in three patients with rheumatoid arthritis-A case series.

We report three rheumatoid arthritis (RA) patients with false-positive procalcitonin (PCT) based on semiquantitative immunochromatography assays without infection, but who had negative PCT assay results based on quantitative methods. Immunochromatography was useful for screening; however, other heterophilic antibodies rather than rheumatoid factor were possible to affect, especially in RA flare.

Nutritional status as the risk factor of serious infection in patients with rheumatoid arthritis.

Objectives: The aim of this study was to identify the risk factors associated with severe infection in RA patients, with a particular focus on the association of the nutritional status.Methods: We retrospectively analyzed data from 74 patients with RA (male, n = 21; female, n = 53; age 74.2 ± 12.4) admitted to our hospital between 2016 and 2017 for infection (infection group). We also recruited control RA patients (n = 222) who were matched for age, gender and disease duration, with a match ratio of 1:3 (non-infection group). The nutritional condition was assessed based on controlling nutrition status (CONUT) score, and prognostic nutritional index (PNI). The data of the infection group were obtained from the most recent visit prior to the present admission, and non-infection group from the last regular visit in 2017.Results: The respiratory tract was the most frequent site of infection. The BMI and PNI were significantly lower and the CONUT score significantly higher in the infection group than in the non-infection group. A logistic regression analysis revealed that the CONUT score, underlying lung disease and use of prednisolone and biological disease-modifying anti-rheumatic drugs were independent and significant risk factors for serious infection.Conclusion: Poor nutritional status increases the risk of serious infection.

A Distinct Subset of Fibroblastic Stromal Cells Constitutes the Cortex-Medulla Boundary Subcompartment of the Lymph Node.

The spatiotemporal regulation of immune responses in the lymph node (LN) depends on its sophisticated tissue architecture, consisting of several subcompartments supported by distinct fibroblastic stromal cells (FSCs). However, the intricate details of stromal structures and associated FSC subsets are not fully understood. Using several gene reporter mice, we sought to discover unrecognized stromal structures and FSCs in the LN. The four previously identified FSC subsets in the cortex are clearly distinguished by the expression pattern of reporters including PDGFRß, CCL21-ser, and CXCL12. Herein, we identified a unique FSC subset expressing both CCL21-ser and CXCL12 in the deep cortex periphery (DCP) that is characterized by preferential B cell localization. This subset was clearly different from CXCL12highLepRhigh FSCs in the medullary cord, which harbors plasma cells. B cell localization in the DCP was controlled chiefly by CCL21-ser and, to a lesser extent, CXCL12. Moreover, the optimal development of the DCP as well as medulla requires B cells. Together, our findings suggest the presence of a unique microenvironment in the cortex-medulla boundary and offer an advanced view of the multi-layered stromal framework constructed by distinct FSC subsets in the LN.

Visualizing the Rapid and Dynamic Elimination of Allogeneic T Cells in Secondary Lymphoid Organs.

Allogeneic organ transplants are rejected by the recipient immune system within several days or weeks. However, the rejection process of allogeneic T (allo-T) cells is poorly understood. In this study, using fluorescence-based monitoring and two-photon live imaging in mouse adoptive transfer system, we visualized the fate of allo-T cells in the in vivo environment and showed rapid elimination in secondary lymphoid organs (SLOs). Although i.v. transferred allo-T cells efficiently entered host SLOs, including lymph nodes and the spleen, ∼70% of the cells had disappeared within 24 h. At early time points, allo-T cells robustly migrated in the T cell area, whereas after 8 h, the numbers of arrested cells and cell fragments were dramatically elevated. Apoptotic breakdown of allo-T cells released a large amount of cell debris, which was efficiently phagocytosed and cleared by CD8+ dendritic cells. Rapid elimination of allo-T cells was also observed in nu/nu recipients. Depletion of NK cells abrogated allo-T cell reduction only in a specific combination of donor and recipient genetic backgrounds. In addition, F1 hybrid transfer experiments showed that allo-T cell killing was independent of the missing-self signature typically recognized by NK cells. These suggest the presence of a unique and previously uncharacterized modality of allorecognition by the host immune system. Taken together, our findings reveal an extremely efficient and dynamic process of allogeneic lymphocyte elimination in SLOs, which could not be recapitulated in vitro and is distinct from the rejection of solid organ and bone marrow transplants.

Fatal visceral disseminated varicella zoster infection during initial remission induction therapy in a patient with lupus nephritis and rheumatoid arthritis-possible association with mycophenolate mofetil and high-dose glucocorticoid therapy: a case report.

BACKGROUND: Visceral disseminated varicella zoster viral (VZV) infection is a rare but severe complication with a high mortality rate in immunosuppressed individuals, and an increased susceptibility to VZV has been reported in kidney transplant recipients who are treated with mycophenolate mofetil (MMF). In Japan, MMF is currently approved for patients with lupus nephritis (LN) and data to indicate its optimal dosage are still insufficient. CASE PRESENTATION: A 46-year-old Japanese woman with rheumatoid arthritis was diagnosed as having systemic lupus erythematosus (SLE) and LN class III (A/C). Although initial remission-induction therapy with prednisolone and tacrolimus was started, her serum creatinine level and urinary protein excretion were elevated. Methylprednisolone pulse therapy was added, and tacrolimus was switched to MMF. Two months after admission when she was taking 40 mg of PSL and 1500 mg of MMF daily, she suddenly developed upper abdominal pain and multiple skin blisters, and disseminated visceral VZV infection was diagnosed. Laboratory examinations demonstrated rapid exacerbation of severe acute liver failure and coagulation abnormalities despite immediate multidisciplinary treatment, and she died of hemorrhagic shock 7 days after the onset of abdominal pain. A serum sample collected at the time of admission revealed that she had recursive VZV infection. CONCLUSIONS: MMF together with high-dose glucocorticoid therapy may increase the risk of VZV infection in Asian patients with SLE. Accumulation of evidence for parameters of safety, such as the area under the blood concentration-time curve of mycophenolic acid, should be urgently considered in order to establish a safer protocol for remission induction therapy in Asian patients with LN.

Extensively re-organized systemic lymph nodes provide a feasible environment for self-reactivity in lupus-prone NZB × NZW F1 mice.

Lymphadenopathy is a frequently observed symptom in systemic lupus erythematosus, although the immunological role of lymph nodes (LNs) in systemic autoimmunity remains largely unknown. Here, we performed comprehensive and systematic analyses of LNs in lupus-prone NZB × NZW F1 (BWF1) mice, demonstrating extensive tissue re-organization of the systemic LNs with follicular expansion, hyper germinal center (GC) formation, atrophy of the paracortical T-cell area and expansion of the medulla in aged BWF1 mice bearing glomerulonephritis. The proportion of B cells was significantly increased in these reactive LNs but not in the spleen, and lymphocyte subsets involved in antibody production, i.e. GC B cells, follicular helper T cells and plasma cells, were elevated. Draining LNs of the affected organs, such as the renal and cervical nodes, showed enhanced tissue re-organization and accumulation of effector lymphocytes, suggesting the presence of a positive feedback loop of regional responses. LN cells isolated from disease-bearing animals produced anti-DNA antibody, indicating activation of autoreactive lymphocytes in situ. The substantial development of disease and LN alterations in mice that received a splenectomy at a young age points to the importance of other secondary lymphoid organs, most likely LNs, for the progression of autoimmune responses independent of the spleen. Taken together, our findings highlight the value of taking LN alterations and activities into consideration for understanding the pathogenesis of systemic autoimmunity.

Association between Fish Consumption and Prefrontal Function during a Cognitive Task in Male Japanese Workers: A Multi-Channel Near-Infrared Spectroscopy Study.

The purpose of this study was to examine the relationship between fish consumption and prefrontal function during a cognitive task in male Japanese workers. The study included 208 male workers who underwent medical health examinations 3 months after a change in their work assignment. We measured the hemoglobin concentration changes in the prefrontal region during working memory tasks using 52-channel near-infrared spectroscopy. The frequency of fish consumption was calculated on the basis of the subjects' self-reported customary intake frequency over the previous 3 months. A significant positive relationship was observed between fish consumption and left dorsolateral prefrontal function during a working memory task. To our knowledge, this is the first study to report an association between fish consumption and functional cortical activity with an ample sample size, suggesting that fish consumption modulates functional activity in the left dorsolateral prefrontal cortex.

Relation of the Glu298Asp polymorphism of the nitric oxide synthase gene to hypertension and serum cholesterol in Japanese workers.

OBJECTIVE: To assess whether the Glu298Asp polymorphism of the endothelial nitric oxide synthase (eNOS) gene possibly mediates the relation of blood pressure and serum cholesterol. METHOD: Regular health examination in 2003 of 1,694 Japanese workers from the Shimane Prefecture, Japan. RESULTS: The frequencies of the Glu/Glu, Glu/Asp, and Asp/Asp genotypes were 85.9%, 13.4%, and 0.7%, respectively. After adjustment for age, sex, BMI, and lifestyle (drinking, smoking, exercise and stress), the odds ratio (OR) of hypertension associated with high (> or = 220 mg/dl or under treatment) total cholesterol was 2.08 (95% Confidence Interval (CI) 1.02-4.24) among carriers of the eNOS 298Asp allele versus 1.18 (95% CI 0.89-1.55, p for interaction=0.50) among non-carriers. Similarly, the ORs of hypertension associated with counseling-need (120-139 mg/dl) and high (> or = 140 mg/dl) levels of LDL cholesterol among carriers of the eNOS 298Asp allele were significantly higher than those among non-carriers, at 2.65 (95% CI 1.16-6.01) versus 1.03 (95% CI 0.77-1.39, p for interaction=0.01), and 2.80 (95% CI 1.33-5.89) versus 0.95 (95% CI 0.71-1.26, p for interaction=0.04), respectively. CONCLUSION: These results indicate that the eNOS 298Asp allele, which is weakly associated with hypertension, may increase the risk of hypertension when associated with high serum lipid levels.

eNOS Glu298Asp polymorphism and hypertension in a cohort study in Japanese.

BACKGROUND: Some recent case-control association studies have suggested negative and positive relationship between Glu298Asp (the substitution of aspartic acid for glutamic acid at amino acid position 298) polymorphism of the endothelial nitric oxide synthase (eNOS) gene and hypertension. To investigate whether the Glu298Asp polymorphism of the eNOS gene affects the incidence of hypertension, a retrospective cohort study was performed. METHODS: The baseline data among Japanese workers in Shimane Prefecture, Japan, were obtained at regular health examination in 1992, and a retrospective cohort study was performed to analyze the influence of Glu298Asp polymorphism on the incidence of hypertension in 1998. RESULTS: The incidences of Glu298Glu, Glu298Asp, and Asp298Asp genotypes in the subjects were 86.4%, 12.6% and 1.1%, respectively. The risk ratios of Glu298Asp and Asp298Asp against Glu298Glu for the incidence of hypertension by single variance analysis were 0.830 in total subjects [95% confidence interval (CI) 0.474-1.452], 0.596 in subjects 20-39 years old (95% CI; 0.207-1.717), and 0.915 in subjects 40-59 years old (95% CI; 0.464-1.805). The risk ratios of Glu298Asp and Asp298Asp against Glu298Glu for the incidence of hypertension by multiple variance analysis adjusted for sex, BMI, serum total cholesterol, serum high-density lipoprotein (HDL) cholesterol, fasting glucose, cigarette smoking, drinking habits, eating habits, and exercise in 1992 were 0.750 in total subjects (95% CI; 0.421-1.335), 0.505 in subjects 20-39 years old (95% CI; 0.170-1.496), and 0.873 in subjects 40-59 years old (95% CI; 0.434-1.757). CONCLUSION: These results suggested no association between the Glu298Asp gene polymorphism and the incidence of hypertension in this selected population.