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Oily fish and raw vegetable consumption can decrease the risk of AQP4-positive neuromyelitis optica spectrum disorders: a Mendelian-randomization study.

ABSTRACT: Neuromyelitis optica spectrum disorders (NMOSD) are severe inflammatory disorders of the central nervous system targeting aquaporin-4 (AQP4). The risk factors for NMOSD remain to be determined, though they may be related to diet and nutrition. This study aimed to explore the possibility of a causal relationship between specific food intake and AQP4-positive NMOSD risk. The study followed a two-sample Mendelian randomization (MR) design. Genetic instruments and self-reported information on the intake of 29 types of food were obtained from a genome-wide association study (GWAS) on 445,779 UK Biobank participants. A total of 132 individuals with AQP4-positive NMOSD and 784 controls from this GWAS were included in our study. The associations were evaluated using inverse-variance-weighted meta-analysis, weighted-median analysis, and MR-Egger regression. A high consumption of oily fish and raw vegetables was associated with a decreased risk of AQP4-positive NMOSD (odds ratio [OR] = 1.78 × 10^-16, 95% confidence interval [CI] = 2.60 × 10^-25-1.22 × 10^-7, p = 0.001; OR = 5.28 × 10^-6, 95% CI = 4.67 × 10^-11-0.598, p = 0.041, respectively). The results were consistent in the sensitivity analyses, and no evidence of directional pleiotropy was observed. Our study provides useful implications for the development of AQP4-positive NMOSD prevention strategies. Further research is needed to determine the exact causal relationship and mechanisms underlying the association between specific food intake and AQP4-positive NMOSD.

SUBMITTER: Wang S

PROVIDER: S-EPMC10256733 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Oily fish and raw vegetable consumption can decrease the risk of AQP4-positive neuromyelitis optica spectrum disorders: a Mendelian-randomization study.

Wang Shengnan S Pan Lin L Wu Rui R Shao Yanqing Y Xue Mengru M Zhu Hao H Min Wanwan W Zheng Xiangyu X Liang Yekun Y Zhu Mingqin M

Scientific reports 20230609 1

Neuromyelitis optica spectrum disorders (NMOSD) are severe inflammatory disorders of the central nervous system targeting aquaporin-4 (AQP4). The risk factors for NMOSD remain to be determined, though they may be related to diet and nutrition. This study aimed to explore the possibility of a causal relationship between specific food intake and AQP4-positive NMOSD risk. The study followed a two-sample Mendelian randomization (MR) design. Genetic instruments and self-reported information on the in ...[more]

PMID: 37296187

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Project description:ImportanceImmunoglobulin G autoantibodies for aquaporin 4 (AQP4-IgG) serve as diagnostic biomarkers for neuromyelitis optica spectrum disorder (NMOSD), and the most sensitive and specific laboratory tests for their detection are cell-based assays (CBAs). Nevertheless, the limited availability of special instruments limits the widespread use of CBAs in routine laboratories.ObjectiveTo validate an enzyme immunodot assay for simple and rapid detection of AQP4-IgG.Design, setting, and participantsThis multicenter case-control study, conducted from May 2020 to February 2023, involved 4 medical centers (3 in China and 1 in Korea). The study included patients with AQP4-IgG-positive NMOSD, patients with other immune-related diseases, and healthy control individuals. Participants were excluded if they did not agree to participate or if their serum sample had turbidity.ExposuresSerum AQP4 antibodies measured with immunodot assay.Main outcomes and measuresThe main outcome was performance of the immunodot assay compared with the gold standard CBA for detecting AQP4-IgG. To examine generalizability, cross-validation in Korea and at a second site in China, validation of patients with other immune-related diseases, and follow-up validation of the original cohort were performed.ResultsA total of 836 serum samples were collected; 400 were included in the diagnostic study and 436 in the validation sets. In a head-to-head diagnostic study involving 200 patients with NMOSD with AQP4-IgG (mean [SD] age, 43.1 [13.5] years; 188 [94%] female) and 200 healthy controls, use of an immunodot assay demonstrated antibody detection performance comparable to that of the gold standard (κ = 98.0%). The validation sets included 47 patients with NMOSD and 26 patients with other autoimmune diseases from Korea, 31 patients with NMOSD at a second site in China, 275 patients with other diseases, and 57 patients with NMOSD at follow-up. In the validation study, of 436 cases, 2 (<1%) were false positive and none were false negative. The CBA identified 332 AQP4-IgG-positive samples and 504 negative samples (200 [40%] in controls and 304 [60%] in patients with other diseases); 2 of the positive cases (<1%) were false negative and 4 of the negative cases (<1%) were false positive. The overall sensitivity of the immunodot assay was 99.4% (95% CI, 97.8%-99.9%), and the specificity was 99.2% (95% CI, 98.0%-99.8%).Conclusions and relevanceThis case-control study found that the immunodot assay was comparable to CBA for detecting AQP4-IgG. With its time- and cost-efficient characteristics, the immunodot assay may be a practical option for AQP4-IgG detection.

Project description:Pathogenic antibodies targeting the aquaporin-4 water channel on astrocytes are associated with relapsing inflammatory neuromyelitis optica spectrum disorders. The clinical phenotype is characterized by recurrent episodes of optic neuritis, longitudinally extensive transverse myelitis, area postrema attacks and less common brainstem and cerebral events. Patients often develop major residual disability from these attacks, so early diagnosis and initiation of attackpreventing medications is important. Accurate prediction of relapse would assist physicians in counselling patients, planning treatment and designing clinical trials. We used a large multicentre dataset of 441 patients from the UK, USA, Japan and Martinique who collectively experienced 1976 attacks, and applied sophisticated mathematical modelling to predict likelihood of relapse and disability at different time points. We found that Japanese patients had a lower risk of subsequent attacks except for brainstem and cerebral events, with an overall relative relapse risk of 0.681 (P = 0.001) compared to Caucasians and African patients, who had a higher likelihood of cerebral attacks, with a relative relapse risk of 3.309 (P = 0.009) compared to Caucasians. Female patients had a higher chance of relapse than male patients (P = 0.009), and patients with younger age of onset were more likely to have optic neuritis relapses (P < 0.001). Immunosuppressant drugs reduced and multiple sclerosis disease-modifying agents increased the likelihood of relapse (P < 0.001). Patients with optic neuritis at onset were more likely to develop blindness (P < 0.001), and those with older age of onset were more likely to develop ambulatory disability. Only 25% of long-term disability was related to initial onset attack, indicating the importance of early attack prevention. With respect to selection of patients for clinical trial design, there would be no gain in power by selecting recent onset patients and only a small gain by selecting patients with recent high disease activity. We provide risk estimates of relapse and disability for patients diagnosed and treated with immunosuppressive treatments over the subsequent 2, 3, 5 and 10 years according to type of attack at onset or the first 2-year course, ethnicity, sex and onset age. This study supports significant effects of onset age, onset phenotype and ethnicity on neuromyelitis optica spectrum disorders outcomes. Our results suggest that powering clinical treatment trials based upon relapse activity in the preceding 2 years may offer little benefit in the way of attack risk yet severely hamper clinical trial success.

Project description:BackgroundAquaporin-4-immunoglobulin G (AQP4-IgG) seropositive neuromyelitis optica spectrum disorder (herein called NMO) is an autoimmune disease of the central nervous system in which AQP4-IgG binding to AQP4 on astrocytes results in complement-dependent astrocyte injury and secondary inflammation, demyelination, and neuron loss. We previously reported evidence for a complement bystander mechanism for early oligodendrocyte injury in NMO. Herein, we tested the hypothesis that complement bystander injury, which involves diffusion to nearby cells of activated soluble complement components from complement-injured astrocytes, is a general phenomenon that may contribute to neuronal injury in NMO.MethodsPrimary cocultures of rat astrocytes and cortical neurons were established to study complement-dependent cell death after exposure to AQP4-IgG and complement. In animal experiments, AQP4-IgG was delivered to adult rats by intracerebral injection. Cell cultures and rat brain were studied by immunofluorescence.ResultsIn primary astrocyte-neuron cocultures, addition of AQP4-IgG and complement resulted in death of neurons nearby astrocytes. Deposition of complement membrane attack complex C5b-9 was seen on neurons nearby astrocytes, whereas C1q, the initiating protein in the complement pathway, was seen only on astrocytes. Neuron death was not seen with a complement inhibitor, with C1q- or C6-depleted complement, in pure neuron cultures exposed to AQP4-IgG and complement or in cocultures exposed to an astrocyte toxin. Intracerebral injection in rats of AQP4-IgG and a fixable dead cell fluorescent marker produced death of neurons near astrocytes, with C5b-9 deposition. Neuron death was not seen in rats receiving a complement inhibitor or in AQP4-IgG-injected AQP4 knockout rats.ConclusionThese results support a novel mechanism for early neuron injury in NMO and provide evidence that complement bystander injury may be a general phenomenon for brain cell injury following AQP4-IgG-targeted astrocyte death.

Dataset Information

Oily fish and raw vegetable consumption can decrease the risk of AQP4-positive neuromyelitis optica spectrum disorders: a Mendelian-randomization study.

Publications

Oily fish and raw vegetable consumption can decrease the risk of AQP4-positive neuromyelitis optica spectrum disorders: a Mendelian-randomization study.

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