Exploring the genetic diversity of the Japanese population: Insights from a large-scale whole genome sequencing analysis.

The Japanese archipelago is a terminal location for human migration, and the contemporary Japanese people represent a unique population whose genomic diversity has been shaped by multiple migrations from Eurasia. We analyzed the genomic characteristics that define the genetic makeup of the modern Japanese population from a population genetics perspective from the genomic data of 9,287 samples obtained by high-coverage whole-genome sequencing (WGS) by the National Center Biobank Network. The dataset comprised populations from the Ryukyu Islands and other parts of the Japanese archipelago (Hondo). The Hondo population underwent two episodes of population decline during the Jomon period, corresponding to the Late Neolithic, and the Edo period, corresponding to the Early Modern era, while the Ryukyu population experienced a population decline during the shell midden period of the Late Neolithic in this region. Haplotype analysis suggested increased allele frequencies for genes related to alcohol and fatty acid metabolism, which were reported as loci that had experienced positive natural selection. Two genes related to alcohol metabolism were found to be 12,500 years out of phase with the time when they began to increase in the allele frequency; this finding indicates that the genomic diversity of Japanese people has been shaped by events closely related to agriculture and food production.

Soluble APP-α and APP-ß in cerebrospinal fluid as potential biomarkers for differential diagnosis of mild cognitive impairment.

OBJECTIVES: Concentrations of soluble amyloid precursor proteins-α (sAPPα) and -ß (sAPPß) in cerebrospinal fluid (CSF) may reflect the neuropathology of Alzheimer's disease (AD). We previously reported that the concentrations of both sAPPα and sAPPß were significantly higher in patients with mild cognitive impairment (MCI) due to AD (MCI-AD) than in control subjects without cognitive impairment. The present study analyzed whether these sAPPs are useful in the differential diagnosis of MCI. METHODS: A modified and sensitive method was used to analyze concentrations of sAPPα and sAPPß in CSF of patients with MCI-AD (n = 30) and MCI due to other causes (MCI-others) (n = 24). Phosphorylated tau (p-tau) and amyloid ß-protein 42 (Aß42) were also analyzed using standard methods. RESULTS: CSF concentrations of sAPPα and sAPPß were significantly higher in the MCI-AD than in the MCI-others group (p < 0.001). Furthermore, concentrations of both sAPPα and sAPPß were highly correlated with the concentration of p-tau, consistent with our previous report. CONCLUSIONS: Measurement of both sAPPs in CSF using sensitive methods can be helpful in the precise differential diagnosis of patients with MCI.

Relationship between NAFLD and Periodontal Disease from the View of Clinical and Basic Research, and Immunological Response.

Periodontal disease is an inflammatory disease caused by pathogenic oral microorganisms that leads to the destruction of alveolar bone and connective tissues around the teeth. Although many studies have shown that periodontal disease is a risk factor for systemic diseases, such as type 2 diabetes and cardiovascular diseases, the relationship between nonalcoholic fatty liver disease (NAFLD) and periodontal disease has not yet been clarified. Thus, the purpose of this review was to reveal the relationship between NAFLD and periodontal disease based on epidemiological studies, basic research, and immunology. Many cross-sectional and prospective epidemiological studies have indicated that periodontal disease is a risk factor for NAFLD. An in vivo animal model revealed that infection with periodontopathic bacteria accelerates the progression of NAFLD accompanied by enhanced steatosis. Moreover, the detection of periodontopathic bacteria in the liver may demonstrate that the bacteria have a direct impact on NAFLD. Furthermore, Porphyromonas gingivalis lipopolysaccharide induces inflammation and accumulation of intracellular lipids in hepatocytes. Th17 may be a key molecule for explaining the relationship between periodontal disease and NAFLD. In this review, we attempted to establish that oral health is essential for systemic health, especially in patients with NAFLD.

[A delayed diagnosis of thyroid storm in an elderly patient: A case report].

A 70-year-old woman was hospitalized for diarrhea, vomiting, loss of appetite, fatigue, and dyspnea on exertion for the past 3 weeks and treated with intravenous fluid for dehydration. She was receiving prednisolone for polymyositis. She did not have a history of thyroid disease. On day 4 of hospitalization, the patient was diagnosed with congestive heart failure and tachycardiac atrial fibrillation, and treatment with a diuretic agent was initiated. On day 7 of hospitalization, a clinical laboratory evaluation revealed that the level of free thyroxine was 9.95 ng/dL, free triiodothyronine was >30 pg/mL, and thyroid-stimulating hormone was <0.01 µU/mL, and the patient was initially diagnosed with thyrotoxicosis because of Graves' disease. She showed restlessness and had a fever of 39 °C, tachycardia of ≥140 beats/min, pulmonary edema, and frequent diarrhea, all of which were consistent with the symptoms of thyroid storm. Her general condition gradually improved with comprehensive treatment of thyroid storm comprising thiamazole, potassium iodide, hydrocortisone, and landiolol. A reassessment revealed that the patient had already had thyrotoxicosis and thyroid storm on admission. Thyroid storm is a potentially fatal disease that must be urgently addressed; however, its symptoms are difficult to distinguish from those caused by other diseases. Furthermore, elderly individuals may not exhibit typical symptoms of thyroid storm, so the diagnosis is difficult. In this case, the diagnosis was delayed because of the absence of typical symptoms of thyroid storm and the influence of a pre-existing medical condition and medication.

Investigating DNA Methylation of SHATI/NAT8L Promoter Sites in Blood of Unmedicated Patients with Major Depressive Disorder.

Major depressive disorder (MDD) is one of the most common psychiatric diseases. However, early detection and diagnosis of MDD is difficult, largely because there is no known biomarker or objective diagnostic examination, and its diagnosis is instead based on a clinical interview. The aim of this study was to develop a novel diagnostic tool using DNA methylation as a blood biomarker. We sought to determine whether unmedicated patients with MDD showed significant differences in DNA methylation in the promoter region of the SHATI/N-acetyltransferase 8 like (SHATI/NAT8L) gene compared to healthy controls. Sixty participants with MDD were recruited from all over Japan. They were diagnosed and assessed by at least two trained psychiatrists according to DSM-5 criteria. DNA was extracted from peripheral blood. We then assessed DNA methylation of the SHATI/NAT8L promoter regions in patients with MDD by pyrosequencing. Methylation levels of the SHATI/NAT8L promoter region at CpG sites in peripheral blood from unmedicated patients were significantly higher than in healthy controls. In contrast, medicated patients with MDD showed significantly lower methylation levels in the same region compared to healthy controls. Since previous studies of DNA methylation in MDD only assessed medicated patients, the methylation status of the SHATI/NAT8L promoter region in unmedicated patients presented herein may prove useful for the diagnosis of MDD. To our knowledge, this is the first attempt to measure methylation of the SHATI/NAT8L gene in drug-naïve patients with psychiatric diseases. Based on our findings, methylation of SHATI/NAT8L DNA might be a diagnostic biomarker of MDD.

Altered ethanolamine plasmalogen and phosphatidylethanolamine levels in blood plasma of patients with bipolar disorder.

AIM: Ethanolamine-containing phospholipids are synthesized in endoplasmic reticulum (ER) and mitochondria. ER stress and mitochondrial dysfunction have been implicated in bipolar disorder (BP). In this study, we aimed to examine the relationship of ethanolamine plasmalogen (PLE) and phosphatidylethanolamine (PTE) levels in blood plasma with BP. METHODS: Plasma PLE and PTE levels were compared between 34 patients with BP (DSM-IV) and 38 healthy control participants matched for age, sex, and ethnicity (Japanese). Furthermore, the relationships of plasma PLE and PTE levels with clinical variables were explored. RESULTS: Plasma PLE levels were significantly lower in patients with BP than in healthy controls (P = 0.0033). In subgroup analyses, plasma PLE levels were significantly lower in patients with BP type I (BP I) than in healthy controls (P = 0.0047); furthermore, plasma PTE levels were significantly lower in patients with BP I than in controls (P = 0.016) and patients with BP type II (BP II) (P = 0.010). Receiver-operating characteristic curve analysis revealed that the discriminatory power of plasma PTE levels for distinguishing between BP I and II was fair (area under the curve = 0.78; P = 0.0095). There were no significant correlations of plasma PLE or PTE levels with depression or manic symptoms in patients. CONCLUSIONS: Plasma PLE and PTE levels were associated with BP I, but not with BP II. Moreover, plasma PTE levels differed between patients with BP I and II. Our findings highlight the importance of ethanolamine phospholipids in the pathophysiology of BP, especially BP I.

Genome-wide quantitative trait loci mapping of the human cerebrospinal fluid proteome.

Cerebrospinal fluid (CSF) is virtually the only one accessible source of proteins derived from the central nervous system (CNS) of living humans and possibly reflects the pathophysiology of a variety of neuropsychiatric diseases. However, little is known regarding the genetic basis of variation in protein levels of human CSF. We examined CSF levels of 1,126 proteins in 133 subjects and performed a genome-wide association analysis of 514,227 single nucleotide polymorphisms (SNPs) to detect protein quantitative trait loci (pQTLs). To be conservative, Spearman's correlation was used to identify an association between genotypes of SNPs and protein levels. A total of 421 cis and 25 trans SNP-protein pairs were significantly correlated at a false discovery rate (FDR) of less than 0.01 (nominal P < 7.66 × 10-9). Cis-only analysis revealed additional 580 SNP-protein pairs with FDR < 0.01 (nominal P < 2.13 × 10-5). pQTL SNPs were more likely, compared to non-pQTL SNPs, to be a disease/trait-associated variants identified by previous genome-wide association studies. The present findings suggest that genetic variations play an important role in the regulation of protein expression in the CNS. The obtained database may serve as a valuable resource to understand the genetic bases for CNS protein expression pattern in humans.

Reduced Serum and Cerebrospinal Fluid Levels of Autotaxin in Major Depressive Disorder.

BACKGROUND: The autotaxin/lysophosphatidic acid axis is involved in diverse biological processes including neurodevelopment, inflammation, and immunological functioning. The lysophosphatidic acid 1 receptor has been implicated in the pathophysiology of major depressive disorder and in the mechanism of action of antidepressants. However, it is unclear whether central or peripheral autotaxin levels are altered in patients with major depressive disorder. METHODS: Serum autotaxin levels were measured by an enzyme-linked immunosorbent assay in 37 patients with major depressive disorder diagnosed using DSM-IV-TR who underwent electroconvulsive therapy and were compared with those of 47 nondepressed controls matched for age and sex between January 2011 and December 2015. Patient serum levels of autotaxin before and after electroconvulsive therapy were also compared. In a separate sample set, cerebrospinal fluid autotaxin levels were compared between 26 patients with major depressive disorder and 27 nondepressed controls between December 2010 and December 2015. A potential association was examined between autotaxin levels and clinical symptoms assessed with the Hamilton Depression Rating Scale. RESULTS: Before electroconvulsive therapy, both serum and cerebrospinal fluidautotaxin levels were significantly lower in major depressive disorder patients than in controls (serum: P = .001, cerebrospinal fluid: P = .038). A significantly negative correlation between serum, but not cerebrospinal fluid, autotaxin levels and depressive symptoms was observed (P = .032). After electroconvulsive therapy, a parallel increase in serum autotaxin levels and depressive symptoms improvement was observed (P = .005). CONCLUSION: The current results suggest that serum autotaxin levels are reduced in a state-dependent manner. The reduction of cerebrospinal fluidautotaxin levels suggests a dysfunction in the autotaxin/lysophosphatidic acid axis in the brains of patients with major depressive disorder.

Unique anti-myeloma activity by thiazolidine-2,4-dione compounds with Pim inhibiting activity.

Proviral Integrations of Moloney virus 2 (PIM2) is overexpressed in multiple myeloma (MM) cells, and regarded as an important therapeutic target. Here, we aimed to validate the therapeutic efficacy of different types of PIM inhibitors against MM cells for their possible clinical application. Intriguingly, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a reduced PIM2 protein levels and impaired MM cell survival preferentially in acidic conditions, in contrast to other types of PIM inhibitors, including AZD1208, CX-6258 and PIM447. SMI-16a also suppressed the drug efflux function of breast cancer resistance protein, minimized the sizes of side populations and reduced in vitro colony-forming capacity and in vivo tumourigenic activity in MM cells, suggesting impairment of their clonogenic capacity. PIM2 is known to be subject to ubiquitination-independent proteasomal degradation. Consistent with this, the proteasome inhibitors bortezomib and carfilzomib increased PIM2 protein levels in MM cells without affecting its mRNA levels. However, SMI-16a mitigated the PIM2 protein increase and cooperatively enhanced anti-MM effects in combination with carfilzomib. Collectively, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a uniquely reduce PIM2 protein in MM cells, which may contribute to their profound efficacy in addition to their immediate kinase inhibition. Their combination with proteasome inhibitors is envisioned.

Increased cerebrospinal fluid complement C5 levels in major depressive disorder and schizophrenia.

Inflammation has been implicated in a variety of psychiatric disorders. We aimed to determine whether levels of complement C5 protein in the cerebrospinal fluid (CSF), which may reflect activation of the complement system in the brain, are altered in patients with major psychiatric disorders. Additionally, we examined possible associations of CSF C5 levels with clinical variables. Subjects comprised 89 patients with major depressive disorder (MDD), 66 patients with bipolar disorder (BPD), 96 patients with schizophrenia, and 117 healthy controls, matched for age, sex, and ethnicity (Japanese). Diagnosis was made according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria. CSF C5 levels were measured by enzyme-linked immunosorbent assay. CSF C5 levels were significantly increased in the patients with MDD (p < 0.001) and in the patients with schizophrenia (p = 0.001), compared with the healthy controls. The rate of individuals with an "abnormally high C5 level" (i.e., above the 95th percentile value of the control subjects) was significantly increased in all psychiatric groups, relative to the control group (all p < 0.01). Older age, male sex, and greater body mass index tended to associate with higher C5 levels. There was a significantly positive correlation between C5 levels and chlorpromazine-equivalent dose in the patients with schizophrenia. Thus, we found, for the first time, elevated C5 levels in the CSF of patients with major psychiatric disorders. Our results suggest that the activated complement system may contribute to neurological pathogenesis in a portion of patients with major psychiatric disorders.

Plasma Nervonic Acid Is a Potential Biomarker for Major Depressive Disorder: A Pilot Study.

Background: Diagnostic biomarkers of major depressive disorder, bipolar disorder, and schizophrenia are urgently needed, because none are currently available. Methods: We performed a comprehensive metabolome analysis of plasma samples from drug-free patients with major depressive disorder (n=9), bipolar disorder (n=6), schizophrenia (n=17), and matched healthy controls (n=19) (cohort 1) using liquid chromatography time-of-flight mass spectrometry. A significant effect of diagnosis was found for 2 metabolites: nervonic acid and cortisone, with nervonic acid being the most significantly altered. The reproducibility of the results and effects of psychotropic medication on nervonic acid were verified in cohort 2, an independent sample set of medicated patients [major depressive disorder (n=45), bipolar disorder (n=71), schizophrenia (n=115)], and controls (n=90) using gas chromatography time-of-flight mass spectrometry. Results: The increased levels of nervonic acid in patients with major depressive disorder compared with controls and patients with bipolar disorder in cohort 1 were replicated in the independent sample set (cohort 2). In cohort 2, plasma nervonic acid levels were also increased in the patients with major depressive disorder compared with the patients with schizophrenia. In cohort 2, nervonic acid levels were increased in the depressive state in patients with major depressive disorder compared with the levels in the remission state in patients with major depressive disorder and the depressive state in patients with bipolar disorder. Conclusion: These results suggested that plasma nervonic acid is a good candidate biomarker for the depressive state of major depressive disorder.

Search for plasma biomarkers in drug-free patients with bipolar disorder and schizophrenia using metabolome analysis.

AIM: There is an urgent need for diagnostic biomarkers of bipolar disorder (BD) and schizophrenia (SZ); however, confounding effects of medication hamper biomarker discovery. In this study, we conducted metabolome analyses to identify novel plasma biomarkers in drug-free patients with BD and SZ. METHODS: We comprehensively analyzed plasma metabolites using capillary electrophoresis time-of-flight mass spectrometry in patients with SZ (n = 17), BD (n = 6), and major depressive disorder (n = 9) who had not received psychotropics for at least 2 weeks, and in matched healthy controls (n = 19). The results were compared with previous reports, or verified in an independent sample set using an alternative analytical approach. RESULTS: Lower creatine level and higher 2-hydroxybutyric acid level were observed in SZ than in controls (uncorrected P = 0.016 and 0.043, respectively), whereas they were unaltered in a previously reported dataset. Citrulline was nominally significantly decreased in BD compared to controls (uncorrected P = 0.043); however, this finding was not replicated in an independent sample set of medicated patients with BD. N-methyl-norsalsolinol, a metabolite of dopamine, was suggested as a candidate biomarker of BD; however, it was not detected by the other analytical method. Levels of betaine, a previously reported candidate biomarker of schizophrenia, were unchanged in the current dataset. CONCLUSION: Our preliminary findings suggest that the effect of confounding factors, such as duration of illness and medication, should be carefully controlled when searching for plasma biomarkers. Further studies are required to establish robust biomarkers for these disorders.

Serum carboxy-terminal telopeptide of type I collagen levels are associated with carotid atherosclerosis in patients with cardiovascular risk factors.

Carboxy-terminal telopeptide of type I collagen (ICTP) is generated through matrix metalloproteinase (MMP)-dependent type I collagen digestion, and has been widely utilized as a biomarker for bone turnover. The fact that atherosclerotic lesions are rich in both type I collagen and MMP-producing macrophages led to the hypothesis that serum ICTP concentrations may serve as a non-invasive clinical biomarker for atherosclerosis. Therefore, the association of serum ICTP concentrations with the maximum intima-media thickness (IMT) of carotid arteries, a surrogate index of systemic atherosclerosis, or brachial-ankle pulse wave velocity (baPWV) in patients with atherosclerotic risk factors was evaluated. A total of 52 male and 65 female (mean age: 62.8 yrs) patients without renal failure, malignancies or bone diseases known to affect serum ICTP concentrations were recruited. Patients with max IMTs ≥1.1 mm showed significantly higher serum ICTP concentrations compared with patients with max IMTs <1.1 mm (3.33 ± 0.97 vs 2.82 ± 0.65 ng/mL, p<0.05). Serum ICTP concentration was also positively correlated with max IMT (p<0.001) or baPWV values (p<0.05). Multivariate analyses also revealed that serum ICTP concentrations were correlated with max IMT (p<0.001; 95% CI 0.200 to 0.454). These results suggest that serum ICTP concentrations can be used as a non-invasive biomarker for systemic atherosclerosis.

T-cadherin is essential for adiponectin-mediated revascularization.

Adipose tissue secretes protein factors that have systemic actions on cardiovascular tissues. Previous studies have shown that ablation of the adipocyte-secreted protein adiponectin leads to endothelial dysfunction, whereas its overexpression promotes wound healing. However, the receptor(s) mediating the protective effects of adiponectin on the vasculature is not known. Here we examined the role of membrane protein T-cadherin, which localizes adiponectin to the vascular endothelium, in the revascularization response to chronic ischemia. T-cadherin-deficient mice were analyzed in a model of hind limb ischemia where blood flow is surgically disrupted in one limb and recovery is monitored over 28 days by laser Doppler perfusion imaging. In this model, T-cadherin-deficient mice phenocopy adiponectin-deficient mice such that both strains display an impaired blood flow recovery compared with wild-type controls. Delivery of exogenous adiponectin rescued the impaired revascularization phenotype in adiponectin-deficient mice but not in T-cadherin-deficient mice. In cultured endothelial cells, T-cadherin deficiency by siRNA knockdown prevented the ability of adiponectin to promote cellular migration and proliferation. These data highlight a previously unrecognized role for T-cadherin in limb revascularization and show that it is essential for mediating the vascular actions of adiponectin.

Androgen receptor promotes sex-independent angiogenesis in response to ischemia and is required for activation of vascular endothelial growth factor receptor signaling.

BACKGROUND: Hypoandrogenemia is associated with an increased risk of ischemic diseases. Because actions of androgens are exerted through androgen receptor (AR) activation, we studied hind-limb ischemia in AR knockout mice to elucidate the role of AR in response to ischemia. METHODS AND RESULTS: Both male and female AR knockout mice exhibited impaired blood flow recovery, more cellular apoptosis, and a higher incidence of autoamputation after ischemia. In ex vivo and in vivo angiogenesis studies, AR-deficient vascular endothelial cells showed reduced angiogenic capability. In ischemic limbs of AR knockout mice, reductions in the phosphorylation of the Akt protein kinase and endothelial nitric oxide synthase were observed despite a robust increase in hypoxia-inducible factor 1α and vascular endothelial cell growth factor (VEGF) gene expression. In in vitro studies, siRNA-mediated ablation of AR in vascular endothelial cells blunted VEGF-stimulated phosphorylation of Akt and endothelial nitric oxide synthase. Immunoprecipitation experiments documented an association between AR and kinase insert domain protein receptor that promoted the recruitment of downstream signaling components. CONCLUSIONS: These results document a physiological role of AR in sex-independent angiogenic potency and provide evidence of novel cross-talk between the androgen/AR signaling and VEGF/kinase insert domain protein receptor signaling pathways.

[A discriminant model of mental disorders based on wave form patterns obtained by multi-channel near-infrared spectroscopy].

Multi-channel near-infrared spectroscopy (NIRS) was approved on 2009 as the first advanced medical care modality for use in the field of psychiatry in Japan. We performed NIRS for 185 outpatients in our hospital and 59 healthy subjects to measure hemoglobin concentration changes during verbal fluency tests trying to evaluate the relationships between the wave forms obtained by NIRS and mental disorders. We classified the prefrontal cortex oxy-hemoglobin wave forms obtained from the NIRS into 2 types and sub-classified into 5 wave patterns partly referenced previous papers a) Flat or increasing oxy-Hb form: (1) flat wave pattern, (2) early peak wave pattern, (3) late peak wave pattern during of the task and (4) reascending wave pattern after the task and b) decreasing oxy-Hb form: (5) Decrease wave pattern during the task. Focused on flat or increasing oxy-Hb form, the associations between these 4 wave patterns and psychiatric disorders were confirmed employing the Chi-square test. It was found that the flat wave pattern during the task and depression correlated with a sensitivity of 51.5% and specificity of 90.2%, the late peak wave pattern and bipolar disorder correlated with a sensitivity of 65.9% and specificity of 73.2%, and the re-ascending wave pattern after the task and schizophrenia correlated with a sensitivity of 58.9% and specificity of 94.6%. Our findings suggest that the discriminant model based on wave pattern has the potential to provide information supporting a diagnosis of mental disorder in the setting of clinical laboratory testing.

Social difficulties and care burden of adult Duchenne muscular dystrophy in Japan: a questionnaire survey based on the Japanese Registry of Muscular Dystrophy (Remudy).

BACKGROUND: Little is known about the social difficulties and health care needs of adult Duchenne muscular dystrophy (DMD) patients in Japan, as well as the financial and physical stress experienced by their caregivers. This study aimed to clarify the social circumstances surrounding adult DMD patients and assess the degree of involvement of family members in their care and the associated economic burden of the disorder in Japan. METHODS: Adult DMD patients were identified through the Registry of Muscular Dystrophy (Remudy) in Japan and invited to complete a questionnaire together with a caregiver. Data on health care use, quality of life, work status, informal care, and household expenses were collected to estimate the costs associated with DMD from social and caregiver household perspectives. RESULTS: In total, 234 (63.7%) of 367 adult DMD patients (mean age, 27.4 ± 6.0; range, 20-48 years) completed the questionnaire. Of these, 38 (21%) had developmental disorders (mental retardation, autism, and learning disorders), 57 (33%) experienced bullying in school, and 44 (77%) indicated the reason for bullying to be their physical handicap. Employment histories were noted by 72 (31%), although 23 (10%) lost their jobs mainly due to physical difficulties. Of the 234 patients, 164 (74%) lived with their relatives, and 78% of care time was supplied by family members, in particular, their mothers. The mean rate of care work provided by family members was 81%. Household income of families with an adult DMD patient was lower, whereas the rate of living with parent(s) and grandparent(s) was higher, in comparison with the general Japanese population. CONCLUSIONS: Adult DMD patients in Japan experience many social difficulties from childhood up to adulthood. As adults, many DMD patients experience bullying and workplace difficulties. Families were found to provide most of the care and financial support for DMD patients. Our results suggest the need to improve public patient care systems, including financial support, to address the physical and economic burdens of care for adult DMD patients in Japan.

Humoral immune response against SARS-CoV-2 and polyethylene glycol elicited by anti-SARS-CoV-2 mRNA vaccine, and effect of pre-existing anti-polyethylene glycol antibody in patients with hematological and autoimmune diseases.

Background: The effects of vaccination are modified by hematological and autoimmune diseases and/or treatment. Anti-SARS-CoV-2 mRNA vaccine contains polyethylene glycol (PEG), it is largely unknown whether PEG influences the effects of vaccination or induces a humoral response. This study examined whether anti-PEG antibodies before vaccination (pre-existing) influenced the acquisition of SARS-CoV-2 antibodies and evaluated the relationship between the development of anti-SARS-CoV-2 antibodies and anti-PEG antibodies after SARS-CoV-2 vaccination in hematological and autoimmune diseases. Methods: Anti-SARS-CoV-2 antibody IgG, anti-PEG IgG, and IgM titers were evaluated in patients with hematological and autoimmune diseases after the second dose of BNT162B2. Anti-PEG IgG and IgM titers were also measured before vaccination to examine changes after vaccination and the relationship with vaccine efficacy. Results: In patients with hematological (n = 182) and autoimmune diseases (n = 96), anti-SARS-CoV-2 and anti-PEG antibody titers were evaluated after a median of 33 days from 2nd vaccination. The median anti-SARS-CoV-2 antibody titers were 1901 AU/mL and 3832 AU/mL in patients with hematological and autoimmune disease, respectively. Multiple regression analysis showed that age and days from 2nd vaccination were negatively associated with anti-SARS-CoV-2 antibody titers. Anti-CD20 antibody treatment was negatively correlated with anti-SARS-CoV-2 antibody titers in hematological disease, and C-reactive protein (CRP) was positively correlated with anti-SARS-CoV-2 antibody titers in autoimmune disease. Baseline anti-PEG antibody titers were significantly higher in patients with autoimmune disease but were not correlated with anti-SARS-CoV-2 antibody titers. Patients with increased anti-PEG IgG acquired higher anti-SARS-CoV-2 antibody titers in patients with autoimmune disease. Conclusions: Anti-SARS-CoV-2 antibody acquisition was suboptimal in patients with hematological disease, but both anti-SARS-CoV-2 antibody and anti-PEG IgG were acquired in patients with autoimmune disease, reflecting robust humoral immune response. Pre-existing anti-PEG antibody titers did not affect anti-SARS-CoV-2 antibody acquisition.