Japanese Healthy Controls Research Articles

Metagenomic gut microbiome analysis of Japanese patients with multiple chemical sensitivity/idiopathic environmental intolerance

BackgroundAlthough the pathology of multiple chemical sensitivity (MCS) is unknown, the central nervous system is reportedly involved. The gut microbiota is important in modifying central nervous system diseases. However, the relationship between the gut microbiota and MCS remains unclear. This study aimed to identify gut microbiota variations associated with MCS using shotgun metagenomic sequencing of fecal samples.MethodsWe prospectively recruited 30 consecutive Japanese female patients with MCS and analyzed their gut microbiomes using shotgun metagenomic sequencing. The data were compared with metagenomic data obtained from 24 age- and sex-matched Japanese healthy controls (HC).ResultsWe observed no significant difference in alpha and beta diversity of the gut microbiota between the MCS patients and HC. Focusing on the important changes in the literatures, at the genus level, Streptococcus, Veillonella, and Akkermansia were significantly more abundant in MCS patients than in HC (p < 0.01, p < 0.01, p = 0.01, respectively, fold change = 4.03, 1.53, 2.86, respectively). At the species level, Akkermansia muciniphila was significantly more abundant (p = 0.02, fold change = 3.3) and Faecalibacterium prausnitzii significantly less abundant in MCS patients than in HC (p = 0.03, fold change = 0.53). Functional analysis revealed that xylene and dioxin degradation pathways were significantly enriched (p < 0.01, p = 0.01, respectively, fold change = 1.54, 1.46, respectively), whereas pathways involved in amino acid metabolism and synthesis were significantly depleted in MCS (p < 0.01, fold change = 0.96). Pathways related to antimicrobial resistance, including the two-component system and cationic antimicrobial peptide resistance, were also significantly enriched in MCS (p < 0.01, p < 0.01, respectively, fold change = 1.1, 1.2, respectively).ConclusionsThe gut microbiota of patients with MCS shows dysbiosis and alterations in bacterial functions related to exogenous chemicals and amino acid metabolism and synthesis. These findings may contribute to the further development of treatment for MCS.Trial registrationThis study was registered with the University Hospital Medical Information Clinical Trials Registry as UMIN000031031. The date of first trial registration: 28/01/2018.

The protective association of HLA-C*12:02 and HLA-DQB1*06:01 with severe acute hepatitis of unknown origin in the Japanese population.

Global surveillance has been conducted to elucidate the pathogenesis of acute hepatitis of unknown origin (AHUO), However, the factors associated with the aggravation of this serious disease are unclear. Therefore, we conducted a HLA association study to identify HLA alleles or haplotypes predisposing or protective against Japanese AHUO. The HLA 5 locus (HLA-A, HLA-B, C, DRB1, and DQB1) 4-digit genotyping results of 72 AHUO patients who underwent liver transplantation at our institution between 2000 and 2021 were compared to those of 873 healthy Japanese controls. Protective associations of HLA-B*52:01 (p-corrected (pc) = 3.15 × 10-3 ), HLA-C*12:02 (pc = 1.66 ×10-3 ), HLA-DQB1*06:01 (pc = 1.42 × 10-2 ), and HLA-DRB1*15:02 (pc = 1.36 × 10-2 ) with severe AHUO in Japanese patients were observed. The amino acid residues of tryptophan at position 156, which are located in the antigen-binding grooves of the HLA-C protein, showed a protective association with AHUO, showing a significant difference from other amino acid variations (pc = 9.0 × 10-4 ). Furthermore, 5 amino acid residues of the HLA-DQB1 protein were also protectively associated with AHUO with a significant difference from other amino acid variations (pc = 1.42 × 10-2 to 2.89 × 10-2 ). These alleles have a protective association with the aggravation of AHUO in the Japanese population.

#5795 THE APOPROTEIN E (APOE) POLYMORPHISM AND PROPROTEIN CONVERTASE SUBTILISIN KEXIN 9 (PCSK9) IN HEMODIALYSIS (HD) PATIENTS

Abstract Background and Aims The apoE polymorphism and PCSK9 play an important role in lipid metabolism in healthy subjects, however, its role in HD patients remains unclear. We investigated the apoE polymorphism and PCSK9 as well as a lipid profile to clarify the impact of these factors on prognosis in HD patients. We also examined the association of cardiovascular (CVD) events in dead HD patients and clinical features. Method HD patients (n = 296, m/f; 207/89, DM; 152, age; 69.8±12.1, HD duration; 68.7±72.0 months) were subjected to this study. Written informed consent was obtained from each patient. Of these patients 85 subjects (m/f; 61/24, DM; 54, HD duration; 98.6±53.5 months) died during this study (from June 2011 to December 2022). Blood samples were collected to analyze the apoE genotypes by the invader method, serum concentrations of PCSK9-heterodimers and PCSK9-free fragments were measured using ELISA (BML Co. Ltd., Tokyo, Japan) and serum concentrations of apoA1, apoA2, apoB, apo C2, apoC3 and apoE were estimated using turbidimetric immunoassay. For the death cases we used multivariable logistic regression to control for the potentially confounding roles of type 2 diabetes mellitus (DM), apoE genotypes, and serum concentrations of PCSK9-heterodimers, PCSK9-free segments, apoA1, apoA2, apoB, apo C2, apoC3 and apoE. Survival probabilities in dead HD patients with CVD events according to the apoE genotypes were analyzed using the Kaplan-Meier curves. A p value less than 0.05 was considered statistically significant. Results The spoE allele frequencies in HD patients (n = 296) were ɛ2; 0.044, ɛ3; 0.870 and ɛ4; 0.086, whereas those in Japanese healthy controls were ɛ2; 0.036, ɛ3; 0.848 and ɛ4; 0.116 (Eto M., et al. Clin Genet 30:422-427, 1986.), demonstrating the ɛ2 frequency in HD patients had a trend to be higher than that in Japanese healthy controls (p = 0.096). The serum concentrations of PCSK9-heterodimers and PCSK9-free fragments in female HD patients (n = 89, 227.0±88.0 ng/ml and 41.9±19.1 ng/ml, respectively) were significantly higher than those in male HD patients (n = 207, 195.9±70.3 ng/ml, p = 0.001, and 35.8±15.3 ng/ml, p&amp;lt;0.004, respectively) . The serum concentrations of PCSK9-heterodimers in HD patients with DM (n = 152); 213.8±77.6 ng/ml showed a trend to be higher than those in HD patients without DM (n = 144); 196.3±76.1 ng/ml (p = 0.05). The multivariable logistic regression analysis demonstrated the serum concentration of apoA1 and apoE polymorphism showed statistically significant impact on CVD events in dead HD patients (Table 1). The Kaplan-Meier analysis revealed the apoE polymorphism had a significant impact on the survival probability in dead HD patients with CVD events (Figure 1). Conclusion Recent studies reported the association between apoE2 and renal insufficiency in Japanese type2 DM. ApoE2 may be one of the attributable factors that lead to the end stage kidney disease. PCSK9-heterodimers bind to LDL cholesterol receptors (LDLr) and prevent LDLr from shuttling back to the surface and instead target it for degradation, however, PCSK9-free segments have weaker effects to bind to LDLr. Significance of higher serum concentrations of PCSK9-heterodimers andPCSK9-free fragments in female HD patients than male HD patients depends on future investigation. ApoE2 and the serum concentration of apoA1 contribute to CVD events. The prognosis of the HD patients with apoE2 or apoE4 were poorer than that with apoE3/3. The apoE polymorphism and PCSK9 may be key factors in lipid metabolism as well as prognosis of HD patients.

Replication Study of the Association of GAS6 and PROS1 Polymorphisms with Behçet’s Disease in a Japanese Population

ABSTRACT Purpose To investigate whether polymorphisms of GAS6 and PROS1, which each encode protein ligands for a family of tyrosine kinase receptors, are associated with Behçet’s disease (BD) in a Japanese population. Methods We recruited 734 Japanese patients with BD and 1789 Japanese healthy controls. In all participants, we genotyped two single-nucleotide polymorphisms (SNPs) reportedly associated with BD: rs9577873 in GAS6 and rs4857037 in PROS1. Results We found that GAS6 rs9577873 was not significantly associated with BD. In contrast, PROS1 rs4857037, specifically the A allele, was associated with increased risk for BD. The A allele was also significantly associated with BD under additive and recessive genetic models. Expression analysis revealed that this allele was significantly associated with increased PROS1 expression. Conclusions Our findings suggest that increased PROS1 expression related to the A risk allele of rs4857037 affects tyrosine kinase receptor signaling, contributing to the development of BD.

Anti-Neurofascin 155 Antibody-Positive Chronic Inflammatory Demyelinating Polyneuropathy/Combined Central and Peripheral Demyelination: Strategies for Diagnosis and Treatment Based on the Disease Mechanism.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated demyelinating disease of the peripheral nervous system (PNS). A small number of CIDP patients harbors autoantibodies against nodal/paranodal proteins, such as neurofascin 155 (NF155), contactin 1, and contactin-associated protein 1. In most cases, the predominant immunoglobulin (IgG) subclass is IgG4. Node/paranode antibody-positive CIDP demonstrates distinct features compared with antibody-negative CIDP, including a poor response to intravenous immunoglobulin. The neuropathology of biopsied sural nerve shows Schwann cell terminal loop detachment from axons without macrophage infiltration or inflammation. This is partly attributable to IgG4, which blocks protein–protein interactions without inducing inflammation. Anti-NF155 antibody-positive (NF155+) CIDP is unique because of the high frequency of subclinical demyelinating lesions in the central nervous system (CNS). This is probably because NF155 coexists in the PNS and CNS. Such cases showing demyelinating lesions in both the CNS and PNS are now termed combined central and peripheral demyelination (CCPD). NF155+ CIDP/CCPD commonly presents hypertrophy of spinal nerve roots and cranial nerves, such as trigeminal and oculomotor nerves, and extremely high levels of cerebrospinal fluid (CSF) protein, which indicates nerve root inflammation. In the CSF, the CXCL8/IL8, IL13, TNFα, CCL11/eotaxin, CCL2/MCP1, and IFNγ levels are significantly higher and the IL1β, IL1ra, and GCSF levels are significantly lower in NF155+ CIDP than in non-inflammatory neurological diseases. Even compared with anti-NF155 antibody-negative (NF155−) CIDP, the CXCL8/IL8 and IL13 levels are significantly higher and the IL1β and IL1ra levels are significantly lower than those in NF155+ CIDP. Canonical discriminant analysis revealed NF155+ and NF155− CIDP to be separable with IL4, IL10, and IL13, the three most significant discriminators, all of which are required for IgG4 class switching. Therefore, upregulation of both Th2 and Th1 cytokines and downregulation of macrophage-related cytokines are characteristic of NF155+ CIDP, which explains spinal root inflammation and the lack of macrophage infiltration in the sural nerves. All Japanese patients with NF155+ CIDP/CCPD have one of two specific human leukocyte antigen (HLA) haplotypes, which results in a significantly higher prevalence of HLA-DRB1*15:01-DQB1*06:02 compared with healthy Japanese controls. This indicates an involvement of specific HLA class II molecules and relevant T cells in addition to IgG4 anti-NF155 antibodies in the mechanism underlying IgG4 NF155+ CIDP/CCPD.

Genetic factors for susceptibility to and manifestations of neuromyelitis optica.

ObjectiveTo identify genetic factors associated with susceptibility to and clinical features of neuromyelitis optica spectrum disorders (NMOSD).MethodsGenome‐wide single nucleotide polymorphism (SNP) genotyping was conducted in 211 Japanese patients with NMOSD fulfilling the 2006 criteria with or without anti‐aquaporin‐4 (AQP4) antibody and 1,919 Japanese healthy controls (HCs). HLA‐DRB1 and HLA‐DPB1 alleles were genotyped in 184 NMOSD cases and 317 HCs. Multiple sclerosis (MS) risk alleles outside the major histocompatibility complex (MHC) region were tested in NMOSD and MS genetic burden (MSGB) scores were compared between HCs and NMOSD.ResultsA SNP (rs1964995) in the MHC region was associated with NMOSD susceptibility (odds ratio (OR) = 2.33, P = 4.07 × 10−11). HLA‐DRB1*08:02 (OR = 2.86, P = 3.03 × 10−4) and HLA‐DRB1*16:02 (OR = 8.39, P = 1.92 × 10−3) were risk alleles for NMOSD susceptibility whereas HLA‐DRB1*09:01 was protective (OR = 0.27, P = 1.06 × 10−5). Three MS risk variants were associated with susceptibility and MSGB scores were significantly higher in NMOSD than in HCs (P = 0.0095). A SNP in the KCNMA1 (potassium calcium‐activated channel subfamily M alpha 1) gene was associated with disability score with genome‐wide significance (rs1516512, P = 2.33 × 10−8) and transverse myelitis (OR = 1.77, P = 0.011). KCNMA1 was immunohistochemically detected in the perivascular endfeet of astrocytes and its immunoreactivity was markedly diminished in active spinal cord lesions in NMOSD.InterpretationSpecific HLA‐DRB1 alleles confer NMOSD susceptibility and KCNMA1 is associated with disability and transverse myelitis in NMOSD.

HLA-DRB1 allele and autoantibody profiles in Japanese patients with inclusion body myositis.

Inclusion body myositis (IBM) is an idiopathic inflammatory myopathy, characterized by unique clinical features including finger flexor and quadriceps muscle weakness and a lack of any reliable treatment. The human leukocyte antigen (HLA)-DRB1 allele and autoantibody profiles in Japanese IBM patients have not been fully elucidated. We studied 83 Japanese IBM patients with a mean age of 69 years (49 males and 34 females) who participated in the 'Integrated Diagnosis Project for Inflammatory Myopathies' from January 2011 to September 2016. IBM was diagnosed by histological diagnosis. Various autoantibodies were screened by RNA immunoprecipitation and enzyme-linked immunosorbent assays. HLA-DRB1 genotyping was performed using polymerase chain reaction-sequence based typing. A total of 460 unrelated healthy Japanese controls were also studied. The allele frequencies of DRB1*01:01, DRB1*04:10, and DRB1*15:02 were significantly higher in the IBM group than in the healthy control group (Corrected P = 0.00078, 0.00038 and 0.0046). There was a weak association between the DRB1*01:01 allele and severe leg muscle weakness and muscle atrophy. While hepatitis type C virus infection and autoantibodies to cytosolic 5'-nucleotidase 1A were found in 18 and 28 patients, respectively, no significant association with HLA-DRB1 alleles was observed. Japanese IBM patients had the specific HLA-DRB1 allele and autoantibody profiles.

Unique HLA haplotype associations in IgG4 anti-neurofascin 155 antibody-positive chronic inflammatory demyelinating polyneuropathy

To clarify the immunogenetic background of patients with immunoglobulin G (IgG)4 anti-neurofascin 155 (NF155) antibody-positive chronic inflammatory demyelinating polyneuropathy (CIDP), we genotyped the extended human leukocyte antigen (HLA) haplotypes in 22 Japanese patients with this disorder and compared them with those of healthy Japanese controls. All IgG4 anti-NF155 antibody-positive CIDP patients exclusively carried either HLA-DRB1*15:01-DRB5*01:01-DQA1*01:02-DQB1*06:02 or -(A*24:02)-B*52:01-C*12:02-DRB1*15:02-DRB5*01:02-DQA1*01:03-DQB1*06:01, resulting in significantly increased HLA-DRB1*15, -DRB1*15:01, -DQB1*06:01/06:02, -DQB1*06:02, and -DRB1*15:01-DQB1*06:02 frequencies compared with healthy Japanese controls. These findings indicate the involvement of specific HLA class II molecules in the pathomechanisms of IgG4 anti-NF155 antibody-positive CIDP.

Identification of HLA-A*02:06:01 as the primary disease susceptibility HLA allele in cold medicine-related Stevens-Johnson syndrome with severe ocular complications by high-resolution NGS-based HLA typing

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening acute inflammatory vesiculobullous reactions of the skin and mucous membranes. These severe cutaneous drug reactions are known to be caused by inciting drugs and infectious agents. Previously, we have reported the association of HLA-A*02:06 and HLA-B*44:03 with cold medicine (CM)-related SJS/TEN with severe ocular complications (SOCs) in the Japanese population. However, the conventional HLA typing method (PCR-SSOP) sometimes has ambiguity in the final HLA allele determination. In this study, we performed HLA-disease association studies in CM-SJS/TEN with SOCs at 3- or 4-field level. 120 CM-SJS/TEN patients with SOCs and 817 Japanese healthy controls are HLA genotyped using the high-resolution next-generation sequencing (NGS)-based HLA typing of HLA class I genes, including HLA-A, HLA-B, and HLA-C. Among the alleles of HLA class I genes, HLA-A*02:06:01 was strongly associated with susceptibility to CM-SJS/TEN (p = 1.15 × 10−18, odds ratio = 5.46). Four other alleles (HLA-A*24:02:01, HLA-B*52:01:01, HLA-B*46:01:01, and HLA-C*12:02:02) also demonstrated significant associations. HLA haplotype analyses indicated that HLA-A*02:06:01 is primarily associated with susceptibility to CM-SJS/TEN with SOCs. Notably, there were no specific disease-causing rare variants among the high-risk HLA alleles. This study highlights the importance of higher resolution HLA typing in the study of disease susceptibility, which may help to elucidate the pathogenesis of CM-SJS/TEN with SOCs.

The CFTR gene variants in Japanese children with idiopathic pancreatitis

The cystic fibrosis transmembrane conductance regulator (CFTR) gene has been reported as one of the pancreatitis susceptibility genes. Although many variants of CFTR have been reported in Caucasian patients, there are few data in Japanese patients. We aimed to survey CFTR variants in Japanese children with idiopathic pancreatitis. Twenty-eight Japanese paediatric patients with idiopathic pancreatitis were enroled, who were not previously diagnosed by genetic analysis of PRSS1 and SPINK1. The entire CFTR gene was sequenced in the patients by combining LA-PCR and next-generation sequencing analysis. To determine a splice-affecting variant, CFTR expression was investigated in the nasal epithelial cells by RT-PCR. One (3.6%) and 15 (53.6%) of 28 patients had pathogenic and functionally affected variants in the CFTR gene, respectively. Two variants, p.Arg352Gln and p.Arg1453Trp, were found more frequently in the patients compared with one in Japanese healthy controls (p = 0.0078 and 0.044, respectively). We confirmed skipping of exon 10 in the nasal epithelial cells in one patient having a splice-affecting variant (c.1210-12 T(5)) in intron 9. Functionally affected variants of the CFTR gene are not so rare in Japanese paediatric patients with idiopathic pancreatitis. Surveying CFTR gene variants in a Japanese sample could help identify pancreatitis risk in these children.

Association Study of ARMC9 Gene Variants with Vogt-Koyanagi-Harada Disease in Japanese Patients

ABSTRACTPurpose: To investigate whether variants in the ARMC9 gene encoding KU-MEL-1 are associated with Vogt-Koyanagi-Harada (VKH) disease in a Japanese population.Methods: We recruited 380 Japanese patients with VKH disease and 744 Japanese healthy controls to genotype seven single-nucleotide polymorphisms (SNPs) in ARMC9. We also performed imputation analysis of the ARMC9 region and 195 imputed SNPs were included in the statistical analysis.Results: We observed an increased frequency of the A allele of rs28690417 in patients compared with controls (P = 0.0097, odds ratio (OR) = 1.46). The A allele had a dominant effect on VKH disease risk (P = 0.011, OR = 1.51). However, these significant differences disappeared after Bonferroni correction (corrected P > 0.05). The remaining 201 SNPs did not show any significant association with disease risk.Conclusions: Our study suggests that ARMC9 variants do not play a critical role in the development of VKH disease.

Sensorimotor Gating in Depressed and Euthymic Patients with Bipolar Disorder: Analysis on Prepulse Inhibition of Acoustic Startle Response Stratified by Gender and State.

Prepulse inhibition (PPI) of the acoustic startle reflex is an operational measure of sensorimotor gating. The findings on PPI deficits in bipolar disorder (BD) are inconsistent among studies due to various confounding factors such as gender. This study aimed to assess sensorimotor gating deficits in patients with BD stratified by gender and state (depressed/euthymic), and to explore related clinical variables. Subjects were 106 non-manic BD patients (26 BD I and 80 BD II; 63 with depression and 43 euthymic) and 232 age-, gender-, and ethnicity-matched (Japanese) healthy controls. Depression severity was assessed using the Hamilton Depression Rating Scale-21. The electromyographic activity of the orbicularis oculi muscle was measured by a computerized startle reflex test unit. Startle magnitude, habituation, and PPI were compared among the three clinical groups: depressed BD, euthymic BD, and healthy controls. In a second analysis, patients were divided into four groups using the quartile PPI levels of controls of each gender, and a ratio of the low-PPI group (<1st quartile of controls) was compared. Effects of psychosis and medication status were examined by the Mann-Whitney U test. Clinical correlates such as medication dosage and depression severity with startle measurements were examined by Spearman's correlation. Male patients with depression, but not euthymic male patients, showed significantly lower PPI at a prepulse of 86 dB and 120 ms lead interval than did male controls. More than half of the male patients with depression showed low-PPI. In contrast, PPI in female patients did not differ from that in female controls in either the depressed or euthymic state. Female patients with active psychosis showed significantly lower PPI than those without psychosis. Female patients on typical antipsychotics had significantly lower PPI, than those without such medication. PPI showed a significant positive correlation with lamotrigine dosage in male patients and lithium dosage in female patients. These findings suggest that sensorimotor gating is impaired in male BD patients with depression. However, we obtained no evidence for such abnormalities in female BD patients except for those with current psychosis. The observed associations between medication and startle measurements warrant further investigation.

Specific association of the rs6500265 and rs9933632 single-nucleotide polymorphisms in Japanese patients with antipyretic analgesic-related Stevens-Johnson syndrome and toxic epidermal necrolysis with severe ocular involvements.

A recent study using the microarray for single-nucleotide polymorphisms (SNPs) genotyping specifically designed for the Japanese population in combination with genome-wide imputation showed the association of several SNPs with cold medicine-related Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with severe ocular complications. However, it remains to be determined whether these polymorphisms are associated with the onset of antipyretic analgesic (AA)-related SJS/TEN, the progression of severe ocular involvements (SOIs), or both AA-related SJS/TEN and SOI phenotypes. To gain a better understanding of the features of these genetic markers, we compared the allele and carrier frequencies of these SNPs among our original SJS/TEN patient groups: (a) AA-related SJS/TEN with SOIs, (b) AA-related SJS/TEN without SOIs, and (c) AA-unrelated SJS/TEN with SOIs. AA-related SJS/TEN with SOIs were found to be associated significantly with both rs6500265 [allele frequency: odds ratio (OR): 2.18; 95% confidence interval (CI): 1.30-3.65; P=0.0052; carrier frequency: OR: 2.52; 95% CI: 1.33-4.78; P=0.058] and rs9933632 (allele frequency: OR: 2.28: 95% CI: 1.37-3.79; P=0.0032; carrier frequency: OR: 2.76; 95% CI: 1.46-5.22; P=0.0031). In contrast, allele and carrier frequencies of these SNPs in patients with AA-related SJS/TEN without SOIs or with SOIs not treated with any AAs were comparable with those in healthy Japanese controls. Collectively, our findings indicate that the rs6500265 and rs9933632 SNPs could be specific markers for AA-related SJS/TEN with SOIs, suggesting that certain genetic backgrounds contribute toward the etiology of this complex syndrome.

Abstract 91: Moyamoya Disease Susceptibility Gene, RNF213 p.R4810K Variant, is a Common Risk Factor for Atherothrombotic Brain Infarction in a Japanese Population

Background and Purpose: RNF213 has been identified as a susceptibility gene for moyamoya disease. The p.R4810K variant is found in about 80% of East Asian patients with moyamoya disease, and 20 - 25% of those with proximal intracranial arterial stenosis. In this study, we examined the association of RNF213 p.R4810K variant with non-cardioembolic stroke in a Japanese population. Methods: We analyzed 383 consecutive patients with acute non-cardioembolic stroke, who were admitted to the National Cerebral and Cardiovascular Center from June 2012 to May 2017 and participated in NCVC Biobank, and 1011 healthy local Japanese controls. Patients diagnosed with moyamoya disease were excluded. Written informed consent was obtained from all study participants. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for age, sex, and conventional risk factors for stroke. Results: The RNF213 p.R4810K variant was found in 5.2% of acute non-cardioembolic stroke patients and in 2.1% of healthy controls (adjusted OR 3.9, 95% CI 1.6 - 9.3, p=0.003). The mean age of stroke onset was lower in patients with the RNF213 p.R4810K variant than those without the variant (58.1±15.5 years vs. 69.1±13.2 years, p&lt;0.001). Among stroke subtypes, only atherothrombotic brain infarction (ATBI) was significantly associated with this variant (adjusted OR 11.5, 95% CI 3.4 - 36.2, p&lt;0.001, see also Table 1). When stratified by sex, these associations were more evident in women (Men: adjusted OR for ATBI 1.9, 95% CI 0.3 - 10.2, p=0.47; Women: adjusted OR for ATBI 58.0, 95% CI 10.3 - 327.3, p&lt;0.001, see also Table 1). Conclusion: The RNF213 p.R4810K variant is a genetic risk factor for non-cardioembolic stroke in Japan, especially for atherothrombotic brain infarction in women.

Age-related effects and gender differences in Japanese healthy controls for [123I] FP-CIT SPECT.

Dopamine transporter (DAT) imaging with [123I]FP-CIT (DaTSCAN) is a widely used diagnostic tool for Parkinsonism and dementia. Since it was approved by the Japanese Ministry of Health, Labor, and Welfare in 2013, there have been no articles focusing on a Japanese normal population. The aim of this study was to examine the effect of aging and gender on DAT availability in Japanese people. SPECT imaging of 30 healthy Japanese controls (17 males, 13 females; range 50-86years, mean 70years) was performed. SPECT images were reconstructed using a three-dimensional order subset expectation maximization (OSEM) algorithm with correction of the point spread function and scatter correction, without attenuation correction. The specific binding ratio (SBR) was calculated by DATview software. Statistical analyses were performed using linear regression analysis, analysis of variance, and multiple comparison analysis. A strong correlation between the SBR and age was observed. The correlation coefficient in males and females were -0.566 and -0.502, respectively. The analysis of variance revealed that aging led to a decline of the SBR, and a significant difference (p = 0.005) was observed among generations. Gender also affected the SBR, and there was a significant difference between males and females (p = 0.036). The SBR in females was higher than in males. Consequently, the multiple comparison revealed a significant difference between 50s and 70s (p = 0.015) and 50s and 80s (p = 0.006). This is the first [123I]FP-CIT SPECT study on subjects with normal dopamine function in Asian countries. This study provides a database of [123I]FP-CIT SPECT in Japanese healthy controls. Higher DAT availability was found in women than in men. An average age-related decline in DAT availability of 8.9% was found in both genders. The data collected in this study would be helpful for Japanese physicians to make a differential diagnosis in Parkinsonian syndrome. The registration identification number for this study is UMIN000018045.

Analysis of the association between the LUM rs3759223 variant and high myopia in a Japanese population.

PurposeMany studies have investigated the relationship of the lumican gene (LUM) rs3759223 variant with the risk of high myopia, but the results have been inconsistent and inconclusive. In this study, we investigated whether LUM rs3759223 is associated with high myopia in a Japanese population.MethodsWe recruited 1,585 Japanese patients with high myopia (spherical equivalent [SE] <−9.00 diopters [D]) and 1,011 Japanese healthy controls (SE ≥−1.00 D). The rs3759223 variant was genotyped using the TaqMan assay, and the allelic and genotypic diversity among cases and controls was analyzed according to the SE level.ResultsIn the allelic tests, the odds ratio (OR) for the T allele of rs3759223 tended to increase with the progression of SE, and the highest OR (1.56) was found in patients with SE <−15 D in both eyes. The OR of the T allele tended to increase with the progression of SE in the additive, dominant, and recessive inheritance models. However, we found no significant associations for any of the alleles or genotype models.ConclusionThese data support the possibility that the LUM rs3759223 T allele accelerates the progression of SE in the Japanese population, although no significant associations were observed in this study. Additional genetic studies with larger samples that take into account the degree of SE are needed to clarify the contribution of rs3759223 to the risk of high myopia.

HLA-C*12:02 is a susceptibility factor in late-onset type of psoriasis in Japanese

Psoriasis is thought to be a multifactorial disease triggered by both genetic and environmental factors. The HLA-C locus on chromosome 6p21.33 remains the strongest susceptibility candidate locus in psoriasis. The strong association between psoriasis and the HLA-Cw6 allele has been well documented in various races. It is known that psoriatic patients with early onset are more likely to be familial and associated with HLA-Cw6. Familial occurrence of Japanese psoriasis is smaller than other populations. Furthermore, males are predominant over females in Japanese psoriasis. We investigated the relation between HLA-C alleles and age of onset, and in each gender for Japanese psoriasis, and discuss male predominance in the incidence of psoriasis in Japan. Four hundred forty six unrelated Japanese patients with psoriasis vulgaris and 557 sex- and age-matched unrelated Japanese healthy controls were investigated by genotyping. We confirmed the association between early-onset type of psoriasis with HLA-C*06:02 allele in Japanese. In addition, we detected the association between the late-onset type of psoriasis and the HLA-C*12:02 allele in Japanese. No significant differences in allele frequency were observed between females and males. Our results suggest that there is no genetic factor effect on male predominance in Japanese. In contract, the effect of environmental risk factors on the onset of Japanese psoriatic patients is stronger in males than in females. As a result, male predominant in psoriasis may occur in Japan.

Understanding of HLA-conferred susceptibility to chronic hepatitis B infection requires HLA genotyping-based association analysis.

Associations of variants located in the HLA class II region with chronic hepatitis B (CHB) infection have been identified in Asian populations. Here, HLA imputation method was applied to determine HLA alleles using genome-wide SNP typing data of 1,975 Japanese individuals (1,033 HBV patients and 942 healthy controls). Together with data of an additional 1,481 Japanese healthy controls, association tests of six HLA loci including HLA-A, C, B, DRB1, DQB1, and DPB1, were performed. Although the strongest association was detected at a SNP located in the HLA-DP locus in a SNP-based GWAS using data from the 1,975 Japanese individuals, HLA genotyping-based analysis identified DQB1*06:01 as having the strongest association, showing a greater association with CHB susceptibility (OR = 1.76, P = 6.57 × 10−18) than any one of five HLA-DPB1 alleles that were previously reported as CHB susceptibility alleles. Moreover, HLA haplotype analysis showed that, among the five previously reported HLA-DPB1 susceptibility and protective alleles, the association of two DPB1 alleles (DPB1*09:01, and *04:01) had come from linkage disequilibrium with HLA-DR-DQ haplotypes, DRB1*15:02-DQB1*06:01 and DRB1*13:02-DQB1*06:04, respectively. The present study showed an example that SNP-based GWAS does not necessarily detect the primary susceptibility locus in the HLA region.

Does arteriosclerosis contribute to hemifacial spasm?

Hemifacial spasm (HFS) is caused by pulsative vascular compression of the root exit zone (REZ) of the facial nerve. However, the mechanism that causes the offending vessels to compress the REZ has not been clarified. Elongation of intracranial arteries due to arteriosclerosis is one possibility, but such arteriosclerotic changes are not observed very frequently among patients with HFS. The aim of the present study was to investigate whether arteriosclerotic changes would contribute to the pathogenesis of HFS. This study included 111 HFS patients, all of whom were Japanese. The prevalence rates of hypertension, hyperlipidemia, and diabetes mellitus were examined as risk factors of atherosclerosis, and the cardio-ankle vascular index (CAVI) was measured as an indicator of arteriosclerotic change. The severity of white matter lesions (WMLs) in HFS patients was measured by magnetic resonance imaging. These data were compared with data from healthy Japanese controls. The prevalence rates of the risk factors for atherosclerosis in the HFS patients were not higher than those in the general Japanese population. The CAVI scores for the HFS patients were similar to, or lower than those in the healthy controls for all age groups except 60 to 69-year-old men. The severity of WMLs in the HFS patients was not significantly worse than that in the controls. It is suggested that arteriosclerotic changes are not involved in the pathogenesis of HFS, and that vascular compression syndromes are attributable to anatomical features of the intracranial arteries and facial nerves formed during the prenatal stage.

Study of association of PAX6 polymorphisms with susceptibility to high myopia in a Japanese population.

PurposeMany studies have investigated the relationship of paired box 6 (PAX6) gene polymorphisms with the risk of high myopia, but the results across studies remain inconsistent and ambiguous. In the present work, we investigated whether PAX6 polymorphisms are associated with high myopia in a Japanese population.MethodsA total of 1,585 Japanese patients with high myopia (spherical equivalent [SE] <−9.00 diopters [D]) and 1,011 Japanese healthy controls (SE≥−1.00 D) were recruited. To compare genotype frequencies between cases and controls, we genotyped five single nucleotide polymorphisms in the PAX6 gene that are reportedly associated with high/extreme myopia: rs662702, rs3026393, rs644242, rs3026390, and rs667773.ResultsFor rs662702, rs644242, and rs667773, odds ratios (ORs) for their risk alleles tended to increase with the progression of SE and axial length in the additive and recessive models. Of these, rs644242 had the highest OR (2.56) in patients with SE<−15 D in both eyes in the recessive model. On the other hand, for rs3026393 and rs3026390, the ORs for their risk alleles tended to increase according to the progression of SE and axial length in the dominant model. Of the two, rs3026393 had the highest OR (2.32) in patients with SE<−15 D in both eyes in the dominant model. However, no significant associations were identified in this study.ConclusionWe found that these PAX6 single nucleotide polymorphisms were associated with an increased risk of extreme myopia. Although the results, which are in agreement with some previous studies, did not reach statistical significance, PAX6 single nucleotide polymorphisms may be important risk factors for the development of extreme myopia. Further genetic studies with larger sample sizes and taking into account the degree of myopia are needed to clarify the contribution of PAX6 variants in myopia development.