Nao Nishida

National Center for Global Health and Medicine in Japan, Ichikawa, Chiba, Japan

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Publications (85)515.7 Total impact

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    ABSTRACT: We previously identified TNFSF15 as the most significant susceptibility gene at non-HLA loci for both primary biliary cirrhosis (PBC) and Crohn's diseases (CD) in the Japanese population. The aim of this study is to identify further disease susceptibility genes shared by PBC and CD. We selected 15 and 33 genetic variants that were significantly associated with PBC and CD, respectively, based on previously reported genome-wide association studies of the Japanese population. Next, an association study was independently performed for these genetic variants in CD (1312 CD patients and 3331 healthy controls) and PBC (1279 PBC patients and 1015 healthy controls) cohorts. Two CD susceptibility genes, ICOSLG rs2838519 and IL12B rs6556412, were also nominally associated with susceptibility to PBC (P=3.85 × 10(-2) and P=8.40 × 10(-3), respectively). Three PBC susceptibility genes, CXCR5 rs6421571, STAT4 rs7574865 and NFKB1 rs230534, were nominally associated with susceptibility to CD (P=2.82 × 10(-2), P=3.88 × 10(-2) and P=2.04 × 10(-2), respectively). The effect of ICOSLG and CXCR5 variants were concordant but the effect of STAT4, NFKB1 and IL12B variants were discordant for PBC and CD. TNFSF15 and ICOSLG-CXCR5 might constitute a shared pathogenic pathway in the development of PBC and CD in the Japanese population, whereas IL12B-STAT4-NFKB1 might constitute an opposite pathogenic pathway, reflecting the different balance between Th1 and Th17 in the two diseases.Journal of Human Genetics advance online publication, 18 June 2015; doi:10.1038/jhg.2015.59.
    Journal of Human Genetics 06/2015; DOI:10.1038/jhg.2015.59 · 2.53 Impact Factor
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    ABSTRACT: A genome-wide association study (GWAS) identified tumor necrosis factor superfamily member 15 (TNFSF15) as the strongest associated gene with susceptibility to primary biliary cirrhosis (PBC) outside the HLA loci in the Japanese population. However, causal functional variants of the TNFSF15 locus and the molecular mechanism underlying disease susceptibility have not been clarified. Here, to identify the functional causal variants of the TNFSF15 locus, integrated analysis comprising in silico analysis, a case-control association study and in vitro functional analysis was performed. Initially, 32 functional candidate single-nucleotide polymorphisms (SNPs) in the expression regulatory motifs, the coding region, or the untranslated regions (UTRs) of the TNFSF15 locus were selected by in silico analysis. By the case-control association studies using PBC patients (n = 1279) and healthy controls (n = 1091) in the Japanese population, rs4979462 [P = 1.85 × 10(-14) (our previous study)], rs56211063 (P = 2.21 × 10(-14)), and rs55768522 (r (2) = 1 with rs4979462) were likely candidates for causal variants. Among these SNPs, rs4979462 was identified as the causal variant by in vitro functional analysis using luciferase assay and electrophoretic mobility shift assay (EMSA). Super-shift assay clarified that PBC-susceptible allele of rs4979462 generated a novel NF-1 binding site. Moreover, higher endogenous TNFSF15 protein and mRNA expression levels were observed in individuals with the PBC-susceptible allele of rs4979462. This study identified the causal variant for PBC susceptibility in the TNFSF15 locus and clarified its underlying molecular mechanism. TNFSF15 and NF-1 are considered to be potential targets for the treatment of PBC.
    Human Genetics 04/2015; 134(7). DOI:10.1007/s00439-015-1556-3 · 4.52 Impact Factor
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    ABSTRACT: Various hypotheses for the peopling of the Japanese archipelago have been proposed, which can be classified into three models: transformation, replacement, and hybridization. In recent years, one of the hybridization models ("dual-structure model") has been widely accepted. According to this model, Neolithic hunter-gatherers known as Jomon, who are assumed to have originated in southeast Asia and lived in the Japanese archipelago >10,000 years ago, admixed with an agricultural people known as Yayoi, whom were migrants from the East Asian continent 2,000-3,000 years ago. Meanwhile, some anthropologists propose that rather, morphological differences between the Jomon and Yayoi people can be explained by microevolution following the lifestyle change. To resolve this controversy, we compared three demographic models by approximate Bayesian computation (ABC) using genome-wide single nucleotide polymorphism (gwSNP) data from the Ainu people who are thought to be direct descendants of indigenous Jomon. If we assume Chinese people sampled in Beijing (CHB) from HapMap have the same ancestry as Yayoi, then the hybridization model is predicted to be between 29 and 63 times more likely than the replacement and transformation models, respectively. Furthermore, our data provide strong support for a model in which the Jomon lineages had population structure diversified in local areas before the admixture event. Initial divergence between the Jomon and Yayoi ancestries was dated to late Pleistocene, followed by the divergence of Jomon lineages at early Holocene. These results suggest gwSNP data provides a detailed picture of the complex hybridization model for Japanese population history. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    Molecular Biology and Evolution 03/2015; DOI:10.1093/molbev/msv045 · 14.31 Impact Factor
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    ABSTRACT: Cytopenia during interferon-based (IFN-based) therapy for chronic hepatitis C (CHC) often necessitates reduction of doses of drugs and premature withdrawal from therapy resulting in poor response to treatment. To identify genetic variants associated with IFN-induced neutropenia, we conducted a genome-wide association study (GWAS) in 416 Japanese CHC patients receiving IFN-based therapy. Based on the results, we selected 192 candidate single nucleotide polymorphisms (SNPs) to carry out a replication analysis in an independent set of 404 subjects. The SNP rs2305482, located in the intron region of the PSMD3 gene on chromosome 17, showed a strong association when the results of GWAS and the replication stage were combined (OR = 2.18, P = 3.05 × 10(-7) in the allele frequency model). Logistic regression analysis showed that rs2305482 CC and neutrophil count at baseline were independent predictive factors for IFN-induced neutropenia (OR = 2.497, P = 0.0072 and OR = 0.998, P < 0.0001, respectively). Furthermore, rs2305482 genotype was associated with the doses of pegylated interferon (PEG-IFN) that could be tolerated in hepatitis C virus genotype 1-infected patients treated with PEG-IFN plus ribavirin, but not with treatment efficacy. Our results suggest that genetic testing for this variant might be useful for establishing personalized drug dosing in order to minimize drug-induced adverse events.
    Human Genetics 12/2014; 134(3). DOI:10.1007/s00439-014-1520-7 · 4.52 Impact Factor
  • Journal of Clinical Psychopharmacology 12/2014; 35(1). DOI:10.1097/JCP.0000000000000268 · 3.76 Impact Factor
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    ABSTRACT: Elucidation of the genetic susceptibility factors for diabetic retinopathy (DR) is important to gain insight into the pathogenesis of DR, and may help to define genetic risk factors for this condition. In the present study, we conducted a three-stage genome-wide association study (GWAS) to identify DR susceptibility loci in Japanese patients, which comprised a total of 837 type 2 diabetes patients with DR (cases) and 1,149 without DR (controls). From the stage 1 genome-wide scan of 446 subjects (205 cases and 241 controls) on 614,216 SNPs, 249 SNPs were selected for the stage 2 replication in 623 subjects (335 cases and 288 controls). Eight SNPs were further followed up in a stage 3 study of 297 cases and 620 controls. The top signal from the present association analysis was rs9362054 in an intron of RP1-90L14.1 showing borderline genome-wide significance (Pmet = 1.4×10-7, meta-analysis of stage 1 and stage 2, allele model). RP1-90L14.1 is a long intergenic non-coding RNA (lincRNA) adjacent to KIAA1009/QN1/CEP162 gene; CEP162 plays a critical role in ciliary transition zone formation before ciliogenesis. The present study raises the possibility that the dysregulation of ciliary-associated genes plays a role in susceptibility to DR.
    PLoS ONE 11/2014; 9(11):e111715. DOI:10.1371/journal.pone.0111715 · 3.53 Impact Factor
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    ABSTRACT: This study examined the genetic diversity and dynamicity of circulating Mycobacterium tuberculosis in Thailand using nearly neutral molecular markers. The single nucleotide polymorphism (SNP)-based genotypes of 1,414 culture-positive M. tuberculosis isolates from 1,282 pulmonary tuberculosis (PTB) and 132 extra-pulmonary TB (EPTB) patients collected from 1995-2011 were characterized. Among the eight SNP cluster groups (SCG), SCG2 (44.1%), which included the Beijing (BJ) genotype, and SCG1 (39.4%), an East-African Indian genotype, were dominant. Comparisons between the genotypes of M. tuberculosis isolates causing PTB and EPTB in HIV-negative cases revealed similar prevalence trends, although genetic diversity was higher in the PTB patients. The identification of 10 reported sequence types (STs) and three novel STs was hypothesized to indicate preferential expansion of the SCG2 genotype, especially the modern BJ ST10 (15.6%) and ancestral BJ ST19 (13.1%). An association between SCG2 and SCG1 genotypes and particular patient age-groups implies the existence of different genetic advantages among the bacterial population. The results revealed that increasing numbers of young patients were infected with M. tuberculosis SCGs 2 and 5, which contrasts with the reduction of the SCG1 genotype. Our results indicate the selection and dissemination of potent M. tuberculosis genotypes in this population. The determination of heterogeneity and dynamic population changes of circulating M. tuberculosis strains in Bacillus Calmette-Guérin vaccination countries are beneficial for vaccine development and control strategies.
    Journal of Clinical Microbiology 10/2014; DOI:10.1128/JCM.01467-14 · 4.23 Impact Factor
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    ABSTRACT: Interferon regulatory factor 2 (IRF2) negatively regulates type I interferon (IFN) responses, while it plays a role in induction of Th1 differentiation. Previous linkage and association studies in European-American populations suggested genetic role of IRF2 in systemic lupus erythematosus (SLE); however, this observation has not yet been confirmed. No studies have been reported in the Asian populations. Here we investigated whether IRF2 polymorphisms contribute to susceptibility to SLE in a Japanese population. Association study of 46 IRF2 tag single nucleotide polymorphisms (SNPs) detected association of an intronic SNP, rs13146124, with SLE. When the association was analyzed in 834 Japanese patients with SLE and 817 healthy controls, rs13146124 T was significantly increased in SLE compared with healthy controls (dominant model, P = 5.4×10-4, Bonferroni-corrected P [Pc] = 0.026, odds ratio [OR] 1.48, 95% confidence interval [CI] 1.18-1.85). To find causal SNPs, resequencing was performed by next-generation sequencing. Twelve polymorphisms in linkage disequilibrium with rs13146124 (r2: 0.30-1.00) were identified, among which significant association was observed for rs66801661 (allele model, P = 7.7×10-4, Pc = 0.037, OR 1.53, 95%CI 1.19-1.96) and rs62339994 (dominant model, P = 9.0×10-4, Pc = 0.043, OR 1.46, 95%CI 1.17-1.82). The haplotype carrying both of the risk alleles (rs66801661A-rs62339994A) was significantly increased in SLE (P = 9.9×10-4), while the haplotype constituted by both of the non-risk alleles (rs66801661G-rs62339994G) was decreased (P = 0.0020). A reporter assay was carried out to examine the effect of the IRF2 haplotypes on the transcriptional activity, and association of the IRF2 risk haplotype with higher transcriptional activity was detected in Jurkat T cells under IFNγ stimulation (Tukey's test, P = 1.2×10-4). In conclusion, our observations supported the association of IRF2 with susceptibility to SLE, and the risk haplotype was suggested to be associated with transcriptional activation of IRF2.
    PLoS ONE 10/2014; 9(10):e109764. DOI:10.1371/journal.pone.0109764 · 3.53 Impact Factor
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    ABSTRACT: The influence of genetic variation at the interleukin-28B (IL28B) locus on the natural course of hepatitis C virus (HCV) infection has not been fully investigated. The goal of this study was to examine whether an IL28B polymorphism (rs8099917) is associated with natural clearance of HCV and with disease parameters of HCV infection in an HCV hyperendemic area of Japan. The patients were 502 anti-HCV antibody-positive residents who participated in liver disease screening program from 2002 to 2004. Patients who underwent interferon-based therapy or had hepatocellular carcinoma were excluded. Of these patients, 149 were negative for HCV RNA (prior infection) and 353 were positive for HCV RNA or HCV core antigen (HCV carriers). In multivariate analysis, the IL28B TT genotype was a predictor for prior HCV infection. In addition, nine of the patients with prior HCV infection were positive for anti-HCV antibody with positive for HCV core antigen or HCV RNA before 2001, and these nine patients all had the IL28B TT genotype. Furthermore, the IL28B TT genotype was associated independently with higher HCV core antigen levels in HCV carriers. In contrast, the IL28B genotype did not affect the biochemical markers, such as alanine aminotransferase, hepatic fibrosis markers, and α-fetoprotein, and the degree of hepatic fibrosis assessed by transient elastography in HCV carriers. We concluded that IL28B polymorphism (TT genotype) is associated with spontaneous clearance of HCV and conversely with high viral loads in HCV carriers. In contrast, the IL28B genotype does not affect disease progression such as hepatic fibrosis. J. Med. Virol. © 2014 Wiley Periodicals, Inc.
    Journal of Medical Virology 08/2014; 86(11). DOI:10.1002/jmv.24037 · 2.22 Impact Factor
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    ABSTRACT: Older female patients exhibit a poor response to the current standard treatment for hepatitis C, interferon-α, and ribavirin (PEG-IFN-α/RBV). In this study, we reported that the combination of age and the genotype of a novel SNP can predict response to standard treatment (P = 7.31 × 10(-8) ). The model incorporating genotype of the novel SNP, rs1287948, predicts response more accurately (AUC = 0.934; 95% CI = 0.881-0.988) in women as compared with the model using age and the previously identified SNP, rs8099917. J. Med. Virol. © 2014 Wiley Periodicals, Inc.
    Journal of Medical Virology 07/2014; 86(7). DOI:10.1002/jmv.23939 · 2.22 Impact Factor
  • Journal of Hepatology 04/2014; 60(1):S323. DOI:10.1016/S0168-8278(14)60918-1 · 10.40 Impact Factor
  • Journal of Hepatology 04/2014; 60(1):S323. DOI:10.1016/S0168-8278(14)60919-3 · 10.40 Impact Factor
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    ABSTRACT: Genome-wide association studies highlighted single nucleotide polymorphisms (SNPs) within the IFNL3/IL28B locus predict the treatment outcome for patients with HCV. Furthermore, SNPs in newly discovered IFNL4 are shown to have population-specific correlation with spontaneous clearance of HCV. The aim of this study was to examine the prevalence and clinical significance of the outlined SNPs in a population from Central Asia, a multi-ethnic region with a developing economy and a high prevalence of HCV infection. One hundred and thirty-five chronic HCV patients from Uzbekistan were enrolled. DNA specimens were extracted from peripheral blood mononuclear cells and the IFNL3 SNPs (rs8099917, rs12979860) were genotyped by the Invader Plus assay, the TaqMan assay, and by direct sequence analysis. The IFL4 region (ss469415590) was sequenced. Of the 135 patients that completed 24 or 48 weeks of treatment with Peg-IFN-α plus RBV, 87.4% were of Central Asian (CA) ancestry and 12.6% were of Eastern European (EE) ancestry. A non-virological response was observed in 21.2% of CA and in 35.3% of EE, respectively (p<0.32). The rs12979860 was strongly associated with treatment response (OR, 5.2; 95% CI, 1.9-14.6; p<0.004) in the overall sample; however, SNP rs8099917 was the most predictive of outcome for CA group (OR, 6.9; 95% CI, 2.6-18.0; p<0.002). The allele frequency of IFNL4 SNP, ss469415590, was identical with that of rs12979860 in all samples. SNPs in IFNL3 and IFNL4 can be used to predict HCV treatment outcome in a population of Central Asian ancestry.
    PLoS ONE 03/2014; 9(3):e93011. DOI:10.1371/journal.pone.0093011 · 3.53 Impact Factor
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    ABSTRACT: Previous studies have revealed the association between SNPs located on human leukocyte antigen (HLA) class II genes, including HLA-DP and HLA-DQ, and chronic hepatitis B virus (HBV) infection, mainly in Asian populations. HLA-DP alleles or haplotypes associated with chronic HBV infection or disease progression have not been fully identified in Asian populations. We performed trans-ethnic association analyses of HLA-DPA1, HLA-DPB1 alleles and haplotypes with hepatitis B virus infection and disease progression among Asian populations comprising Japanese, Korean, Hong Kong, and Thai subjects. To assess the association between HLA-DP and chronic HBV infection and disease progression, we conducted high-resolution (4-digit) HLA-DPA1 and HLA-DPB1 genotyping in a total of 3,167 samples, including HBV patients, HBV-resolved individuals and healthy controls. Trans-ethnic association analyses among Asian populations identified a new risk allele HLA-DPB1*09∶01 (P = 1.36×10(-6); OR = 1.97; 95% CI, 1.50-2.59) and a new protective allele DPB1*02∶01 (P = 5.22×10(-6); OR = 0.68; 95% CI, 0.58-0.81) to chronic HBV infection, in addition to the previously reported alleles. Moreover, DPB1*02∶01 was also associated with a decreased risk of disease progression in chronic HBV patients among Asian populations (P = 1.55×10(-7); OR = 0.50; 95% CI, 0.39-0.65). Trans-ethnic association analyses identified Asian-specific associations of HLA-DP alleles and haplotypes with HBV infection or disease progression. The present findings will serve as a base for future functional studies of HLA-DP molecules in order to understand the pathogenesis of HBV infection and the development of hepatocellular carcinoma.
    PLoS ONE 01/2014; 9(2):e86449. DOI:10.1371/journal.pone.0086449 · 3.53 Impact Factor
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    ABSTRACT: Background: Genome-Wide-Association Studies revealed that single nucleotide polymorphisms (SNPs) around interleukin (IL)-28B were associated with response to the anti-hepatitis C virus (HCV) therapy and HCV spontaneous clearance. IL28B SNPs can predict HCV clearance by anti-HCV therapy at approximately 80%. However, the remaining 20% patients show discordance between IL28B genotype and the response, suggesting that other factors might be involved in HCV clearance. We previously reported that the length of the TA dinucleotide repeat in the promoter region of IL28Bhas a wide variation and the transcriptional activity of the promoter increased gradually in a TA repeat length-dependent manner. In this study, we determined the length of TA repeat to investigate the correlation to with HCV spontaneous clearance. Methods: Total 2041 Japanese genomic samples were enrolled (274 with HCV spontaneous clearance, 457 with chronic HCV infection and 1310 healthy donors). IL28BSNPs were genotyped using Invader assay. The length of TA repeat was determined by 3130xl sequencer and GeneMapper software. Results: The variation of TA repeat number ranged from 10 to 18, and the most frequent number was 12 (84.8%) in our population. A univariate analysis showed significant differences between groups with HCV spontaneous clearance and chronic infection in sex (women, 67.0% vs. 51.4%), age (68.1 ± 11.1 vs. 64.0 ± 10.8 years), IL28B (rs8099917) genotypes (TT, 92.0% vs. 67.4%), and TA repeat number (≧12/12, 99.6% vs. 95.0%) (all P≦0.01). Multiple logistic regression model showed women (OR, 2.05; 95%CI, 1.47-2.87), older age (OR, 1.03; 95%CI, 1.01-1.04), IL28B (rs8099917) genotype TT (OR, 5.40; 95%CI, 3.31-8.80), and TA repeat number ≧12/12 (OR, 10.7; 95%CI, 1.40-82.4) as independently significant factors for HCV spontaneous clearance. Analyzing these 4 factors by decision tree model, among women aged ≧68 years with IL28B (rs8099917) genotype TT, those with TA repeat genotype ≧12/12 had a high probability of spontaneous clearance. Conclusion: TA repeat number ≧12/12 in the promoter region of IL28B was associated to HCV spontaneous clearance. It could be the novel genetic factor to improve the predictive value for HCV clearance with IL28B SNPs.
    IDWeek 2013 Meeting of the Infectious Diseases Society of America; 10/2013
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    ABSTRACT: Atypical psychosis with a periodic course of exacerbation and features of major psychiatric disorders [schizophrenia (SZ) and bipolar disorder (BD)] has a long history in clinical psychiatry in Japan. Based upon the new criteria of atypical psychosis, a Genome-Wide Association Study (GWAS) was conducted to identify the risk gene or variants. The relationships between atypical psychosis, SZ and BD were then assessed using independent GWAS data. Forty-seven patients with solid criteria of atypical psychosis and 882 normal controls (NCs) were scanned using an Affymetrics 6.0 chip. GWAS SZ data (560 SZ cases and 548 NCs) and GWAS BD (107 cases with BD type 1 and 107 NCs) were compared using gene-based analysis. The most significant SNPs were detected around the CHN2/CPVL genes (rs245914, P = 1.6 × 10(-7)) , COL21A1 gene (rs12196860, P = 2.45 × 10(-7) ), and PYGL/TRIM9 genes (rs1959536, P = 7.73 × 10(-7) ), although none of the single-nucleotide polymorphisms exhibited genome-wide significance (P = 5 × 10(-8) ). One of the highest peaks was detected on the major histocompatibility complex region, where large SZ GWASs have previously disclosed an association. The gene-based analysis suggested significant enrichment between SZ and atypical psychosis (P = 0.01), but not BD. This study provides clues about the types of patient whose diagnosis lies between SZ and BD. Studies with larger samples are required to determine the causal variant. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 10/2013; 162(7):679-86. DOI:10.1002/ajmg.b.32164 · 3.27 Impact Factor
  • 08/2013; 1(1):45-50. DOI:10.14218/JCTH.2013.010XX
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    ABSTRACT: Through a genome-wide association study of a Japanese population, we recently identified TNFSF15, a gene encoding TNF-like ligand 1A (TL1A), as a susceptibility gene for primary biliary cirrhosis (PBC). We investigated the clinical significance of TL1A and one of its receptors, decoy receptor 3 (DcR3), in PBC. We analysed the systemic and local expression of TL1A and DcR3 in 110 PBC patients and 46 healthy controls using enzyme-linked immunosorbent assay, quantitative polymerase chain reaction and immunohistochemical staining. Serum TL1A levels were significantly increased in PBC patients at both early and late stages as compared with healthy controls, and its levels were significantly decreased in early-stage PBC patients after ursodeoxycholic acid (UDCA) treatment. TL1A was immunohistochemically localized to biliary epithelial cells, Kupffer cells, blood vessels and infiltrating mononuclear cells in the PBC liver. In addition, TL1A messenger RNA expression was increased in the PBC liver as compared with the non-diseased liver. Serum DcR3 levels were also significantly increased in PBC patients, and were significantly decreased after UDCA treatment in early-stage PBC patients. These results indicate that TL1A and DcR3 may play an important role in the pathogenesis of PBC.
    Liver international: official journal of the International Association for the Study of the Liver 08/2013; 34(5). DOI:10.1111/liv.12296 · 4.41 Impact Factor
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    ABSTRACT: The role of low-frequency variants in type 1 diabetes (T1D) susceptibility still remains to be clarified. In the present study, we analyzed low-frequency variants of the T1D candidate genes in Japanese. We first screened for protein-changing variants of 24 T1D candidate genes in 96 T1D patients and 96 control subjects, and then the association with T1D was tested in 706 T1D patients and 863 control subjects recruited from the collaborating institutions in Japan. In total, 56 protein-changing variants were discovered; among them, 34 were low-frequency variants (allele frequency < 5%). The association analysis of the low-frequency variants revealed that only the A908V variant of GLIS3 was strongly associated with resistance to T1D (Haldane's odds ratio = 0.046, p = 8.21 x 10(-4), and pc = 2.22 x 10(-2)). GLIS3 is a zinc finger transcription factor that is highly expressed in pancreatic beta cells, and regulates beta cell development and insulin gene expression. GLIS3 mRNA is also moderately expressed in the human thymus. The precise mechanism responsible for the association is unclear at present, but the A908V variant may affect autoimmunity to the GLIS3 protein itself; the 908V-containing epitope may induce central or peripheral tolerance more efficiently than that of 908A.
    Biochemical and Biophysical Research Communications 07/2013; 437(4). DOI:10.1016/j.bbrc.2013.06.102 · 2.28 Impact Factor
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    ABSTRACT: To discover susceptibility genes of late-onset Alzheimer's disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values <2×10(-5) were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P = 7.33×10(-7) in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P = 1.77×10(-9)) and rs3781834 (P = 1.04×10(-8)). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P = 1.71×10(-5)) and rs744373 near BIN1 (P = 1.39×10(-4)). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations.
    PLoS ONE 07/2013; 8(4):e58618. DOI:10.1371/journal.pone.0058618 · 3.53 Impact Factor