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GWAS Identified IL4R and the Major Histocompatibility Complex Region as the Associated Loci of Total Serum IgE Levels in 9,260 Japanese Individuals

  • Author Footnotes
    12 These authors equally contributed to this work.
    Kosuke Shido
    Footnotes
    12 These authors equally contributed to this work.
    Affiliations
    Department of Dermatology, Graduate School of Medicine, Tohoku University, Sendai, Japan
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  • Author Footnotes
    12 These authors equally contributed to this work.
    Kaname Kojima
    Footnotes
    12 These authors equally contributed to this work.
    Affiliations
    Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan

    RIKEN Center for Advanced Intelligence Project, Tokyo, Japan
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  • Author Footnotes
    12 These authors equally contributed to this work.
    Matsuyuki Shirota
    Footnotes
    12 These authors equally contributed to this work.
    Affiliations
    Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan

    Division of Interdisciplinary Medical Science, Graduate School of Medicine, Tohoku University, Sendai, Japan

    Graduate School of Information Sciences, Tohoku University, Sendai, Japan
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  • Kenshi Yamasaki
    Correspondence
    Corresponding author
    Affiliations
    Department of Dermatology, Graduate School of Medicine, Tohoku University, Sendai, Japan
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  • Ikuko N. Motoike
    Affiliations
    Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
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  • Atsushi Hozawa
    Affiliations
    Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
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  • Soichi Ogishima
    Affiliations
    Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan

    Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, Japan
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  • Naoko Minegishi
    Affiliations
    Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan

    Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, Japan
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  • Kozo Tanno
    Affiliations
    Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Sendai, Japan
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  • Fumiki Katsuoka
    Affiliations
    Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
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  • Gen Tamiya
    Affiliations
    Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan

    RIKEN Center for Advanced Intelligence Project, Tokyo, Japan

    Department of Statistical Genetics and Genomics, Graduate School of Medicine, Tohoku University, Sendai, Japan

    Department of AI and Innovative Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan
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  • Setsuya Aiba
    Affiliations
    Department of Dermatology, Graduate School of Medicine, Tohoku University, Sendai, Japan
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  • Masayuki Yamamoto
    Affiliations
    Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan

    Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, Japan

    Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan
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  • Kengo Kinoshita
    Affiliations
    Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan

    Graduate School of Information Sciences, Tohoku University, Sendai, Japan

    Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, Japan

    Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
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  • Author Footnotes
    12 These authors equally contributed to this work.
Published:April 13, 2021DOI:https://doi.org/10.1016/j.jid.2021.02.762
      IgE is an antibody produced by the immune system in response to helminth and parasites, and it has previously been found to be involved in eczema, ichthyosis, and lupus, among other skin disorders (
      • Bayry J.
      Lupus pathogenesis: role of IgE autoantibodies.
      ;
      • Johansson E.K.
      • Bergström A.
      • Kull I.
      • Lind T.
      • Söderhäll C.
      • van Hage M.
      • et al.
      IgE sensitization in relation to preschool eczema and filaggrin mutation.
      ;
      • Kiritsi D.
      • Valari M.
      • Fortugno P.
      • Hausser I.
      • Lykopoulou L.
      • Zambruno G.
      • et al.
      Whole-exome sequencing in patients with ichthyosis reveals modifiers associated with increased IgE levels and allergic sensitizations.
      ). According to twin and family studies, genetic factors affect total IgE levels, and their heritability was estimated as 36‒78% (
      • Jacobsen H.P.
      • Herskind A.M.
      • Nielsen B.W.
      • Husby S.
      IgE in unselected like-sexed monozygotic and dizygotic twins at birth and at 6 to 9 years of age: high but dissimilar genetic influence on IgE levels.
      ;
      • Meyers D.A.
      • Beaty T.H.
      • Freidhoff L.R.
      • Marsh D.G.
      Inheritance of total serum IgE (basal levels) in man.
      ). GWASs of total IgE levels in European populations (two studies in 14,628 and 11,299 German individuals and one study in 8,539 Latino individuals) identified SNPs near FCER1A, IL13, signal transducer and activator of transcription gene (i.e., STAT6), and ZNF365 (
      • Granada M.
      • Wilk J.B.
      • Tuzova M.
      • Strachan D.P.
      • Weidinger S.
      • Albrecht E.
      • et al.
      A genome-wide association study of plasma total IgE concentrations in the Framingham Heart Study.
      ;
      • Moffatt M.F.
      • Gut I.G.
      • Demenais F.
      • Strachan D.P.
      • Bouzigon E.
      • Heath S.
      • et al.
      A large-scale, consortium-based genomewide association study of asthma.
      ;
      • Pino-Yanes M.
      • Gignoux C.R.
      • Galanter J.M.
      • Levin A.M.
      • Campbell C.D.
      • Eng C.
      • et al.
      Genome-wide association study and admixture mapping reveal new loci associated with total IgE levels in Latinos.
      ;
      • Weidinger S.
      • Gieger C.
      • Rodriguez E.
      • Baurecht H.
      • Mempel M.
      • Klopp N.
      • et al.
      Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus.
      ), whereas GWASs of total IgE levels in Asian populations (three studies in 3,654 Japanese individuals, 877 Korean individuals, and 3,495 Chinese individuals, respectively) identified no significant loci other than the major histocompatibility complex region (
      • Kim J.H.
      • Cheong H.S.
      • Park J.S.
      • Jang A.S.
      • Uh S.T.
      • Kim Y.H.
      • et al.
      A genome-wide association study of total serum and mite-specific IgEs in asthma patients.
      ;
      • Liao M.
      • Shi D.
      • Wang Y.
      • Zhang K.
      • Chen X.
      • Gao Y.
      • et al.
      Genome-wide scan on total serum IgE levels identifies no common variants in a healthy Chinese male population.
      ;
      • Yatagai Y.
      • Sakamoto T.
      • Masuko H.
      • Kaneko Y.
      • Yamada H.
      • Iijima H.
      • et al.
      Genome-wide association study for levels of total serum IgE identifies HLA-C in a Japanese population.
      ) (summarized in Supplementary Table S1). In this study, we performed a GWAS of total IgE levels in Japanese individuals participating in the Tohoku Medical Megabank Project cohort study conducted in Miyagi and Iwate prefectures using imputed genotypes of 4,534 and 4,725 individuals as discovery and replication sets, respectively (Supplementary Tables S2 and S3 and Supplementary Figures S1-S3). Two loci reached the genome-wide significance level of 5.0 × 10−8 in the discovery set and were replicated in the replication set: one locus was located in the major histocompatibility complex region on chromosome 6, and the lead SNP of the other locus, rs144651842, was located in the exon 3 of IL4R on chromosome 16 (β-coefficient = −0.26, standard error = 0.048, P = 4.8 × 10−8 for the discovery set) (Supplementary Table S3 and Figure 1a). The P-values for these loci in the GWAS of the combined discovery and replication sets were smaller than those of the discovery set (Supplementary Table S3 and Figure 1b and Supplementary Figure S4e). The median genomic inflation factors for the discovery and combined sets were both 1.0475 (Supplementary Figure S5).
      Figure thumbnail gr1
      Figure 1Manhattan plots of the GWAS of total IgE levels. (a) The discovery set of 4,534 Japanese individuals. (b) The combined set of 9,260 Japanese individuals. The dots in purple indicate directly genotyped variants, whereas the dots in gray indicate imputed variants in the Manhattan plots. The red horizontal line indicates the genome-wide significance level of 5.0 × 10–8, and the lead SNPs of signals reaching the genome-wide significance level are marked by the arrows with closest genes. MHC, major histocompatibility complex.
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