title: Variants associated with autoimmune Type 1 diabetes in Japanese children: implications for age-specific effects of cis-regulatory haplotypes at 17q12-q21.
abstract: The aim of this study was to clarify the significance of previously reported susceptibility variants in the development of autoimmune Type 1 diabetes in non-white children. Tested variants included rs2290400, which has been linked to Type 1 diabetes only in one study on white people. Haplotypes at 17q12-q21 encompassing rs2290400 are known to determine the susceptibility of early-onset asthma by affecting the expression of flanking genes.
  
  
  
  We genotyped 63 variants in 428 Japanese people with childhood-onset autoimmune Type 1 diabetes and 457 individuals without diabetes. Possible association between variants and age at diabetes onset was examined using age-specific quantitative trait locus analysis and ordered-subset regression analysis.
  
  
  
  Ten variants, including rs2290400 in GSDMB, were more frequent among the people with Type 1 diabetes than those without diabetes. Of these, rs689 in INS and rs231775 in CTLA4 yielded particularly high odds ratios of 5.58 (corrected P value 0.001; 95% CI 2.15-14.47) and 1.64 (corrected P value 5.3 × 10-5; 95% CI 1.34-2.01), respectively. Age-specific effects on diabetes susceptibility were suggested for rs2290400; heterozygosity of the risk alleles was associated with relatively early onset of diabetes, and the allele was linked to the phenotype exclusively in the subgroup of age at onset ≤ 5.0 years.
  
  
  
  The results indicate that rs2290400 in GSDMB and polymorphisms in INS and CTLA4 are associated with the risk of Type 1 diabetes in Japanese children. Importantly, cis-regulatory haplotypes at 17q12-q21 encompassing rs2290400 probably determine the risk of autoimmune Type 1 diabetes predominantly in early childhood.
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ayabe
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Fukami
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.|Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ogata
authors.affiliation: Department of Pediatrics, Osaka City University Hospital, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kawamura
authors.affiliation: Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Urakami
authors.affiliation: Department of Pediatrics, Yokohama City Minato Red Cross Hospital, Yokohama, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kikuchi
authors.affiliation: Department of Clinical Laboratory, Shikoku Medical Center for Children and Adults, Zentsuji, Japan.|Department of Pediatrics, Graduate School of Medical Sciences Tokushima University, Tokushima, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Yokota
authors.affiliation: Department of Pediatrics, Kyushu University Hospital, Fukuoka, Japan.|Department of Pediatrics, Oita University Hospital, Yufu, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ihara
authors.affiliation: Department of Pediatrics, Ehime University Hospital, Toon, Japan.|Department of Pediatrics, Sumitomo Besshi Hospital, Niihama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Takemoto
authors.affiliation: Department of Pediatrics, Asahikawa Medical University Hospital, Asahikawa, Japan.|Department of Pediatrics, Asahikawa-Kosei General Hospital, Asahikawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Mukai
authors.affiliation: Department of Pediatrics, JR Sendai Hospital, Sendai, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Nishii
authors.affiliation: Department of Pediatrics, Saitama Medical University Hospital, Saitama, Japan.|Department of Pediatrics, Niigata University Medical and Dental Hospital, Niigata, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kikuchi
authors.affiliation: Department of Pediatrics, Nagano Red Cross Hospital, Nagano, Japan.|Department of Pediatrics, Shinshu Ueda Medical Center, Ueda, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Mori
authors.affiliation: Department of Pediatrics, Dokkyo Medical University Hospital, Shimotsuga, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Shimura
authors.affiliation: Department of Pediatrics, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan.
authors.forename: G
authors.initials: G
authors.lastname: Sasaki
authors.affiliation: Department of Pediatrics, Yokosuka Kyosai Hospital, Yokosuka, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Kizu
authors.affiliation: Department of Pediatrics, Kitasato University Hospital, Sagamihara, Japan.|Department of Pediatrics and Adolescent Medicine, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Takubo
authors.affiliation: Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Soneda
authors.affiliation: Department of Pediatrics, National Mie Hospital, Tsu, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Fujisawa
authors.affiliation: Department of Pediatrics, Osaka Medical College, Takatsuki, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Takaya
authors.affiliation: Department of Pediatrics, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan.
authors.forename: Z
authors.initials: Z
authors.lastname: Kizaki
authors.affiliation: Department of Pediatrics, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kanzaki
authors.affiliation: Department of Pediatrics, Tottori Prefectural Kousei Hospital, Kurayoshi, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hanaki
authors.affiliation: Department of Pediatrics, Teine Keijinkai Hospital, Sapporo, Japan.|Department of Early Childhood Care and Education, Seitoku University Junior College, Matsudo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Matsuura
authors.affiliation: Department of Pediatrics, Kanazawa University, Kanazawa, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kasahara
authors.affiliation: Department of Pediatrics, University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kosaka
authors.affiliation: Takahashi Clinic, Kobe, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Pediatrics, Teikyo University Chiba Medical Center, Ichihara, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Minamitani
authors.affiliation: Matsuo Kodomo Clinic, Kyoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Matsuo
authors.affiliation: Department of Metabolism and Endocrinology, Saitama Children's Medical Center, Saitama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Mochizuki
authors.affiliation: Department of Pediatrics, University of Yamanashi Hospital, Chuo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Miyanosawa Koike Child Clinic, Sapporo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Koike
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medical Subspecialties, National Medical Center for Children and Mothers, Tokyo, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Horikawa
authors.affiliation: Teno Clinic, Izumo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Teno
authors.affiliation: Department of Pediatrics, Chuno Kosei Hospital, Seki, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tsubouchi
authors.affiliation: Department of Pediatrics, Osaka City General Hospital, Osaka, Japan.|Department of Pediatrics, Osaka Police Hospital, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Mochizuki
authors.affiliation: Igarashi Children's Clinic, Sendai, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Igarashi
authors.affiliation: Department of Pediatrics, Saitama Medical University Hospital, Saitama, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Amemiya
authors.affiliation: Department of Pediatrics, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Sugihara
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007223:Infant; D007564:Japan / Q000208:ethnology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055815:Young Adult