title: A low-frequency GLIS3 variant associated with resistance to Japanese type 1 diabetes.
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 × 10(-4), and pc=2.22 × 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.
authors.affiliation: Division of Endocrinology and Diabetes, Faculty of Medicine, Saitama Medical University, Moroyama-machi, Iruma-gun, Japan. awata@saitama-med.ac.jp
authors.forename: Takuya
authors.initials: T
authors.lastname: Awata
authors.forename: Hisakuni
authors.initials: H
authors.lastname: Yamashita
authors.forename: Susumu
authors.initials: S
authors.lastname: Kurihara
authors.forename: Tomoko
authors.initials: T
authors.lastname: Morita-Ohkubo
authors.forename: Yumi
authors.initials: Y
authors.lastname: Miyashita
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Katayama
authors.forename: Eiji
authors.initials: E
authors.lastname: Kawasaki
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Tanaka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ikegami
authors.forename: Taro
authors.initials: T
authors.lastname: Maruyama
authors.forename: Akira
authors.initials: A
authors.lastname: Shimada
authors.forename: Kazuma
authors.initials: K
authors.lastname: Takahashi
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Kawabata
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Nao
authors.initials: N
authors.lastname: Nishida
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Mawatari
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D044466:Asian People; D016022:Case-Control Studies; D004268:DNA-Binding Proteins; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007564:Japan; D008297:Male; D008875:Middle Aged; D012097:Repressor Proteins; D013950:Thymus Gland / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult; D016335:Zinc Fingers
chemical_list: D004268:DNA-Binding Proteins; C512851:GLIS3 protein, human; D007328:Insulin; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors
keywords: GLIS3; Genetic susceptibility; Japanese; Low-frequency variants; Type 1 diabetes