title: A functional SNP in the NKX2.5-binding site of ITPR3 promoter is associated with susceptibility to systemic lupus erythematosus in Japanese population.
abstract: Systemic lupus erythematosus (SLE) is one of the common autoimmune diseases with complex genetic components. To identify a gene(s) susceptible to SLE, we performed a case-control association study using genome-wide gene-based single nucleotide polymorphisms (SNPs) in Japanese population. Here we report that an SNP (rs3748079) located in a promoter region of the inositol 1,4,5-triphosphate receptor type 3 (ITPR3) gene on chromosome 6p21 was significantly associated with SLE in two independent Japanese case-control samples [P=0.0000000178 with odds ratio of 1.88, 95% confidence interval (CI) of 1.51-2.35]. This particular SNP also revealed associations with rheumatoid arthritis (RA) (P=0.0084 with odds ratio of 1.23, 95% CI of 1.05-1.43) and with Graves' disease (GD) (P=0.00036 with odds ratio of 1.57, 95% CI of 1.22-2.02). We found the binding of NKX2.5 specific to the non-susceptible T allele in the region including this SNP. Furthermore, an SNP in NKX2.5 also revealed an association with SLE (P=0.0037 with odds ratio of 1.74, 95% CI of 1.19-2.55). Individuals with risk genotype of both ITPR3 and NKX2.5 loci have higher risk for SLE (odds ratio=5.77). Our data demonstrate that genetic and functional interactions of ITPR3 and NKX2.5 play a crucial role in the pathogenesis of SLE.
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato, Tokyo, 108-8639, Japan.|Department of Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Oishi
authors.affiliation: Laboratory for Genotyping, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, 230-0045, Japan.
authors.forename: Aritoshi
authors.initials: A
authors.lastname: Iida
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato, Tokyo, 108-8639, Japan.|Department of Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Otsubo
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato, Tokyo, 108-8639, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kamatani
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato, Tokyo, 108-8639, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Usami
authors.affiliation: Department of Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Takei
authors.affiliation: Department of Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Uchida
authors.affiliation: Department of Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Tsuchiya
authors.affiliation: Laboratory for Genotyping, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, 230-0045, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Saito
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato, Tokyo, 108-8639, Japan.
authors.forename: Yozo
authors.initials: Y
authors.lastname: Ohnisi
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, 108-8639, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tokunaga
authors.affiliation: Department of Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
authors.forename: Kosaku
authors.initials: K
authors.lastname: Nitta
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kawaguchi
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.affiliation: Laboratory for Rheumatic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, 230-0045, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kochi
authors.affiliation: Laboratory for Rheumatic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, 230-0045, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shimane
authors.affiliation: Laboratory for Rheumatic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, 230-0045, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato, Tokyo, 108-8639, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
authors.forename: Wako
authors.initials: W
authors.lastname: Yumura
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato, Tokyo, 108-8639, Japan. koichima@ims.u-tokyo.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuda
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000235:genetics; D001665:Binding Sites; D016022:Case-Control Studies; D047369:Chromatin Immunoprecipitation; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006111:Graves Disease / Q000235:genetics; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics*; D007564:Japan / Q000453:epidemiology; D008156:Luciferases / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C506929:ITPR3 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; C095552:NKX2-5 protein, human; D012333:RNA, Messenger; D014157:Transcription Factors; D008156:Luciferases