A functional SNP in the NKX2.5-binding site of ITPR3 promoter is associated with susceptibility to systemic lupus erythematosus in Japanese population.
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.
Oishi
Tetsuya
T
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.
Iida
Aritoshi
A
Laboratory for Genotyping, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, 230-0045, Japan.
Otsubo
Shigeru
S
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.
Kamatani
Yoichiro
Y
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato, Tokyo, 108-8639, Japan.
Usami
Masayuki
M
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato, Tokyo, 108-8639, Japan.
Takei
Takashi
T
Department of Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
Uchida
Keiko
K
Department of Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
Tsuchiya
Ken
K
Department of Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
Saito
Susumu
S
Laboratory for Genotyping, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, 230-0045, Japan.
Ohnisi
Yozo
Y
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato, Tokyo, 108-8639, Japan.
Tokunaga
Katsushi
K
Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, 108-8639, Japan.
Nitta
Kosaku
K
Department of Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
Kawaguchi
Yasushi
Y
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
Kamatani
Naoyuki
N
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
Kochi
Yuta
Y
Laboratory for Rheumatic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, 230-0045, Japan.
Shimane
Kenichi
K
Laboratory for Rheumatic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, 230-0045, Japan.
Yamamoto
Kazuhiko
K
Laboratory for Rheumatic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Kanagawa, 230-0045, Japan.
Nakamura
Yusuke
Y
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, the University of Tokyo, 4-6-1 Shirokanedai, Minato, Tokyo, 108-8639, Japan.
Yumura
Wako
W
Department of Medicine, Kidney Center, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
Matsuda
Koichi
K
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.
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*
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