Abstract
Cold-induced autoinflammatory syndrome 1 (CIAS1) gene is a member of the NALP subfamily of the CATERPILLER protein family that is expressed predominantly in peripheral blood leukocytes, which is to regulate apoptosis or inflammation through the activation of NF-κB and caspase. Recent genetic analyses suggested an association between inflammation and oxidative stress-related genes in the development of hypertension. This is the first genetic study indicating an association between the CIAS1 gene and susceptibility to essential hypertension (EH). The frequency of subject with the homozygote of 12 repeat allele was significantly higher in patients with hypertension compared with control subjects (987 cases, 924 controls) (P=0.030; odds ratio=1.24) at a novel VNTR polymorphism of CIAS1 intron 4 loci. We also found that the mean of systolic blood pressure of homozygotes of 12 repeat allele was 6.4 mmHg higher than those of homozygotes of non-12 repeat allele in male random population (P=0.009). The frequency of six SNPs spanning of the CIAS1 gene was not significantly between patients and controls. The real-time PCR analysis showed that among healthy young adults, 12-12 subjects expressed CIAS1 mRNA in peripheral leukocytes significantly more abundantly than homozygote of non-12 repeat alleles subjects (P<0.05). Reporter gene assay of the CIAS1-VNTR in HL60 stimulated by lipopolysaccharides showed that the intronic sequence involving 12 repeat increased the expression of luciferase compared with 9, 7, and 6 repeats. Thus, we propose here the CIAS1 is associated with EH through the dominant expression of transcripts, which may depend on the CIAS1-VNTR genotype.
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Acknowledgements
The study was supported by a grant in aid (No.13204075) from Japanese Ministry of Education, Culture, Sports, Science and Technology. We thank Oyamada T and Nagashima K for technical assistance. We thank Drs Kario, Hoshide S, Sugimoto K, Ishikawa K, Sakamoto A, (Jichi Medical School), Sekiguchi T, and Hara K (Nasu minami) Ohishi T (Ohishi medical clinic) for sample correction.
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Appendix
The Study Group of Millennium Genome Project for Hypertension:
Chairman: Tetsuro Miki (Department of Geriatric Medicine, Ehime University School of Medicine, Ehime)
Michio Yasunami, Akinori Kimura (Department of Molecular Pathogenesis, Medical Research Inst., Tokyo Medical and Dental University), Akira Hata, (Chiba University Graduate School of Medicine, Chiba), Toshio Saruta (Department of Internal Medicine, School of Medicine, Keio University), M Yokota (Department of Clinical Pathophysiology, Nagoya University, Graduate School of Medicine), Tomohiro Katsuya, Toshio Ogihara (Department of Geriatric Medicine, Osaka University Graduate School of Medicine), Hirotsugu Ueshima (Department of Health Science, Shiga University of Medical Science), Katsuhiko Kohara, Yasuharu Tabara, Jun Nakura, Tetsuro Miki (Department of Geriatric Medicine, Ehime University School of Medicine), Sumio Sugano (Human Genome Center, Institute of Medical Science, University of Tokyo), Masayoshi Soma, Tomohiro Nakayama (Second Department of Internal Medicine, and Division of Receptor Biology, Advanced Medical Research Center, Nihon University School of Medicine), Norihiro Kato (Department of Gene Diagnostics and Therapeutics, Research Institute, International Medical Center of Japan), Ichiro Kishimoto, Kazuwa Nakao (Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine), Yuhei Kawano, Kei Kamide (Division of Hypertension and Nephrology, Department of Medicine, National Cardiovascular Center), Naoharu Iwai, Toshiyuki Miyata (Research Institute, National Cardiovascular Center), Takayuki Morisaki, (Department of Bioscience, National Cardiovascular Center Research Institute),Hitonobu Tomoike (Division of Preventive Cardiology, National Cardiovascular Center), Tsutomu Yamazaki (Department of Pharmacoepidemiology, Graduate School of Medicine,Faculty of Medicine, University of Tokyo), Katsushi Tokunaga, (Graduate School of Medicine Faculty, Intemational Health, Intemational Biomedical Sciences, University of Tokyo), Satoshi Umemura, Nobuhito Hirawa (Department of Medicine II, Yokohama City University School of Medicine), Hiroyuki Mano (Division of Functional Genomics, Jichi Medical School), Sadahiko Iwamoto (Division of Human Genetics, Center for Community Medicine, Jichi Medical School).
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Omi, T., Kumada, M., Kamesaki, T. et al. An intronic variable number of tandem repeat polymorphisms of the cold-induced autoinflammatory syndrome 1 (CIAS1) gene modifies gene expression and is associated with essential hypertension. Eur J Hum Genet 14, 1295–1305 (2006). https://doi.org/10.1038/sj.ejhg.5201698
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DOI: https://doi.org/10.1038/sj.ejhg.5201698
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