1. ¹Division of Human Genetics, Center for Community Medicine, Jichi Medical School, Tochigi, Japan
2. ²Department of Public Health, Graduate School of Medicine, Chiba University, Chiba, Japan
3. ³Department of Nephrology and Endocrinology, Advanced Medical Research Center, Nihon University School of Medicine, Tokyo, Japan
4. ⁴Second Department of Internal Medicine, Yokohama City University Medical School, Kanagawa, Japan
5. ⁵Department of Genetics, Radiation Effects Research Foundation, Hiroshima, Japan
6. ⁶Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
7. ⁷Department of Geriatric Medicine, Ehime University School of Medicine, Ehime, Japan
8. ⁸Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical School, Tochigi, Japan
9. ⁹Division of Functional Genomics, Jichi Medical School, Kawachigun, Tochigi, Japan

Correspondence: Professor S Iwamoto, Division of Human Genetics, Center for Community, Medicine, Jichi Medical School, Minamikawachi-machi, Tochigi 329-0498, Japan. Tel: 81 285 44 2111; Fax: 81 285 44 4902; E-mail: siwamoto@jichi.ac.jp

Received 6 October 2005; Revised 29 May 2006; Accepted 16 June 2006; Published online 26 July 2006.

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-B 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.