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
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
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DOI：
10.1038/sj.ejhg.5201698
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发表时间：
2006-12-01
影响因子：
5.2
通讯作者：
Iwamoto, Sadahiko
中科院分区：
文献类型：
--
作者：
Omi, Toshinori;Kumada, Maki;Iwamoto, Sadahiko
冷诱导自身炎症综合征1（CIAS 1）基因是CATERPILLER蛋白家族NALP亚家族成员，主要表达于外周血白细胞，通过激活NF-κ B B和caspase来调节细胞凋亡或炎症。最近的遗传分析表明，炎症和氧化应激相关基因在高血压的发展之间存在关联。这是第一个遗传学研究表明CIAS 1基因与原发性高血压（EH）易感性之间的关联。高血压患者CIAS 1内含子4位点VNTR多态性中12个重复等位基因纯合子的频率显著高于对照组（987例，924例）（P = 0.030;比值比1.24）。男性随机人群中12重复等位基因纯合子的收缩压均值比非12重复等位基因纯合子的收缩压均值高6.4mmHg（P = 0.009）。CIAS 1基因6个SNPs的频率在患者组和对照组之间差异无统计学意义。实时荧光定量PCR结果显示，在健康青年中，12-12重复等位基因个体的外周血白细胞CIAS 1 mRNA表达水平显著高于非12重复等位基因纯合子个体（P < 0.05）。报告基因分析表明，在脂多糖刺激的HL 60细胞中，CIAS 1-VNTR的12个重复的内含子序列与9个、7个和6个重复相比，增加了荧光素酶的表达。因此，我们在这里提出CIAS 1与EH通过转录本的显性表达相关，这可能取决于CIAS 1-VNTR基因型。
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-kappa 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.