Rhee Eun-Jung, Oh Ki-Won, Lee Won-Young, Kim Se-Yeon, Jung Chan-Hee, Kim Byung-Jin, Sung Ki-Chul, Kim Bum-Su, Kang Jin-Ho, Lee Man-Ho, Kim Sun-Woo, Park Jung-Roe
Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Jongro-Ku, Seoul 110-746, South Korea.
Metabolism. 2006 Oct;55(10):1344-51. doi: 10.1016/j.metabol.2006.05.020.
The Klotho knockout mouse is thought to be a good animal model for human aging. Recent studies have reported on the association of KLOTHO gene mutation with cardiovascular disease in humans. We observed the frequencies of single nucleotide polymorphisms, that is, G-395A in the promoter region, C1818T in exon 4, and a functional variant, KL-VS, of KLOTHO gene in Koreans, and we investigated their relationships with the presence of coronary artery disease (CAD) in patients who had undergone coronary angiograms. A total of 274 subjects who underwent coronary angiograms because of chest pain were enrolled, and their blood pressure, body mass index, fasting blood glucose level, and lipid profiles were measured. Genotypings were performed on samples of their blood with real-time polymerase chain reaction. Two single nucleotide polymorphisms, G-395A and C1818T, complied with Hardy-Weinberg equilibrium. For the KL-VS genotype, 1 homozygote subject for the adverse allele was detected among the entire population (GG for F352V and CC for C370S). When the subjects were classified into 4 groups according to the number of stenotic vessels, there were no differences among the mean values of the cardiovascular risk factors, except for age and the fasting blood glucose levels, which showed a significant difference between that of the normal and the diseased vessel groups. There were no differences in the prevalence of CAD according to the genotypes of the G-395A polymorphism; however, for the C1818T polymorphism, those subjects with the T allele showed a lower prevalence of CAD than those with the CC genotype. When the subjects were divided into 2 groups according to age, in the group younger than 60 years, T allele carriers of the C1818T polymorphism showed a lower prevalence of CAD than did the noncarriers. In the group older than 60 years, A allele carriers of the G-395A polymorphism showed a lower prevalence of CAD than did the noncarriers. On the haplotype analysis, the GG-CC haplotype showed an increased risk for CAD with an odds ratio of 2.594 (95% confidence interval, 1.385-4.858; P = 0.003). Differential effects of age were observed in the association of KLOTHO G-395A and C1818T polymorphisms with CAD in Koreans. The KL-VS variant seems to be rarely found in the Korean population. These results infer the possibility of the KLOTHO gene being a candidate gene of atherosclerosis in humans, and further research on this topic needs to be done.
klotho基因敲除小鼠被认为是研究人类衰老的良好动物模型。最近的研究报道了KLOTHO基因突变与人类心血管疾病的关联。我们观察了韩国人群中KLOTHO基因单核苷酸多态性的频率，即启动子区域的G-395A、外显子4的C1818T以及一个功能性变体KL-VS，并研究了它们与接受冠状动脉造影患者的冠状动脉疾病（CAD）存在情况的关系。共有274名因胸痛接受冠状动脉造影的受试者入组，测量了他们的血压、体重指数、空腹血糖水平和血脂谱。用实时聚合酶链反应对他们的血液样本进行基因分型。两个单核苷酸多态性G-395A和C1818T符合哈迪-温伯格平衡。对于KL-VS基因型，在整个人群中检测到1名不良等位基因纯合子受试者（F352V为GG，C370S为CC）。当根据狭窄血管数量将受试者分为4组时，除年龄和空腹血糖水平外，心血管危险因素的平均值在各组间无差异，年龄和空腹血糖水平在正常血管组和病变血管组之间存在显著差异。根据G-395A多态性的基因型，CAD患病率无差异；然而，对于C1818T多态性而言，携带T等位基因的受试者CAD患病率低于CC基因型受试者。当根据年龄将受试者分为2组时，在60岁以下组中，C1818T多态性的T等位基因携带者CAD患病率低于非携带者。在60岁以上组中，G-395A多态性的A等位基因携带者CAD患病率低于非携带者。单倍型分析显示，GG-CC单倍型使CAD风险增加，优势比为2.594（95%置信区间为1.385 - 4.858；P = 0.003）。在韩国人群中，观察到KLOTHO基因G-395A和C1818T多态性与CAD关联存在年龄差异效应。KL-VS变体在韩国人群中似乎很少见。这些结果提示KLOTHO基因有可能是人类动脉粥样硬化的候选基因，并需要对此主题进行进一步研究。
