Polymorphisms at the Werner locus: II. 1074Leu/Phe, 1367Cys/Arg, longevity, and atherosclerosis
Polymorphisms at the Werner locus: II. 1074Leu/Phe, 1367Cys/Arg, longevity, and atherosclerosis
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DOI：
10.1002/1096-8628(20001211)95:4
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发表时间：
2000-12-11
期刊：
影响因子：
--
通讯作者：
Oshima, J
中科院分区：
文献类型：
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作者：
Castro, E;Edland, SD;Oshima, J
Werner综合征（WS）是由WRN基因座的常染色体隐性无效突变引起的早衰样综合征。WRN基因编码一个180 kD的核蛋白，包含核酸外切酶和解旋酶结构域。WS患者发生各种形式的动脉硬化，特别是动脉粥样硬化和中膜钙质沉着症。在患有WS的高加索受试者中最常见的死亡原因是心肌梗死。先前的研究已经确定了WRN内的特定多态性，其可以调节动脉粥样硬化的风险。对1074 Leu/Phe和1367 Cys/Arg多态性的人群研究旨在评估WRN在动脉粥样硬化形成中的作用。芬兰和墨西哥人群中1074 Leu/Phe多态性的频率显示1074 Phe/Phe基因型的年龄依赖性下降。在墨西哥新生儿中，而不是在芬兰新生儿中，1074 Leu/Phe和1367 Cys/Arg多态性处于连锁不平衡。在冠状动脉疾病受试者中，1074 Phe等位基因与冠状动脉狭窄呈基因剂量依赖性相关。此外，与1367 Cys/Cys或1367 Cys/Arg基因型相比，1367 Arg/Arg基因型预测冠状动脉闭塞程度较低，如通过NV 50测量的，然而，这些趋势未达到统计学显著性。来自墨西哥缺血性中风患者的样本显示出与墨西哥成年人对照组不同的单倍型频率趋势。这些数据支持这样的假设，即WRN不仅可以介导WS，而且还可以调节更常见的年龄相关疾病，并且可能调节基本的衰老过程，（C）2000 Wiley-Liss，Inc.
Werner syndrome (WS) is a progeroid syndrome caused by autosomal recessive null mutations at the WRN locus. The WRN gene encodes a nuclear protein of 180 kD that contains both exonuclease and helicase domains. WS patients develop various forms of arteriosclerosis, particularly atherosclerosis, and medial calcinosis, The most common cause of death in Caucasian subjects with WS is myocardial infarction, Previous studies have identified specific polymorphisms within WRN that may modulate the risk of atherosclerosis. Population studies of the 1074Leu/Phe and 1367Cys/Arg polymorphisms were undertaken to evaluate the role of WRN in atherogenesis, Frequencies of the 1074Leu/Phe polymorphisms in Finnish and Mexican populations revealed an age-dependent decline of 1074Phe/Phe genotype. In Mexican newborns, but not in Finnish newborns, the 1074Leu/Phe and 1367Cys/Arg polymorphisms were in linkage disequilibrium, Among coronary artery disease subjects, there was a tendency for the 1074Phe allele to be associated with coronary stenosis in a gene dose-dependent manner. Furthermore, the 1367Arg/Arg genotype predicted a lower degree of coronary artery occlusion, as measured by NV50, when compared to the 1367Cys/Cys or 1367Cys/Arg genotypes, However, these tendencies did not achieve statistical significance. Samples from Mexican patients with ischemic stroke showed a trend of haplotype frequencies different from that in a control group of Mexican adults. These data support the hypothesis that WRN may mediate not only WS, but may also modulate more common age-related disorders and, perhaps, a basic aging process, (C) 2000 Wiley-Liss, Inc.