NOS1AP Is a Genetic Modifier of the Long-QT Syndrome
NOS1AP Is a Genetic Modifier of the Long-QT Syndrome
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DOI：
10.1161/circulationaha.109.879643
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发表时间：
2009-10-27
期刊：
影响因子：
37.8
通讯作者：
George, Alfred L., Jr.
中科院分区：
文献类型：
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作者：
Crotti, Lia;Monti, Maria Cristina;George, Alfred L., Jr.
背景：先天性长qt综合征（LQTS）是一种易致心源性猝死的遗传异质性疾病，除原发突变外的遗传因素可能改变危及生命事件的发生概率。最近的证据表明，NOS1AP的常见变异与一般人群的qt间隔时间有关。方法和结果：我们通过基于家族的关联分析，验证了NOS1AP常见变异会改变南非LQTS人群（500名受试者，205名突变携带者）的临床表现风险和qt间隔延长程度的假设，分离出KCNQ1 （A341V）的始创突变。NOS1AP变异与症状的发生（rs4657139, P = 0.019; rs16847548, P = 0.003）、临床严重程度显著相关，表现为心脏骤停和猝死的概率更高（rs4657139, P = 0.028; rs16847548, P = 0.014），在所有突变携带者中，QT间期在前40%的概率更高（rs4657139, P = 0.03; rs16847548, P = 0.03）。结论：这些发现表明，NOS1AP，一个首次被发现影响一般人群QTc间隔的基因，也会影响LQTS患者的猝死风险。NOS1AP遗传变异与危及生命的心律失常风险的关联表明，该基因是LQTS的遗传修饰因子，在其他LQTS人群中得到验证后，这一知识可能在临床上对该疾病患者的风险分层有用。(循环。2009;120:1657 - 1663)。
Background -In congenital long-QT syndrome (LQTS), a genetically heterogeneous disorder that predisposes to sudden cardiac death, genetic factors other than the primary mutation may modify the probability of life-threatening events. Recent evidence indicates that common variants in NOS1AP are associated with the QT-interval duration in the general population.Methods and Results-We tested the hypothesis that common variants in NOS1AP modify the risk of clinical manifestations and the degree of QT-interval prolongation in a South African LQTS population (500 subjects, 205 mutation carriers) segregating a founder mutation in KCNQ1 (A341V) using a family-based association analysis. NOS1AP variants were significantly associated with the occurrence of symptoms (rs4657139, P = 0.019; rs16847548, P = 0.003), with clinical severity, as manifested by a greater probability for cardiac arrest and sudden death (rs4657139, P = 0.028; rs16847548, P = 0.014), and with greater likelihood of having a QT interval in the top 40% of values among all mutation carriers (rs4657139, P = 0.03; rs16847548, P = 0.03).Conclusions-These findings indicate that NOS1AP, a gene first identified as affecting the QTc interval in a general population, also influences sudden death risk in subjects with LQTS. The association of NOS1AP genetic variants with risk for life-threatening arrhythmias suggests that this gene is a genetic modifier of LQTS, and this knowledge may be clinically useful for risk stratification for patients with this disease, after validation in other LQTS populations. (Circulation. 2009;120:1657-1663.)