期刊
CIRCULATION
卷 120, 期 17, 页码 1657-1663出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.109.879643
关键词
arrhythmia; genetics; KCNQ1 protein, human; long-QT syndrome; nitric oxide synthase
资金
- National Institutes of Health [HL068880, NS27941, MH48858]
- Telethon-Italy [GGP07016]
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.)
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