Ogawa R, Kishi R, Takagi A, Sakaue I, Takahashi H, Matsumoto N, Masuhara K, Nakazawa K, Kobayashi S, Miyake F, Echizen H
Department of Pharmacotherapy, Meiji Pharmaceutical University, Kiyose-shi, Tokyo, 204-8588, Japan.
Int J Clin Pharmacol Ther. 2010 Feb;48(2):109-19. doi: 10.5414/cpp48109.
Brugada syndrome (BrS) is a rare sodium channelopathy typically seen in middle-aged, Southeast Asian males conferring high risks of cardiac sudden death. Loss-of-function mutations in SCN5A encoding the alpha-subunit of cardiac sodium channels may account partially for its etiology. We aimed to study whether mutations in the beta-subunits of sodium channel (SCN1B and SCN2B) would also be associated with abnormal cardiac excitation in BrS.
85 Japanese patients suspected to have BrS undertook a diagnostic challenge test with a sodium channel blocker, pilsicainide. Genetic screenings were performed for SCN5A, SCN1B and SCN2B by PCR-SSCP and direct sequence of amplicons in the patients and 50 healthy controls.
30 patients exhibited BrS-like ECG pattern (i.e., a coved-type ST-segment elevation) either at baseline or after the drug challenge. Genetic screenings revealed a sequence variation (p.R190Q) and 3 polymorphisms (p.H558R, p.R1193Q, IVS24+53T > C) in SCN5A, a sequence variation (g.-26G > T) and 2 polymorphisms (IVS1+53G > T and IVS3 +2996(TTA)8-15) in SCN1B and 2 polymorphisms (IVS2+27A > G, IVS2+76G > A) in SCN2B. A logistic analysis revealed that male, middle age (40 - 59 years of age) and IVS3+2996(TTA)8 of SCN1B were significantly (p < 0.05) associated with the development of BrS-like ECG pattern with odds ratios (95% confidence intervals) of 5.9 (1.8 - 19.6), 2.9 (1.4 - 6.1) and 2.3 (1.1 - 4.9), respectively. While the IVS3+2996(TTA)8 allele has not been reported in Caucasians previously, its allelic frequency in the patients exhibiting the BrS-like ECG pattern (0.250) was comparable to that in the healthy controls (0.260).
The IVS3+ 2996(TTA)8 allele commonly seen in Japanese would not be pathogenic itself but may render male, middle-aged Japanese more susceptible to BrS.
Brugada综合征（BrS）是一种罕见的钠通道病，多见于东南亚中年男性，具有较高的心源性猝死风险。编码心脏钠通道α亚基的SCN5A功能丧失突变可能部分解释其病因。我们旨在研究钠通道β亚基（SCN1B和SCN2B）的突变是否也与BrS患者的心脏异常兴奋有关。
85名疑似患有BrS的日本患者接受了钠通道阻滞剂吡西卡尼的诊断激发试验。通过PCR-SSCP以及对患者和50名健康对照者扩增子的直接测序，对SCN5A、SCN1B和SCN2B进行基因筛查。
30名患者在基线时或药物激发后表现出类似BrS的心电图模式（即穹窿型ST段抬高）。基因筛查发现SCN5A有一个序列变异（p.R190Q）和3个多态性（p.H558R、p.R1193Q、IVS24+53T>C），SCN1B有一个序列变异（g.-26G>T）和2个多态性（IVS1+53G>T和IVS3 +2996(TTA)8-15），SCN2B有2个多态性（IVS2+27A>G、IVS2+76G>A）。逻辑分析显示，男性、中年（40-59岁）以及SCN1B的IVS3+2996(TTA)8与类似BrS心电图模式的发生显著相关（p<0.05），优势比（95%置信区间）分别为5.9（1.8-19.6）、2.9（1.4-6.1）和2.3（1.1-4.9）。虽然IVS3+2996(TTA)8等位基因此前在白种人中未被报道，但其在表现出类似BrS心电图模式的患者中的等位基因频率（0.250）与健康对照者（0.260）相当。
在日本人中常见的IVS3+ 2996(TTA)8等位基因本身不具有致病性，但可能使日本中年男性更容易患BrS。
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