A novel microsatellite polymorphism of sodium channel beta1-subunit gene (SCN1B) may underlie abnormal cardiac excitation manifested by coved-type ST-elevation compatible with Brugada syndrome in Japanese.
OBJECTIVE
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Department of Pharmacotherapy, Meiji Pharmaceutical University, Kiyose-shi, Tokyo, 204-8588, Japan. smridron@my-pharm.ac.jp
R
R
Ogawa
R
R
Kishi
A
A
Takagi
I
I
Sakaue
H
H
Takahashi
N
N
Matsumoto
K
K
Masuhara
K
K
Nakazawa
S
S
Kobayashi
F
F
Miyake
H
H
Echizen
D000328:Adult; D000367:Age Factors; D000368:Aged; D044466:Asian People; D053840:Brugada Syndrome / Q000235:genetics*; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007564:Japan; D008012:Lidocaine / Q000031:analogs & derivatives; D016015:Logistic Models; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012737:Sex Factors; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000235:genetics*; D062547:Voltage-Gated Sodium Channel beta-1 Subunit; D062548:Voltage-Gated Sodium Channel beta-2 Subunit
D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C470379:SCN1B protein, human; C117620:SCN2B protein, human; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D062547:Voltage-Gated Sodium Channel beta-1 Subunit; D062548:Voltage-Gated Sodium Channel beta-2 Subunit; D008012:Lidocaine; C042288:pilsicainide