Modulating effects of age and gender on the clinical course of long QT syndrome by genotype.
OBJECTIVE
We aimed to determine whether long QT syndrome (LQTS) genotype has a differential effect on clinical course of disease in male and female children and adults after adjustment for QTc duration.


BACKGROUND
Genotype influences clinical course of the LQTS; however, data on the effect of age and gender on this association are limited.


METHODS
The LQTS genotype, QTc duration, and follow-up were determined in 243 cases of LQTS caused by the KCNQ1 potassium channel gene mutations (LQT1), 209 cases of LQTS caused by the HERG potassium channel gene mutations (LQT2), and 81 cases of LQTS caused by the SCN5A sodium channel gene mutation (LQT3) gene carriers. The probability of cardiac events (syncope, aborted cardiac arrest, or sudden death) was analyzed by genotype, gender, and age (children < or = 15 years and adults 16 to 40 years). In addition, the risk of sudden death and lethality of cardiac events were evaluated in 1,075 LQT1, 976 LQT2, and 324 LQT3 family members from families with known genotype.


RESULTS
During childhood, the risk of cardiac events was significantly higher in LQT1 males than in LQT1 females (hazard ratio [HR] = 1.72), whereas there was no significant gender-related difference in the risk of cardiac events among LQT2 and LQT3 carriers. During adulthood, LQT2 females (HR = 3.71) and LQT1 females (HR = 3.35) had a significantly higher risk of cardiac events than respective males. The lethality of cardiac events was highest in LQT3 males and females (19% and 18%), and higher in LQT1 and LQT2 males (5% and 6%) than in LQT1 and LQT2 females (2% for both). CONCLUSIONS; Age and gender have different, genotype-specific modulating effects on the probability of cardiac events and electrocardiographic presentation in LQT1 and LQT2 patients.
Zareba
Wojciech
W
Department of Medicine, Heart Research Follow-up Program, Medical Center, University of Rochester School of Medicine, Rochester, NY 14642-8653, USA. heartwz@heart.rochester.edu
Moss
Arthur J
AJ
Locati
Emanuela H
EH
Lehmann
Michael H
MH
Peterson
Derick R
DR
Hall
W Jackson
WJ
Schwartz
Peter J
PJ
Vincent
G Michael
GM
Priori
Silvia G
SG
Benhorin
Jesaia
J
Towbin
Jeffrey A
JA
Robinson
Jennifer L
JL
Andrews
Mark L
ML
Napolitano
Carlo
C
Timothy
Katherine
K
Zhang
Li
L
Medina
Aharon
A
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015221:Potassium Channels / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012737:Sex Factors; D015222:Sodium Channels / Q000235:genetics; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C568320:SCN5A protein, human; D015222:Sodium Channels; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG