Abstract 11984: The KCNQ1 rs2074238 Polymorphism Is a Genetic Modifier of Cardiac Risk in Long QT Syndrome
Long QT syndrome (LQTS) is a rare genetic cardiac disease with clinical variability, characterized by a prolongation of the QT interval on electrocardiogram and risk of syncope and sudden death. Stratifying the risk of cardiac events is important for the clinical management of the LQTS patients. Thus, we investigated the role of genetic variants as modifiers of cardiac event risk in LQTS patients carrying heterozygous KCNQ1 or KCNH2 mutations. We genotyped 25 candidate polymorphisms based on either their association with QTc duration (QT corrected for heart rate) in the general population, or their role in adrenergic response, in a matched case-control study including 112 LQTS patient duos from France, Italy and Japan. Duos were composed of two relatives harboring the same mutation; one of whom experienced cardiac events whereas the other was asymptomatic and untreated. As expected, we observed that the presence of cardiac events was associated with longer QTc (490.7 ± 49.1 ms in symptomatic vs. 462.2 ± 39.8 ms in asymptomatic patients, p=0.007). The NOS1AP rs12029454 A-allele showed suggestive evidence of association with longer QTc (484.0 ± 49.6 ms for carriers vs. 471.2 ± 44.3 ms for non-carriers, p=0.006), and this effect was homogeneous in all ethnic groups. Carriers of the KCNQ1 rs2074238 T-allele tended to have shorter QTc (464.1 ± 34.9 ms for carriers vs. 479.1 ± 44.0 ms for non-carriers, p=0.04). This effect was restricted to the Caucasian population because this SNP (Single Nucleotide Polymorphism) was not polymorphic in our Japanese cohort. Interestingly, the rs2074238 T-allele was in addition significantly associated with a decreased risk of cardiac events (OR=0.376 [0.268-0.528], p=0.002). Our results provide the first evidence that rs2074238 in KCNQ1 could be a risk modifier for cardiac events in Caucasian LQTS patients. After confirmation in additional populations, this SNP may be clinically useful for risk stratification in LQTS patients.
- © 2011 by American Heart Association, Inc.