Abstract 2967: Long QT Syndrome Genes Modulate The Effect Of NOS1AP Haplotypes On Cardiac Repolarization
Long QT syndrome (LQTS) is an inherited arrhythmogenic disease characterized by prolonged QT interval and sudden death. LQTS is caused by mutations in genes encoding different subunits of cardiac ion channels. Based on the evidence that polymorphisms in the NOS1AP gene (encoding a neural nitric oxide synthase adaptor protein) modulate the duration of QT interval in the general population, we assessed the relationship of three single nucleotide polymorphisms (SNPs) in the NOS1AP gene (rs4657139, rs16847548, rs12567209) with QTc in 442 LQTS probands, with 245 females (55.4%) and a mean QTc equal to 498.0± 46.2 ms. In 69% of patients a disease-causing mutation was identified in the following genes: 34% KCNQ1; 25% KCNH2, 10% SCN5A while in 31% of patients no mutation could be identified. Analyses were carried out with SPSS 13.0 or with the R haplo.stats package. Minor allele frequency accepted in the haplotype models was 0.05. None of the SNPs individually reached statistical genome-wide association levels with QTc duration. Since linkage disequilibrium among the polymorphisms was high (all D’>0.830), haplotype analysis was performed. The wild-type TTG haplotype showed a frequency of 0.546, whereas ATG and ATA frequencies were 0.075 and 0.063, respectively. Since SCN5A-, KCNE1- and KCNE2-genotyped groups comprised few LQTS patients (43, 8 and 4, respectively), comparisons within these groups could not be performed. In conclusion haplotype analysis showed that polymorphisms in NOS1AP gene can exert a relevant modulation of cardiac repolarization in LQTS patients and that the effect is dependent on the gene in which the LQTS causing mutation is located.