To Modify or Not to Modify: Allele-Specific Effects of 3'UTR- KCNQ1 Single Nucleotide Polymorphisms on Clinical Phenotype in a Long QT 1 Founder Population Segregating a Dominant-Negative Mutation

Background There are conflicting reports with regard to the allele-specific gene suppression effects of single nucleotide polymorphisms (SNPs) in the 3'untranslated region (3'UTR) of the gene in long QT syndrome type 1 (LQT1) populations. Here we assess the allele-specific effects of 3 previously published 3'UTR- 's SNPs in a LQT1 founder population segregating a dominant-negative mutation. Methods and Results Bidirectional sequencing of the ' 3'UTR was performed in the p.Y111C founder population (n=232, 147 genotype positive), with a minor allele frequency of 0.1 for SNP1 (rs2519184) and 0.6 for linked SNP2 (rs8234) and SNP3 (rs107980). Allelic phase was assessed in trios aided by haplotype data, revealing a high prevalence of derived SNP2/3 with p.Y111C (89%). Allele-specific association analyses, corrected using a relatedness matrix, were performed between 3'UTR- SNP genotypes and clinical phenotypes. SNP1 was associated with a significantly higher proportion of symptomatic phenotype compared with no derived SNP1 allele (58% versus 32%, corrected =0.027). SNP2/3 was associated with a significantly lower proportion of symptomatic phenotype compared with no derived SNP2/3 allele (32% versus 69%, corrected =0.010). Conclusions Allele-specific modifying effects on symptomatic phenotype of 3'UTR- SNPs rs2519184, rs8234, and rs107980 were seen in a LQT1 founder population segregating a dominant-negative mutation. The high prevalence of suppressive 3'UTR- SNPs segregating with the founder mutation could contribute to the previously documented low incidence of cardiac events in heterozygous carriers of the p.Y111C mutation.