Key result
Derived SNP2/3 in cis with p.Y111C is linked to ~54% lower symptom risk in LQT1.
Why the study?
Reports have been conflicting regarding the allele-specific gene suppression effects of 3'UTR-KCNQ1 single nucleotide polymorphisms in long QT syndrome type 1 populations.
Do 3'UTR-KCNQ1 single nucleotide polymorphisms modify the clinical phenotype in a long QT syndrome type 1 founder population?
Observational (n=232)
Do 3'UTR-KCNQ1 single nucleotide polymorphisms modify the clinical phenotype in a long QT syndrome type 1 founder population?
Absolute Event Rate: 32% vs 69%
p-value: p=0.010
Specific 3'UTR-KCNQ1 SNPs exert allele-specific modifying effects on the symptomatic phenotype in LQT1, potentially explaining the variable incidence of cardiac events in heterozygous carriers of the p.Y111C mutation.
3'UTR-KCNQ1 SNPs may modify LQT1 symptoms; leaves open their utility for risk stratification pending validation.
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 KCNQ1 gene in long QT syndrome type 1 (LQT1) populations. Here we assess the allele‐specific effects of 3 previously published 3'UTR‐ KCNQ1 's SNPs in a LQT1 founder population segregating a dominant‐negative mutation. Methods and Results Bidirectional sequencing of the KCNQ1 ' s 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 in cis with p.Y111C (89%). Allele‐specific association analyses, corrected using a relatedness matrix, were performed between 3'UTR‐ KCNQ1 SNP genotypes and clinical phenotypes. SNP1 in trans was associated with a significantly higher proportion of symptomatic phenotype compared with no derived SNP1 allele in trans (58% versus 32%, corrected P =0.027). SNP2/3 in cis was associated with a significantly lower proportion of symptomatic phenotype compared with no derived SNP2/3 allele in cis (32% versus 69%, corrected P =0.010). Conclusions Allele‐specific modifying effects on symptomatic phenotype of 3'UTR‐ KCNQ1 SNPs rs2519184, rs8234, and rs107980 were seen in a LQT1 founder population segregating a dominant‐negative mutation. The high prevalence of suppressive 3'UTR‐ KCNQ1 SNPs segregating with the founder mutation could contribute to the previously documented low incidence of cardiac events in heterozygous carriers of the p.Y111C KCNQ1 mutation.
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Winbo et al. (2022) conducted an observational in Long QT syndrome type 1 (LQT1) (n=232). Derived SNP2/3 (rs8234 and rs107980) in cis vs. No derived SNP2/3 allele in cis was evaluated on Symptomatic phenotype (p=0.010). Derived SNP2/3 in cis with p.Y111C was associated with a lower proportion of symptomatic phenotype compared to no derived allele (32% vs 69%, P=0.010) in a LQT1 founder population.
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