Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes

Abstract

Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants. Cases of drug-induced Torsades de Pointes (diTdP), treatment tolerant controls, and general population controls were ascertained across multiple sites using common definitions, and genotyped on the Illumina 610k or 1M-Duo BeadChips. Principal Components Analysis was used to select 216 Northwestern European diTdP cases and 771 ancestry-matched controls, including treatment-tolerant and general population subjects. With these sample sizes, there is 80% power to detect a variant at genome-wide significance with minor allele frequency of 10% and conferring an odds ratio of ≥2.7. Tests of association were carried out for each single nucleotide polymorphism (SNP) by logistic regression adjusting for gender and population structure. No SNP reached genome wide-significance; the variant with the lowest P value was rs2276314, a non-synonymous coding variant in C18orf21 (p = 3×10(-7), odds ratio = 2, 95% confidence intervals: 1.5-2.6). The haplotype formed by rs2276314 and a second SNP, rs767531, was significantly more frequent in controls than cases (p = 3×10(-9)). Expanding the number of controls and a gene-based analysis did not yield significant associations. This study argues that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs.

Figure 1. Plot of power versus odds ratios, using 700 controls (initial analysis) and then >4000 controls.

Figure 2. Population structure of the Caucasian cases and controls.

The red dots represent diTdP cases and blue dots represent controls (drug-exposed patients and population [POPRES] controls). The plot shows the first and second eigen vectors, which clearly separate the Caucasians into a Northwestern group (top) and other groups from Southern and Eastern Europe. The dense cluster on the lower left represents the subjects of Spanish origin from the POPRES collection. The final analysis included subjects with PC1<–0.03.

Figure 3. QQ plot of the results from logistic regression on the Northwestern European cohort.

The x axis is –log10 of the expected P-value and the y axis is –log10 of the observed P-values. Black solid lines denote the null distribution. The bulk of the values (red dots) closely follow the expectation under the null model (black line) showing that there is no significant inflation of test statistic due to factors such as population stratification. The tail end shows significant deviation from null model illustrating that there are a few observed significant associations.

Figure 4. Manhattan Plot of logistic regression on Northwestern European cohort.

Each dot represents a SNP. The x axis represents the position of the SNP on chromosome. The y axis represents the -log₁₀ of logistic regression P-value of the SNP in the case-control association study. rs2276314 and rs4799838 are marked in green with the P-value just below the genome-wide threshold (dashed line).

Figure 5. The effect size (OR) of rs2276314 in different drug-specific groups.

The numbers in parentheses are the numbers of cases for each group. The horizontal blue lines mark the 95% confidence interval of odds ratios.