We performed a genome-wide scan for sequence variants associating with atrial fibrillation in Iceland and followed up the most significant associations in samples from Iceland, Norway and USA. A sequence variant, rs7193343-T, in the ZFHX3 gene on chromosome 16q22 associated significantly with atrial fibrillation (combined OR=1.21, ). This variant also associates with ischemic

Objectives This study tested the hypothesis that response to antiarrhythmic drugs (AADs) is modulated by 3 common loci associated with atrial fibrillation (AF). Background Recent genome wide association studies (GWAS) have identified 3 loci, on chromosomes 4q25 (near PITX2), 16q22 (in ZFHX3), and 1q21 (in KCNN3), that associate with either typical or lone AF. These findings indicate that variable mechanisms contribute to AF susceptibility, and suggest that response to therapy may be genotype-dependent. Methods We studied 478 and 198 Caucasian patients respectively in the discovery cohort and validation cohort, prospectively enrolled in the Vanderbilt AF Registry. Response was defined prospectively as successful rhythm control if the patient remained on the same AAD therapy for a minimum of 6 months with ≥ 75% reduction in symptomatic AF burden. We also evaluated AF recurrence by 12 lead ECG at 3, 6 and 12 months. Symptomatic patients were also given 24-48-hour Holter monitor or 30-days event recorder when AF recurrence was not captured by 12 lead ECG. Results In the discovery cohort, 399 (83%) were successfully rhythm-controlled. Multiple clinical variables (including age, hypertension, lone AF) failed to significantly predict response to AADs. By contrast single nucleotide polymorphism (SNP) rs10033464 at 4q25 was an independent predictor of successful rhythm control in patients with Typical AF carrying the ancestral allele (wild type) vs. carriers of variant allele (odds ratio [OR] 4.7, [95% confidence interval [CI] 1.83-12, P=0.0013. In the validation cohort, 143 (72%) patients met the criteria for successful rhythm control and rs10033464 was again an independent predictor of successful rhythm control, OR: 1.5, 95% CI: 1.02-3.06, P = 0.04. This SNP (rs10033464) was an independent predictor of AF recurrence in the discovery (39% AF recurrence) and validation cohort (38% AF recurrence); OR: 3.27, 95% CI: 1.7–6, P<0.001 and OR: 4.3, 95% CI: 1.98–9.4, P<0.001 respectively. Conclusions These results suggest that a common SNP on chromosome 4q25 associated with AF modulates response to AAD therapy and points to a potential role for stratification of therapeutic approaches by genotype.

Background Drug-induced long QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. Here, we tested the hypothesis that common variants in key genes controlling cardiac electrical properties modify the risk of diLQTS. Methods and Results In a case-control setting, we included 176 patients of European descent from North America and Europe with diLQTS, defined as documented torsades de pointes during treatment with a QT prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed <50 msec QT lengthening during initiation of therapy with a QT-prolonging drug, and 837 controls from the population based KORA study. Subjects were successfully genotyped at 1,424 single nucleotide polymorphisms (SNPs) in 18 candidate genes including 1,386 SNPs tagging common haplotype blocks, and 38 non-synonymous ion channel gene SNPs. For validation we used a set of cases (n=57) and population-based controls of European descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confidence interval: 3.5–22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed controls, and 1.8% of population controls. In the validation cohort the variant allele was present in 3.5% of cases, and in 1.4% of controls. Conclusions This high-density candidate SNP approach identified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction torsades de pointes.

Objectives This study tested the hypothesis that two common polymorphisms in the chromosome 4q25 region that have been associated with atrial fibrillation (AF) contribute to the variable penetrance of familial AF. Background Although mutations in ion channels, gap junction proteins, and signaling molecules have been described for Mendelian forms of AF, penetrance is highly variable. Recent studies have consistently identified 2 common single nucleotide polymorphisms (SNPs) in the chromosome 4q25 region as independent AF susceptibility alleles. Methods We studied 11 families in which AF was present in ≥2 individuals who also shared a candidate gene mutation. These mutations were identified in all subjects with familial lone AF (n=33) as well as apparently unaffected family members (age >50 yrs with no AF; n=17). Results Mutations were identified in SCN5A (n=6); NPPA (n=2); KCNQ1 (n=1); KCNA5 (n=1) and NKX2.5 (n=1). In genetic association analyses, un-stratified and stratified according to age of onset of AF and unaffected age > 50 yrs, there was a highly statistically significant association between the presence of both common (rs2200733, rs10033464) as well as rare variants and AF (un-stratified P=1×10−8; stratified [age of onset <50 yrs and unaffected age >50 yrs], P=7.6×10−5) (un-stratified P<0.0001; stratified [age of onset <50 yrs and unaffected age >50 yrs], P<0.0001). Genetic association analyses showed that the presence of common 4q25 risk alleles predicted whether carriers of rare mutations developed AF (P = 2.2×10−4). Conclusions Common AF-associated 4q25 polymorphisms modify the clinical expression of latent cardiac ion channel and signaling molecule gene mutations associated with familial AF. These findings support the idea that the genetic architecture of AF is complex and includes both rare and common genetic variants.

Background The degree of QT prolongation by drug is highly variable and related to risk for polymorphic ventricular tachycardia due to drugs. Objective to determine factors that affect the degree of QT prolongation by drugs. Methods QT and QTc were measured before and after administration of the QT-prolonging drug ibutilide in 253 normal volunteers aged 18-40 years. Drug effect on QTc prolongation was defined as ΔQTc = QTc after drug minus QTc before drug. Results Ibutilide prolonged QT from 396 ± 31 ms to 418 ± 39 ms (P<0.001) and QTc from 406 ± 15 ms to 446 ± 33 ms (P<0.001). The ΔQTc did not correlate with baseline QTc (Pearson correlation 0.016, P = 0.8). Post-drug QTc was correlated weakly with pre-drug QTc (Pearson correlation 0.484, p<0.001), and strongly with ΔQTc (Pearson correlation 0.882, P < 0.001). ΔQTc was identical for men and women (39 ± 29 ms vs. 39 ± 27 ms, P = 0.9), but displayed significant differences among body mass index categories (P<0.001). Overweight (48 ± 27 ms) and obese (61 ± 31 ms) subjects had significantly more QT prolongation by drug than normal (31 ± 25 ms) or underweight (24 ± 12 ms) subjects. Conclusions QT prolongation by ibutilide does not correlate to baseline QTc, and does not differ between men and women. Overweight and obese subjects have greater drug effect on QTc than subjects with normal or low body mass index. These findings have implications for drug-induced long QT syndrome.