Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis.

BACKGROUND: Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood. METHODS: Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval). RESULTS: We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (KCNQ1, KCNH2, and SCN5A), a controversial monogenic SCD gene (KCNE1), and novel genes (PAM and MFGE8) involved in cardiac conduction. Loss-of-function and pathogenic SCN5A variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (P=8.4×10-5). Similar variants in KCNQ1 and KCNH2 (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (P=4×10-25), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals. CONCLUSIONS: Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.

Genetic testing in Polynesian long QT syndrome probands reveals a lower diagnostic yield and an increased prevalence of rare variants.

BACKGROUND: New Zealand has a multiethnic population and a national cardiac inherited disease registry (Cardiac Inherited Disease Registry New Zealand [CIDRNZ]). Ancestry is reflected in the spectrum and prevalence of genetic variants in long QT syndrome (LQTS). OBJECTIVE: The purpose of this study was to study the genetic testing yield and mutation spectrum of CIDRNZ LQTS probands stratified by self-identified ethnicity. METHODS: A 15-year retrospective review of clinical CIDRNZ LQTS probands with a Schwartz score of ≥2 who had undergone genetic testing was performed. RESULTS: Of the 264 included LQTS probands, 160 (61%) reported as European, 79 (30%) NZ Maori and Pacific peoples (Polynesian), and 25 (9%) Other ethnicities, with comparable clinical characteristics across ethnic groups (cardiac events in 72%; age at presentation 28±19 years; corrected QT interval 512±55 ms). Despite comparable testing (5.3±1.4 LQTS genes), a class III-V LQTS variant was identified in 35% of Polynesian probands as compared with 63% of European and 72% of Other probands (P<.0001). Among variant-positive CIDRNZ LQTS probands (n=148), Polynesians were more likely to have non-missense variants (57% vs 39% and 25% in probands of European and Other ethnicity, respectively; P=.005) as well as long QT syndrome type 1-3 variants not reported elsewhere (71% vs European 22% and Other 28%; P<.0001). Variants found in multiple probands were more likely to be shared within the same ethnic group; P<.01). CONCLUSION: Genetic testing of Polynesian LQTS probands has a lower diagnostic yield, despite comparable testing and clinical disease severity. Rare LQTS variants are more common in Polynesian LQTS probands. These data emphasize the importance of increasing the knowledge of genetic variation in the Polynesian population.

Relation of total bilirubin and QT interval prolongation (from the Third National Health and Nutrition Examination Survey).

OBJECTIVE: The association of bilirubin with cardiovascular disease (CVD) is controversial. We sought to explore the association of total bilirubin (TB) levels with QT interval in a multiracial cohort. METHODS: A total of 6,627 participants (59.0 ± 13.3 years; 52.6% women, 49.7% Non-Hispanic Whites) without CVD from the Third National Health and Nutrition Examination Survey were included in this analysis. QT was automatically measured from digital 12-lead electrocardiogram in a central reading center. A multivariable logistic regression model was used to examine the cross-sectional association between tertiles of TB and prolonged QT interval (≥450 ms in men and ≥460 ms in women). RESULTS: The prevalence of prolonged QT was higher among those with higher levels of TB (prolonged QT prevalence was 4.7%, 6.8%, and 7.0% across TB lower (0-0.4 mg/dl), middle (0.5-1.6 mg/dl), and higher (0.70-4.30 mg/dl) tertiles, respectively). In a model adjusted for potential confounders, participants within the highest TB tertile had significantly greater odds of the prolonged QT interval (Odds ratios [95% confidence interval] 1.53 [1.16-2.02]) compared to those with bilirubin levels in the first tertile. Each 0.29 mg/dl increase in TB levels was associated with a 12% (p-value <.0001) increase in the prevalence of prolonged QT interval. This association was stronger in men than in women (interaction p-value = .04). CONCLUSION: Elevated bilirubin levels are associated with a prolonged QT interval. This finding extends our current knowledge on the relationship between serum bilirubin and CVD by demonstrating a link between higher TB and abnormal cardiac repolarization.

ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals.

BACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest. METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci. CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.

GWAS of the electrocardiographic QT interval in Hispanics/Latinos generalizes previously identified loci and identifies population-specific signals.

QT interval prolongation is a heritable risk factor for ventricular arrhythmias and can predispose to sudden death. Most genome-wide association studies (GWAS) of QT were performed in European ancestral populations, leaving other groups uncharacterized. Herein we present the first QT GWAS of Hispanic/Latinos using data on 15,997 participants from four studies. Study-specific summary results of the association between 1000 Genomes Project (1000G) imputed SNPs and electrocardiographically measured QT were combined using fixed-effects meta-analysis. We identified 41 genome-wide significant SNPs that mapped to 13 previously identified QT loci. Conditional analyses distinguished six secondary signals at NOS1AP (n = 2), ATP1B1 (n = 2), SCN5A (n = 1), and KCNQ1 (n = 1). Comparison of linkage disequilibrium patterns between the 13 lead SNPs and six secondary signals with previously reported index SNPs in 1000G super populations suggested that the SCN5A and KCNE1 lead SNPs were potentially novel and population-specific. Finally, of the 42 suggestively associated loci, AJAP1 was suggestively associated with QT in a prior East Asian GWAS; in contrast BVES and CAP2 murine knockouts caused cardiac conduction defects. Our results indicate that whereas the same loci influence QT across populations, population-specific variation exists, motivating future trans-ethnic and ancestrally diverse QT GWAS.

Population pharmacokinetics of moxifloxacin and its concentration-QT interval relationship modeling in Chinese healthy volunteers.

Moxifloxacin (MX) is an 8-methoxyquinolone antimicrobial drug, which is often used as a positive control in thorough QT (TQT) studies. In the present study we established the population pharmacokinetics model of MX and the relationship of MX concentrations with the QT and various corrected QT (QTc) intervals, and compared the results with other ethnicities. The MX data used for modeling were obtained from a published TQT interval prolongation study of antofloxacin with MX as the positive control. In this four-period crossover study, 24 adult Chinese healthy volunteers received either 200 or 400 mg of oral antofloxacin once daily, 400 mg of MX, or a placebo. Population concentration-effect models were used to investigate the relationship between MX concentrations and QT interval prolongation, baseline-adjusted QTc (ΔQTc), or ΔQTc adjusted with time-matched placebo corrections (ΔΔQTc). The influencing factors of MX PK and the concentration-QTc relationship were determined through covariate screening. Simulation studies were conducted in R2.30 by using the final model with the estimated population mean and intra-individual and inter-individual variability. The estimated pharmacokinetic parameters and the estimated slope of the MX concentration-QT/ΔQTc/ΔΔQTc relationship were described using models and were compared to results for other ethnicities from the literature. We showed that the population pharmacokinetic parameter estimates for total plasma clearance (CL/F), the volume of distribution of central compartment (Vc/F), the distributional clearance in plasma (Q), the volume of distribution of peripheral compartment (Vp/F), and the absorption rate constant (Ka) were 8.22 L/h, 104 L, 3.98 L/h, 37.7 L, and 1.81 1/h, respectively. There was no significant covariate included in the final model. QT interval prolongation of MX estimates ranging from 9.77 to 12.91 ms at the mean average maximum concentration of MX (4.36 µg/mL) and a mean slope ranging from 2.33 to 2.96 ms per µg/mL. In conclusion, no ethnic differences were observed for the MX pharmacokinetic parameters and QT interval prolongation.

Novel Variant in the ANK2 Membrane-Binding Domain Is Associated With Ankyrin-B Syndrome and Structural Heart Disease in a First Nations Population With a High Rate of Long QT Syndrome.

BACKGROUND: Long QT syndrome confers susceptibility to ventricular arrhythmia, predisposing to syncope, seizures, and sudden death. While rare globally, long QT syndrome is ≈15× more common in First Nations of Northern British Columbia largely because of a known mutation in KCNQ1. However, 2 large multigenerational families were affected, but negative for the known mutation. METHODS AND RESULTS: Long QT syndrome panel testing was carried out in the index case of each family, and clinical information was collected. Cascade genotyping was performed. Biochemical and myocyte-based assays were performed to evaluate the identified gene variant for loss-of-function activity. Index cases in these 2 families harbored a novel ANK2 c.1937C>T variant (p.S646F). An additional 16 carriers were identified, including 2 with structural heart disease: one with cardiomyopathy resulting in sudden death and the other with congenital heart disease. For all carriers of this variant, the average QTc was 475 ms (±40). Although ankyrin-B p.S646F is appropriately folded and expressed in bacteria, the mutant polypeptide displays reduced expression in cultured H9c2 cells and aberrant localization in primary cardiomyocytes. Furthermore, myocytes expressing ankyrin-B p.S646F lack normal membrane targeting of the ankyrin-binding partner, the Na/Ca exchanger. Thus, ankyrin-B p.S646F is a loss-of-function variant. CONCLUSIONS: We identify the first disease-causing ANK2 variant localized to the membrane-binding domain resulting in reduced ankyrin-B expression and abnormal localization. Further study is warranted on the potential association of this variant with structural heart disease given the role of ANK2 in targeting and stabilization of key structural and signaling molecules in cardiac cells.

Fine mapping of QT interval regions in global populations refines previously identified QT interval loci and identifies signals unique to African and Hispanic descent populations.

BACKGROUND: The electrocardiographically measured QT interval (QT) is heritable and its prolongation is an established risk factor for several cardiovascular diseases. Yet, most QT genetic studies have been performed in European ancestral populations, possibly reducing their global relevance. OBJECTIVE: To leverage diversity and improve biological insight, we fine mapped 16 of the 35 previously identified QT loci (46%) in populations of African American (n = 12,410) and Hispanic/Latino (n = 14,837) ancestry. METHODS: Racial/ethnic-specific multiple linear regression analyses adjusted for heart rate and clinical covariates were examined separately and in combination after inverse-variance weighted trans-ethnic meta-analysis. RESULTS: The 16 fine-mapped QT loci included on the Illumina Metabochip represented 21 independent signals, of which 16 (76%) were significantly (P-value≤9.1×10-5) associated with QT. Through sequential conditional analysis we also identified three trans-ethnic novel SNPs at ATP1B1, SCN5A-SCN10A, and KCNQ1 and three Hispanic/Latino-specific novel SNPs at NOS1AP and SCN5A-SCN10A (two novel SNPs) with evidence of associations with QT independent of previous identified GWAS lead SNPs. Linkage disequilibrium patterns helped to narrow the region likely to contain the functional variants at several loci, including NOS1AP, USP50-TRPM7, and PRKCA, although intervals surrounding SLC35F1-PLN and CNOT1 remained broad in size (>100 kb). Finally, bioinformatics-based functional characterization suggested a regulatory function in cardiac tissues for the majority of independent signals that generalized and the novel SNPs. CONCLUSION: Our findings suggest that a majority of identified SNPs implicate gene regulatory dysfunction in QT prolongation, that the same loci influence variation in QT across global populations, and that additional, novel, population-specific QT signals exist.

The Genetics of Cardiovascular Disease in Canadian and International Aboriginal Populations.

For Aboriginal populations, as in all populations, understanding the genetic component of cardiovascular disease informs effective treatment and prevention strategies. The term, "genetics of cardiovascular disease," broadly includes the genetics of susceptibility for atherosclerosis, cardiomyopathy, arrhythmia, and congenital heart disease, collectively a major cause of mortality and morbidity throughout the life course. Aboriginal populations are often genetically and culturally distinct, and as would be expected with distinct ethnic differences, there are also differences in rates and types of heart disease, which supports the importance of understanding possible genetic factors that might alter susceptibility. In Canada, higher rates of congenital heart malformations have been identified in some Inuit and First Nations than in the non-Aboriginal population. Moreover, at least 3 different First Nations communities in Canada have been found to have disproportionately higher rates of congenital long QT syndrome, a genetic predisposition to arrhythmia and sudden cardiac death. Although rates of ischemic heart disease historically have been lower in Aboriginal populations, more recent evidence suggests equal or higher rates than in non-Aboriginal populations. Although relatively few Aboriginal communities in Canada have participated in research to explore the genetic component of cardiovascular disease, recent progress in research standards of practice that require collaborative approaches have opened the doors for more involvement. Herein we present what has been learned to date through research and the apparent gaps in the understanding of the genetics of heart disease in Canadian, American, Circumpolar, and other international Indigenous populations.

Moxifloxacin-induced QTc interval prolongations in healthy male Japanese and Caucasian volunteers: a direct comparison in a thorough QT study.

AIM: We investigated whether moxifloxacin-induced QTc prolongations in Japanese and Caucasian healthy male volunteers were significantly different. METHODS: A two period, randomized, crossover, ICH-E14-compliant thorough QT (TQT) study compared placebo-corrected changes in QTc interval from baseline (ΔΔQTc F) and concentration-effect relationships following administration of placebo and 400 mg moxifloxacin to 40 healthy male volunteers from each ethnic population. The point estimates of ΔΔQTc F for each population, and the difference between the two, were calculated at a geometric mean Cmax of moxifloxacin using a linear mixed effects model. The concentration-effect slopes of the two populations were also compared. Equivalence was concluded if the two-sided 90% confidence interval of the difference in ΔΔQTc F was contained within -5 ms to +5 ms limits and the ratio of the slopes was between 0.5 and 2. RESULTS: There were no statistically significant differences between the two populations studied, Japanese vs. Caucasians, respectively, for moxifloxacin Cmax (3.27 ± 0.6 vs. 2.98 ± 0.7 µg ml(-1) ), ΔΔQTc F (9.63 ± 1.15 vs. 11.46 ± 1.19 ms at Cmax of 3.07 µg ml(-1) ) and concentration-response slopes (2.58 ± 0.62 vs. 2.34 ± 0.64 ms per µg ml(-1) ). The difference in the two ΔΔQTc F of -1.8 (90% CI -4.6, 0.9) and the ratio of the two slopes (1.1; 90% CI 0.63, 1.82) were within pre-specified equivalence limits. CONCLUSIONS: Moxifloxacin-induced QTc prolongations did not differ significantly between the Japanese and Caucasian subjects. However, before our findings are more widely generalized, further studies in other populations and with other QT-prolonging drugs are needed to clarify whether inter-ethnic differences in QT sensitivity exist and whether ethnicity of the study population may affect the outcome of a TQT study.

Evidence of heterogeneity by race/ethnicity in genetic determinants of QT interval.

BACKGROUND: QT interval (QT) prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Previous genome-wide association studies in populations of the European descent have identified multiple genetic loci that influence QT, but few have examined these loci in ethnically diverse populations. METHODS: Here, we examine the direction, magnitude, and precision of effect sizes for 21 previously reported SNPs from 12 QT loci, in populations of European (n = 16,398), African (n = 5,437), American Indian (n = 5,032), Hispanic (n = 1,143), and Asian (n = 932) descent as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. Estimates obtained from linear regression models stratified by race/ethnicity were combined using inverse-variance weighted meta-analysis. Heterogeneity was evaluated using Cochran's Q test. RESULTS: Of 21 SNPs, 7 showed consistent direction of effect across all 5 populations, and an additional 9 had estimated effects that were consistent across 4 populations. Despite consistent direction of effect, 9 of 16 SNPs had evidence (P < 0.05) of heterogeneity by race/ethnicity. For these 9 SNPs, linkage disequilibrium plots often indicated substantial variation in linkage disequilibrium patterns among the various racial/ethnic groups, as well as possible allelic heterogeneity. CONCLUSIONS: These results emphasize the importance of analyzing racial/ethnic groups separately in genetic studies. Furthermore, they underscore the possible utility of trans-ethnic studies to pinpoint underlying casual variants influencing heritable traits such as QT.

Racial susceptibility for QT prolongation in acute drug overdoses.

BACKGROUND AND PURPOSE: QT prolongation independently predicts adverse cardiovascular events in suspected poisoning. We aimed to evaluate the association between race and drug-induced QT prolongation for patients with acute overdose. METHODS: This was a cross-sectional observational study at two urban teaching hospitals. Consecutive adult ED patients with acute drug overdose were prospectively enrolled over a two year period. The primary outcome, long-QT, was defined using standard criteria: QTc>470 ms in females and>460 ms in males. The association between race and drug-induced QT prolongation was tested, considering several confounding variables. RESULTS: In 472 patients analyzed (46% female, mean age 42.3), QT prolongation occurred in 12.7%. Blacks had two-fold increased odds of drug-induced QT prolongation (OR 2.01, CI 1.03-3.91) and Hispanics had 48% decreased odds of drug-induced QT prolongation (OR 0.52, CI 0.29-0.94). CONCLUSIONS: We found significant racial susceptibility to drug-induced QT prolongation in this large urban study of acute overdoses.

Electrocardiographic screening of 1-month-old infants for identifying prolonged QT intervals.

BACKGROUND: Neonatal electrocardiographic screening is used to screen infants with prolonged QT intervals, as previously shown in whites. However, this procedure needs to be confirmed in other ethnic groups. METHODS AND RESULTS: In 8 areas in Japan, an ECG was recorded in 4285 infants at 1-month medical checkup. A prospective study showed that a provisional criterion of QTc≥470 ms was appropriate for infants. To assess the validity of the criterion, all infants with a QTc between 460 and 470 ms were followed up. Five infants had a QTc≥470 ms. Four infants were diagnosed with prolonged QT intervals from follow-up ECGs. Four infants showed no symptoms and did not have a family history of long-QT syndrome. Two infants showed progressive prolongation of QT intervals, and medication was started. Genetic testing was performed in 3 of 4 infants with prolonged QT intervals, and it revealed a KCNH2 mutation (3065 delT, L1021fs+34X) in 1 infant. One infant with a QTc≥470 ms and 2 infants with a QTc between 460 and 470 ms showed a decline in their QTc values during follow-up. The study screened another infant with Wolff-Parkinson-White syndrome who was diagnosed with noncompaction before symptoms appeared. CONCLUSIONS: Neonatal electrocardiographic screening can identify infants likely to be affected by long-QT syndrome in the Japanese population, as already shown in whites. This screening may also be useful in identifying other important cardiac diseases.

Drug-induced QT interval prolongation: does ethnicity of the thorough QT study population matter?

Inter-ethnic differences in drug responses have been well documented. Drug-induced QT interval prolongation is a major safety concern and therefore, regulatory authorities recommend a clinical thorough QT study (TQT) to investigate new drugs for their QT-prolonging potential. A positive study, determined by breach of a preset regulatory threshold, significantly influences late phase clinical trials by requiring intense ECG monitoring. A few studies that are currently available, although not statistically conclusive at present, question the assumption that ethnicity of the study population may not influence the outcome of a TQT study. Collective consideration of available pharmacogenetic and clinical information suggests that there may be inter-ethnic differences in QT-prolonging effects of drugs and that Caucasians may be more sensitive than other populations. The information also suggest s that (a) these differences may depend on the QT-prolonging potency of the drug and (b) exposure-response (E-R) analysis may be more sensitive than simple changes in QT(c) interval in unmasking this difference. If the QT response in Caucasians is generally found to be more intense than in non-Caucasians, there may be significant regulatory implications for domestic acceptance of data from a TQT study conducted in foreign populations. However, each drug will warrant an individual consideration when extrapolating the results of a TQT study from one ethnic population to another and the ultimate clinical relevance of any difference. Further adequately designed and powered studies, investigating the pharmacologic properties and E-R relationships of additional drugs with different potencies, are needed in Caucasians, Oriental/Asian and African populations before firm conclusions can be drawn.

Race and gender variation in the QT interval and its association with mortality in patients with coronary artery disease: results from the Duke Databank for Cardiovascular Disease (DDCD).

BACKGROUND: In several studies, prolongation of the corrected QT (QTc) interval has been associated with an increased risk of cardiac events. However, data on race and gender variation in the QTc and its associated risk of death are lacking. METHODS: We prospectively followed 19,252 subjects who underwent cardiac catheterization and had at least 1 native coronary artery stenosis ≥75%. Automated QTc measurements were obtained from a baseline electrocardiogram. RESULTS: The mean age of the population was 62.4 years, with 35% being female and 20% being black. The QTc varied by gender and race (417.9 ± 34.4 ms in men and 433.4 ± 33.6 ms in women, 422.1 ± 34.3 ms in whites and 428.1 ± 36.9 ms in blacks; P < .0001 for both). Risk factors most strongly associated with a prolonged QTc were lower ejection fraction, higher diastolic blood pressure, history of myocardial infarction, and lower glomerular filtration rate. Black race and female gender were also independently associated with a prolonged QTc, after adjustment for cardiac risk factors. Moreover, there was an independent association between QTc and all-cause mortality (hazard ratio 1.037 per 10-ms increase, P < .0001). The increased mortality risk associated with a 10-ms increase in the QTc interval was significantly greater for men compared with women (4.6% vs 2.4%, P = .004) and slightly greater for blacks compared with other races (5.0% vs 3.3%, P = .057). CONCLUSIONS: Among patients with coronary artery disease, QTc prolongation is independently associated with all-cause mortality. The increased mortality risk is higher for men than for women, with a trend toward higher mortality in blacks.

Prevalence and risk factors of prolonged QTc interval among Chinese patients with type 2 diabetes.

OBJECTIVES: The aim of this study was to evaluate the prevalence and the risk factors of prolonged QTc interval among Chinese patients with type 2 diabetes. METHODS: The retrospective study included 3156 outpatients from the Diabetes Centre, the 306th Hospital of PLA, during the period from September 2003 to June 2010. QT interval was measured manually in the 12-lead conventional electrocardiogram. The QT interval corrected for heart rate (QTc) was calculated using Bazett's formula. Additional demographic and laboratory data were also collected. Potential risk factors of prolonged QTc interval were assessed using multivariable regression. RESULTS: The prevalence of prolonged QTc interval among Chinese patients with type 2 diabetes was 30.1%. Height (OR 0.156, 95% CI 0.032~0.748), waist circumference (OR 1.025, 95% CI 1.010~1.040), diastolic blood pressure (OR 1.016, 95% CI 1.007~1.026), postprandial glucose (OR 1.040, 95% CI 1.022~1.059), fasting insulin (OR 1.014, 95% CI 1.003~1.025), and presence of microalbuminuria (OR 1.266, 95% CI 1.033~1.551) were significant risk factors. CONCLUSIONS: The prevalence of prolonged QTc interval among Chinese patients with type 2 diabetes is high. Risk factors for prolongation of QTc interval were low height, high waist circumference, increasing diastolic blood pressure levels, high postprandial glucose levels, high fasting insulin levels, and presence of microalbuminuria.

Invited commentary: sex-steroid hormones and QT-interval duration.

In this issue of the Journal, Zhang et al. (Am J Epidemiol. 2011;174(4):403-411) make a substantial contribution to research in the area of hormonal influences on cardiac repolarization by demonstrating an inverse association between testosterone levels and the Bazett's adjusted QT interval (QTc) and RR-adjusted QT interval in men but not in postmenopausal women. They suggest that testosterone levels might explain the difference in QTc-interval duration between men and women and could contribute to population variability in QTc-interval duration among men. In this commentary, the gender difference and the role of testosterone in human cardiac repolarization are addressed. In addition, the gender differences in the congenital long-QT syndrome, drug-induced ventricular arrhythmias, and sudden cardiac death are discussed.

Sex-steroid hormones and electrocardiographic QT-interval duration: findings from the third National Health and Nutrition Examination Survey and the Multi-Ethnic Study of Atherosclerosis.

The association between physiologic levels of sex hormones and QT-interval duration in humans was evaluated using data from 727 men enrolled in the Third National Health and Nutrition Examination Survey and 2,942 men and 1,885 postmenopausal women enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). Testosterone, estradiol, and sex hormone-binding globulin levels were measured in serum and free testosterone was calculated from those values. QT interval was measured using a standard 12-lead electrocardiogram. In men from the Third National Health and Nutrition Survey, the multivariate adjusted differences in average QT-interval duration comparing the highest quartiles with the lowest quartiles of total testosterone and free testosterone were -8.5 ms (95% confidence interval (CI): -15.5, -1.4) and -8.0 ms (95% CI: -13.2, -2.8), respectively. The corresponding differences were -1.8 ms (95% CI: -3.8, -0.2), and -4.7 ms (95% CI: -6.7, -2.6), respectively, in men from MESA and -0.6 ms (95% CI: -3.0, 1.8) and 0.8 ms (95% CI: -1.6, 3.3), respectively, in postmenopausal women from MESA. Estradiol levels were not associated with QT-interval duration in men, but there was a marginally significant positive association in postmenopausal women. The findings suggest that testosterone levels may explain differences in QT-interval duration between men and women and could be a contributor to population variability in QT-interval duration among men.

Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants.

BACKGROUND: Genetic testing for long-QT syndrome (LQTS) has diagnostic, prognostic, and therapeutic implications. Hundreds of causative mutations in 12 known LQTS-susceptibility genes have been identified. Genetic testing that includes the 3 most commonly mutated genes is available clinically. Distinguishing pathogenic mutations from innocuous rare variants is critical to the interpretation of test results. We sought to quantify the value of mutation type and gene/protein region in determining the probability of pathogenicity for mutations. METHODS AND RESULTS: Type, frequency, and location of mutations across KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3) were compared between 388 unrelated "definite" (clinical diagnostic score >or=4 and/or QTc >or=480 ms) cases of LQTS and >1300 healthy controls for each gene. From these data, estimated predictive values (percent of mutations found in definite cases that would cause LQTS) were determined according to mutation type and location. Mutations were 10 times more common in cases than controls (0.58 per case versus 0.06 per control). Missense mutations were the most common, accounting for 78%, 67%, and 89% of mutations in KCNQ1, KCNH2, and SCN5A in cases and >95% in controls. Nonmissense mutations have an estimated predictive value >99% regardless of location. In contrast, location appears to be critical for characterizing missense mutations. Relative frequency of missense mutations between cases and controls ranged from approximately 1:1 in the SCN5A interdomain linker to infinity in the pore, transmembrane, and linker in KCNH2. These correspond to estimated predictive values ranging from 0% in the interdomain linker of SCN5A to 100% in the transmembrane/linker/pore regions of KCNH2. The estimated predictive value is also high in the linker, pore, transmembrane, and C terminus of KCNQ1 and the transmembrane/linker of SCN5A. CONCLUSIONS: Distinguishing pathogenic mutations from rare variants is of critical importance in the interpretation of genetic testing in LQTS. Mutation type, mutation location, and ethnic-specific BACKGROUND: should be viewed as variants of uncertain significance and prompt further investigation to clarify the likelihood of disease causation. However, mutations in regions such as the transmembrane, linker, and pore of KCNQ1 and KCNH2 may be defined confidently as high-probability LQTS-causing mutations. These findings will have implications for other genetic disorders involving mutational analysis.

Clinical correlates and heritability of QT interval duration in blacks: the Jackson Heart Study.

BACKGROUND: Electrocardiographic QT interval prolongation is a risk factor for sudden cardiac death and drug-induced arrhythmia. The clinical correlates and heritability of QT interval duration in blacks have not been well studied despite their higher risk for sudden cardiac death compared with non-Hispanic whites. We sought to investigate potential correlates of the QT interval and estimate its heritability in the Jackson Heart Study. METHODS AND RESULTS: The Jackson Heart Study comprises a sample of blacks residing in Jackson, Miss, of whom 5302 individuals with data at the baseline examination were available for study. Jackson Heart Study participants on QT-altering medications, with bundle-branch block, paced rhythm, atrial fibrillation/flutter, or other arrhythmias were excluded, resulting in a sample of 4660 individuals eligible for analyses. The relation between QT and potential covariates was tested using multivariable stepwise linear regression. Heritability was estimated using Sequential Oligogenic Linkage Analysis Routine in a subset of 1297 Jackson Heart Study participants in 292 families; the remaining sample included unrelated individuals. In stepwise multivariable linear regression analysis, covariates significantly associated with QT interval duration included R-R interval, sex, QRS duration, age, serum potassium, hypertension, body mass index, coronary heart disease, diuretic use, and Sokolow-Lyon voltage (P < or = 0.01 for all). The heritability of QT interval duration in the age-, sex-, and R-R interval-adjusted model and in the fully adjusted model was 0.41 (SE, 0.07) and 0.40 (SE, 0.07; P < 10(-11) for both), respectively. CONCLUSIONS: There is substantial heritability of adjusted QT interval in blacks, supporting the need for further investigation to identify its genetic determinants.