52 Genetic Loci Influencing Myocardial Mass van der Harst, Pim, MD, PhD; Verweij, Niek, PhD; Vogler, Georg, PhD ...
Journal of the American College of Cardiology,
09/2016, Volume:
68, Issue:
13
Journal Article
Peer reviewed
Open access
Abstract Background Myocardial mass is a key determinant of cardiac muscle function and hypertrophy. Myocardial depolarization leading to cardiac muscle contraction is reflected by the amplitude and ...duration of the QRS complex on the electrocardiogram (ECG). Abnormal QRS amplitude or duration reflect changes in myocardial mass and conduction, and are associated with increased risk of heart failure and death. Objectives This meta-analysis sought to gain insights into the genetic determinants of myocardial mass. Methods We carried out a genome-wide association meta-analysis of 4 QRS traits in up to 73,518 individuals of European ancestry, followed by extensive biological and functional assessment. Results We identified 52 genomic loci, of which 32 are novel, that are reliably associated with 1 or more QRS phenotypes at p < 1 × 10−8 . These loci are enriched in regions of open chromatin, histone modifications, and transcription factor binding, suggesting that they represent regions of the genome that are actively transcribed in the human heart. Pathway analyses provided evidence that these loci play a role in cardiac hypertrophy. We further highlighted 67 candidate genes at the identified loci that are preferentially expressed in cardiac tissue and associated with cardiac abnormalities in Drosophila melanogaster and Mus musculus . We validated the regulatory function of a novel variant in the SCN5A/SCN10A locus in vitro and in vivo. Conclusions Taken together, our findings provide new insights into genes and biological pathways controlling myocardial mass and may help identify novel therapeutic targets.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Purpose We studied incident atrial fibrillation (AF) in the prospective community-based Multi-Ethnic Study of Atherosclerosis (MESA). Reportedly, non-Hispanic blacks (NHBs) have a lower AF ...burden compared with their non-Hispanic white (NHW) counterparts. Information on the epidemiology of AF in Hispanic and Asian populations is much more limited. Methods We excluded participants with a history of AF at enrollment. A total of 6721 MESA participants were monitored for the first AF event ascertained according to hospital discharge International Classification of Diseases, Ninth Revision , codes. Age- and sex-adjusted incidence rates (IRs) of AF were calculated per 1000 person-years of observation. IR ratios were calculated using NHWs as the reference group. Age- and sex-adjusted population attributable fractions (PAFs) of established modifiable AF risk factors were ascertained. Results In the MESA cohort, 47.2% was male; at baseline, 25.7% had hypertension; 12.5% had diabetes. Three hundred five incident hospitalized AF events occurred over a mean follow-up of 7.3 years. Age- and sex-adjusted IRs and IR ratios showed that overall AF incidence was significantly lower among Hispanics, NHBs and Chinese compared with NHWs (all P < .001). Among participants 65 years of age or greater, Hispanics, Chinese, and blacks had significantly lower AF incidence than NHWs (all P ≤ .01), but IRs were similar among participants under age 65 years. The PAF for smoking was 27% among NHBs but lower among other race–ethnic groups. Among NHWs, the PAF for hypertension was 22.2%, but this was higher among NHBs (33.1%), Chinese (46.3%), and Hispanics (43.9%). Conclusions Overall, the incidence of hospitalized AF was significantly lower in Hispanics, NHBs, and Chinese than in NHWs. A larger proportion of AF events appear to be attributable to hypertension among nonwhite populations compared with NHWs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Atrial fibrillation (AF) occurs frequently in patients with chronic obstructive pulmonary disease. Epidemiologic studies have found inconsistent associations between lung function and AF, and none ...have studied pulmonary emphysema, which overlaps only partially with chronic obstructive pulmonary disease in the general population. The aim of this study was to assess the relation among lung function measured by spirometry, the percentage of emphysema-like lung on computed tomography, and incident AF. The Multi-Ethnic Study of Atherosclerosis (MESA) is a multicenter cohort study following 6,814 subjects free of clinical cardiovascular disease, including AF, at baseline. Spirometry was performed in a subset of 3,965 participants. Percentage emphysema was defined on baseline computed tomographic scans as lung regions <950 Hounsfield units. Incident AF was identified from hospital discharge diagnosis and Medicare claims data. Cox proportional hazards models were used to assess independent associations of lung volumes and percentage emphysema with AF. A total of 3,811 participants with valid spirometric results were included in this study. The mean age was 64.5 ± 9.8 years, and 49.4% were men. AF developed in 149 subjects (3.8%) over a mean follow-up period of 4.1 years after spirometry. Lower levels of forced expiratory volume at 1 second and forced vital capacity were associated with a higher risk for AF (hazard ratios 1.21 and 1.19 per 500 ml, respectively, p <0.001) after adjustment for demographic and cardiovascular risk factors. Percentage emphysema was not significantly related to AF. In conclusion, in a multiethnic community-based sample of subjects free of cardiovascular disease at baseline, functional airflow limitation was related to a higher risk for AF.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Background Studies of patients presenting for catheter ablation suggest that premature ventricular contractions (PVCs) are a modifiable risk factor for congestive heart failure (CHF). The ...relationship among PVC frequency, incident CHF, and mortality in the general population remains unknown. Objectives The goal of this study was to determine whether PVC frequency ascertained using a 24-h Holter monitor is a predictor of a decrease in the left ventricular ejection fraction (LVEF), incident CHF, and death in a population-based cohort. Methods We studied 1,139 Cardiovascular Health Study (CHS) participants who were randomly assigned to 24-h ambulatory electrocardiography (Holter) monitoring and who had a normal LVEF and no history of CHF. PVC frequency was quantified using Holter studies, and LVEF was measured from baseline and 5-year echocardiograms. Participants were followed for incident CHF and death. Results Those in the upper quartile versus the lowest quartile of PVC frequency had a multivariable-adjusted, 3-fold greater odds of a 5-year decrease in LVEF (odds ratio OR: 3.10; 95% confidence interval CI: 1.42 to 6.77; p = 0.005), a 48% increased risk of incident CHF (HR: 1.48; 95% CI: 1.08 to 2.04; p = 0.02), and a 31% increased risk of death (HR: 1.31; 95% CI: 1.06 to 1.63; p = 0.01) during a median follow-up of >13 years. Similar statistically significant results were observed for PVCs analyzed as a continuous variable. The specificity for the 15-year risk of CHF exceeded 90% when PVCs included at least 0.7% of ventricular beats. The population-level risk for incident CHF attributed to PVCs was 8.1% (95% CI: 1.2% to 14.9%). Conclusions In a population-based sample, a higher frequency of PVCs was associated with a decrease in LVEF, an increase in incident CHF, and increased mortality. Because of the capacity to prevent PVCs through medical or ablation therapy, PVCs may represent a modifiable risk factor for CHF and death.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract Background Little is known about the incidence of and risk factors for sick sinus syndrome (SSS), a common indication for pacemaker implantation. Objectives This study sought to describe the ...epidemiology of SSS. Methods This analysis included 20,572 participants (mean baseline age 59 years, 43% male) in the ARIC (Atherosclerosis Risk In Communities) study and the CHS (Cardiovascular Health Study), who at baseline were free of prevalent atrial fibrillation and pacemaker therapy, had a heart rate of ≥50 beats/min unless using beta blockers, and were identified as of white or black race. Incident SSS cases were identified by hospital discharge International Classification of Disease-revision 9-Clinical Modification code 427.81 and validated by medical record review. Results During an average 17 years of follow-up, 291 incident SSS cases were identified (unadjusted rate 0.8 per 1,000 person-years). Incidence increased with age (hazard ratio HR: 1.73; 95% confidence interval CI: 1.47 to 2.05 per 5-year increment), and blacks had a 41% lower risk of SSS than whites (HR: 0.59; 95% CI: 0.37 to 0.98). Incident SSS was associated with greater baseline body mass index, height, N-terminal pro–B-type natriuretic peptide, and cystatin C, with longer QRS interval, with lower heart rate, and with prevalent hypertension, right bundle branch block, and cardiovascular disease. We project that the annual number of new SSS cases in the United States will increase from 78,000 in 2012 to 172,000 in 2060. Conclusions Blacks have a lower risk of SSS than whites, and several cardiovascular risk factors were associated with incident SSS. With the aging of the population, the number of Americans with SSS will increase dramatically over the next 50 years.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Previous research suggests that elevated pulse pressure (PP) is a risk factor for atrial fibrillation (AF) independently of mean arterial pressure (MAP). PP may serve as an indirect measure of aortic ...stiffness (reduced distensibility), but whether directly measured aortic distensibility is related to risk for AF has not yet been studied. This analysis included 6,630 participants aged 45 to 84 years from the Multi-Ethnic Study of Atherosclerosis. At baseline, blood pressure and other relevant covariates were measured using standardized protocols. Magnetic resonance imaging–based aortic distensibility was measured in 3,441 participants. Incident AF was identified from hospitalization discharge codes and Medicare claims. Multivariate Cox models were used to estimate the association of blood pressure components and aortic distensibility with AF risk. During a mean follow-up of 7.8 years, 307 AF events (137 among those with aortic distensibility measurements) were identified. In multivariate-adjusted models simultaneously including MAP and PP, each 1-SD increase in PP was associated with a 29% increased risk of AF (95% confidence interval 5% to 59%, p = 0.02), with MAP not being associated with increased AF risk. Overall, aortic distensibility was not consistently associated with AF risk: after removing outliers, each 1-SD increase in aortic distensibility was associated with a 9% increased risk of AF (95% confidence interval −22% to 51%, p = 0.63). In conclusion, in this large community-based cohort, we found that PP, but not MAP or aortic distensibility, was a significant risk factor for AF, emphasizing the importance of PP when assessing the risk for developing AF. Our results cast doubt on the clinical utility of aortic distensibility as a predictor for the development of AF.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Previous studies have raised the question of whether an association exists between physical activity and atrial fibrillation (AF). We used the Multi-Ethnic Study of Atherosclerosis (MESA) database to ...examine the association between physical activity and AF in a diverse population without clinically recognized cardiovascular disease (CVD). MESA participants (n = 5,793) with complete baseline physical activity and covariate data were included. Cox proportional hazards models were used to calculate hazard ratios (HRs) for incident AF by levels of total intentional exercise and vigorous physical activity, independently and in combination. Multivariate models were adjusted for demographics and CVD risk factors. During a mean follow-up of 7.7 ± 1.9 years, 199 AF cases occurred. In the overall MESA population, neither vigorous physical activity nor total intentional exercise was independently associated with incident AF after adjusting for covariates. However, within the group that reported any vigorous physical activity, there was a statistically significant inverse association between total intentional exercise (modeled as a continuous variable) and incident AF. In those who reported any vigorous physical activity, the top tertile of total intentional exercise was associated with a significantly lower risk of incident AF compared with the group with no total intentional exercise in the fully adjusted model (HR 0.46, 95% confidence interval 0.22 to 0.98). In conclusion, neither total intentional exercise nor vigorous physical activity alone was associated with incident AF, but greater total intentional exercise was associated with a lower risk of incident AF in those who participated in any vigorous physical activity. As importantly, no subgroup of participants demonstrated an increased risk of incident AF with greater physical activity. The results re-emphasize the beneficial role of physical activity for cardiovascular health.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objectives This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk. Background AF-associated loci span ...broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored. Methods We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases). Results We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2 , but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements. Conclusions The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine.
To determine whether the QT interval, a marker ...of ventricular repolarization, could be used to predict incident AF.
We examined a prolonged QT interval corrected by using the Framingham formula (QT(Fram)) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition (ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by using other formulas.
Among 14,538 ARIC study participants, a prolonged QT(Fram) predicted a roughly 2-fold increased risk of AF (hazard ratio HR 2.05; 95% confidence interval CI 1.42-2.96; P < .001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in Cardiovascular Health Study and Health, Aging, and Body Composition study and were similar across various QT correction methods. Also in the ARIC study, each 10-ms increase in QT(Fram) was associated with an increased unadjusted (HR 1.14; 95% CI 1.10-1.17; P < .001) and adjusted (HR 1.11; 95% CI 1.07-1.14; P < .001) risk of AF. Findings regarding a short QT interval were inconsistent across cohorts.
A prolonged QT interval is associated with an increased risk of incident AF.
Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated ...by such GWAS confer additional risk of AF.
To study the association of genetic variants with AF at GWAS top loci.
In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital.
One common variant (rs11265611; P = 1.70 × 10(-6)) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r(2) = .69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P = .01).
We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.
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