The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal Mendelian Long QT Syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals we identified 35 common variant QT interval loci, that collectively explain ∼8-10% of QT variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 novel QT loci in 298 unrelated LQTS probands identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode for proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies novel candidate genes for ventricular arrhythmias, LQTS,and SCD.
genome-wide association study; QT interval; Long QT Syndrome; sudden cardiac death; myocardial repolarization; arrhythmias
Atrial fibrillation increases the risks of stroke, heart failure, and death, and anticoagulation therapy increases the risk of gastrointestinal haemorrhage. However, the relative event rates for these outcomes are not well described. We sought to define the risks of major clinical events in older adults after a new diagnosis of atrial fibrillation.
Methods and results
We undertook a population-based, retrospective cohort study of a nationally representative sample of fee-for-service Medicare beneficiaries 65 years or older with incident atrial fibrillation diagnosed between 1999 and 2007. The main outcome measures were mortality and hospitalization or emergency department care for heart failure, myocardial infarction, stroke, or gastrointestinal haemorrhage. Among 186 461 patients with atrial fibrillation and no recent hospitalizations for heart failure, myocardial infarction, stroke, or gastrointestinal haemorrhage, mortality was the most frequent of these major clinical events (19.5% at 1 year; 48.8% at 5 years). By 5 years, 13.7% of patients were hospitalized for heart failure, 7.1% developed new-onset stroke, and 5.7% had gastrointestinal haemorrhage. Myocardial infarction was less frequent (3.9% at 5 years). Rates of mortality, heart failure, myocardial infarction, stroke, and gastrointestinal bleeding increased with older age and higher CHADS2 scores. Among 44 479 patients with previous events, the 5-year risk of death was greatest among patients with recent bleeding events (70.1%) and stroke (63.7%) and lowest among those with recent myocardial infarction (54.9%).
After the diagnosis of incident atrial fibrillation in older adults, mortality was the most frequent major outcome during the first 5 years. Among non-fatal cardiovascular events, heart failure was the most common event.
Atrial fibrillation; Heart failure; Outcome assessment (health care); Mortality
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.
The genetic background of atrial fibrillation (AF) in whites and African Americans is largely unknown. Genes in cardiovascular pathways have not been systematically investigated.
Methods and Results
We examined a panel of approximately 50,000 common single nucleotide polymorphisms (SNPs) in 2,095 cardiovascular candidate genes and AF in three cohorts with participants of European (n=18,524; 2,260 cases) or African American descent (n=3,662; 263 cases) in the National Heart Lung and Blood Institute's Candidate Gene Association Resource. Results in whites were followed up in the German Competence Network for AF (n=906, 468 cases). The top result was assessed in relation to incident ischemic stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology Stroke Consortium (n= 19,602 whites, 1544 incident strokes). SNP rs4845625 in the IL6R gene was associated with AF (relative risk (RR) C allele, 0.90; 95% confidence interval (CI), 0.85–0.95; P=0.0005) in whites, but did not reach statistical significance in African Americans (RR, 0.86; 95% CI, 0.72–1.03; P=0.09). The results were comparable in the German AF Network replication, (RR, 0.71; 95% CI, 0.57–0.89; P=0.003). No association between rs4845625 and stroke was observed in whites. The known chromosome 4 locus near PITX2 in whites also was associated with AF in African Americans (rs4611994, hazard ratio, 1.40; 95% CI, 1.16–1.69; P=0.0005).
In a community-based cohort meta-analysis, we identified genetic association in IL6R with AF in whites. Additionally, we demonstrated that the chromosome 4 locus known from recent genome-wide association studies in whites is associated with AF in African Americans.
atrial fibrillation; single nucleotide polymorphism; epidemiology; cohort study; race/ethnicity
Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
Statins are effectively used to prevent and manage cardiovascular disease, but patient response to these drugs is highly variable. Here, the authors identify two new genes associated with the response of LDL cholesterol to statins and advance our understanding of the genetic basis of drug response.
In this brief report, we provide normal reference ranges for PR duration [unadjusted and heart rate adjusted] and P-wave indices [duration, amplitude and terminal force in V1] in individuals free of cardiovascular disease and its risk factors. We used automatically processed digital ECG data from 1252 US participants [mean age 59 (± 10) years, 738 women, 588 whites, 207 African-Americans, 217 Hispanics, 240 Chinese] from the Multi-Ethnic Study of Atherosclerosis [MESA]. In multivariable adjusted linear regression models with PR and each P-wave variable as a separate outcome, significant age, sex and race differences in these markers were observed. Subsequently, we report reference ranges for abnormal [2nd and 98th percentiles], borderline abnormal [5th and 95th percentiles] and mean [SD] values of PR and P-wave indices stratified by age [middle age (45–64 years) and seniors (65–84 years)], sex [men and women] and race [whites, African Americans, Hispanics and Chinese].
P-wave indices; PR interval; MESA
Sick sinus syndrome (SSS) is a common indication for pacemaker implantation. Limited information exists on the association of sick sinus syndrome (SSS) with mortality and cardiovascular disease (CVD) in the general population.
We studied 19,893 men and women age 45 and older in the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS), two community-based cohorts, who were without a pacemaker or atrial fibrillation (AF) at baseline. Incident SSS cases were validated by review of medical charts. Incident CVD and mortality were ascertained using standardized protocols. Multivariable Cox models were used to estimate the association of incident SSS with selected outcomes.
During a mean follow-up of 17 years, 213 incident SSS events were identified and validated (incidence, 0.6 events per 1,000 person-years). After adjustment for confounders, SSS incidence was associated with increased mortality (hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.14–1.70), coronary heart disease (HR 1.72, 95%CI 1.11–2.66), heart failure (HR 2.87, 95%CI 2.17–3.80), stroke (HR 1.56, 95%CI 0.99–2.46), AF (HR 5.75, 95%CI 4.43–7.46), and pacemaker implantation (HR 53.7, 95%CI 42.9–67.2). After additional adjustment for other incident CVD during follow-up, SSS was no longer associated with increased mortality, coronary heart disease, or stroke, but remained associated with higher risk of heart failure (HR 2.00, 95%CI 1.51–2.66), AF (HR 4.25, 95%CI 3.28–5.51), and pacemaker implantation (HR 25.2, 95%CI 19.8–32.1).
Individuals who develop SSS are at increased risk of death and CVD. The mechanisms underlying these associations warrant further investigation.
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 corrected by the Framingham formula (QTFram) 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 (Health ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by other formulae.
Among 14,538 ARIC participants, a prolonged QTFram predicted a roughly two-fold increased risk of AF (hazard ratio [HR] 2.05, 95% confidence interval [CI] 1.42–2.96, p<0.001). 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 CHS and Health ABC and were similar across various QT correction methods. Also in ARIC, each 10-ms increase in QTFram was associated with an increased unadjusted (HR 1.14, 95%CI 1.10–1.17, p<0.001) and adjusted (HR 1.11, 95%CI 1.07–1.14, p<0.001) risk of AF. Findings regarding a short QT were inconsistent across cohorts.
A prolonged QT interval is associated with an increased risk of incident AF.
atrial fibrillation; epidemiology; risk; QT interval; electrocardiography; ECG
The cardiac sodium channel SCN5A regulates atrioventricular
and ventricular conduction. Genetic variants in this gene are associated with PR and QRS
intervals. We sought to further characterize the contribution of rare and common coding
variation in SCN5A to cardiac conduction.
Methods and Results
In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted
Sequencing Study (CHARGE), we performed targeted exonic sequencing of
SCN5A (n=3699, European-ancestry individuals) and identified 4 common
(minor allele frequency >1%) and 157 rare variants. Common and rare
SCN5A coding variants were examined for association with PR and QRS intervals through
meta-analysis of European ancestry participants from CHARGE, NHLBI’s Exome
Sequencing Project (ESP, n=607) and the UK10K (n=1275) and by examining ESP
African-ancestry participants (N=972). Rare coding SCN5A variants in
aggregate were associated with PR interval in European and African-ancestry participants
(P=1.3×10−3). Three common variants were associated with PR
and/or QRS interval duration among European-ancestry participants and one among
African-ancestry participants. These included two well-known missense variants;
rs1805124 (H558R) was associated with PR and QRS shortening in European-ancestry
participants (P=6.25×10−4 and
P=5.2×10−3 respectively) and rs7626962 (S1102Y) was
associated with PR shortening in those of African ancestry
(P=2.82×10−3). Among European-ancestry participants, two
novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac
conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening
(P=3.35×10−7 and P=2.69×10−4
respectively), and rs6599230 was associated with PR shortening
By sequencing SCN5A, we identified novel common and rare
coding variants associated with cardiac conduction.
PR interval; QRS interval; genetics; sequencing; cohort
Prompt treatment of severe sepsis in the Emergency Department reduces deaths, but the role of prehospital fluid resuscitation is unknown. We sought to determine the risk-adjusted association between prehospital fluid administration and hospital mortality among emergency medical services (EMS) patients admitted with severe sepsis.
We performed a prospective, observational study of patients hospitalized with severe sepsis on admission among 45,394 adult EMS encounters taken to 15 hospitals from 11/2009 to 12/2010 by a two-tier EMS system in King County, Washington. The region mandated recording of prehospital intravenous catheter and fluid administration in prehospital records, along with detailed demographic, incident, physiologic, and hospital adjustment variables. We determined the effect of prehospital intravenous catheter or fluid versus no catheter or fluid on all-cause mortality using multivariable logistic regression.
Of all encounters, 1,350 met criteria for severe sepsis on admission, of whom 205 (15%) died by hospital discharge, 312 (23%) received prehospital intravenous fluid, 90 (7%) received a prehospital catheter alone and 948 (70%) did not receive catheter or fluid. EMS administered a median prehospital fluid volume of 500 mL (interquartile range (IQR): 200, 1000 mL). In adjusted models, the administration of any prehospital fluid was associated with reduced hospital mortality (Odds ratio =0.46; 95% Confidence interval: 0.23, 0.88; P =0.02) compared to no prehospital fluid. The odds of hospital mortality were also lower among severe sepsis patients treated with prehospital intravenous catheter alone (Odds ratio =0.3; 95% Confidence interval: 0.17 to 0.57; P <0.01).
In a population-based study, the administration of prehospital fluid and placement of intravenous access were associated with decreased odds of hospital mortality compared with no prehospital catheter or fluid.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0533-x) contains supplementary material, which is available to authorized users.
Asthma originates from genetic and environmental factors with about half the risk of disease attributable to heritable causes. Genome-wide association studies, mostly in populations of European ancestry, have identified numerous asthma-associated single nucleotide polymorphisms (SNPs). Studies in populations with diverse ancestries allow both for identification of robust associations that replicate across ethnic groups and for improved resolution of associated loci due to different patterns of linkage disequilibrium between ethnic groups. Here we report on an analysis of 745 African-American subjects with asthma and 3,238 African-American control subjects from the Candidate Gene Association Resource (CARe) Consortium, including analysis of SNPs imputed using 1,000 Genomes reference panels and adjustment for local ancestry. We show strong evidence that variation near RAD50/IL13, implicated in studies of European ancestry individuals, replicates in individuals largely of African ancestry. Fine mapping in African ancestry populations also refined the variants of interest for this association. We also provide strong or nominal evidence of replication at loci near ORMDL3/GSDMB, IL1RLML18R1, and 10pl4, all previously associated with asthma in European or Japanese populations, but not at the PYHIN1 locus previously reported in studies of African-American samples. These results improve the understanding of asthma genetics and further demonstrate the utility of genetic studies in populations other than those of largely European ancestry.
We sought to validate a recently published risk algorithm for incident atrial fibrillation (AF) in independent cohorts and other race/ethnic groups.
We evaluated the performance of a Framingham Heart Study (FHS)-derived risk algorithm modified for 5-year incidence of AF in the FHS (n=4764 participants) and two geographically and ethnically diverse cohorts: AGES (Age, Gene/Environment Susceptibility-Reykjavik Study, n=4238), and CHS (Cardiovascular Health Study, n=5410 of whom 874 (16.2%) were African Americans (AA)); aged 45–95 years. The risk algorithm included age, sex, body mass index, systolic blood pressure, electrocardiographic PR-interval, hypertension treatment, and heart failure.
We observed 1359 incident AF events in 100,074 person-years of follow-up. Unadjusted five-year event-rates differed by cohort (AGES 12.8 cases/1000 person-years; CHS whites 22.7 cases/1000 person-years; FHS 4.5 cases/1000 person-years) and race/ethnicity (CHS AA 18.4 cases/1000 person-years).
The strongest risk factors in all samples were age and heart failure. The relative risks for incident AF associated with risk factors were comparable across cohorts and race groups. After recalibration for baseline incidence and risk factor distribution, the Framingham algorithm performed reasonably well in all samples (AGES C-statistic 0.67, 95% confidence interval 0.64–0.71; CHS whites, 0.68, 0.66–0.70; CHS AA 0.66, 0.61–0.71). Risk factors combined in the algorithm explained between 47.0% (AGES) and 63.6% (FHS) of the population attributable risk.
Risk of incident AF in community-dwelling whites and AA can be assessed reliably by routinely available and potentially modifiable clinical variables. Seven risk factors accounted for up to 64% percent of risk.
atrial fibrillation; risk score; epidemiology; cohort study; race/ethnicity
Atrial fibrillation (AF), the most common cardiac rhythm abnormality, is associated with significant morbidity, mortality, and health care expenditures. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure, atrial fibrillation, and mortality.
Methods and Results
The relation between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and AF was studied in 5,445 Cardiovascular Health Study participants, using relative risk regression for predicting prevalent AF, and Cox proportional hazards for predicting incident AF. NT-proBNP levels were strongly associated with prevalent AF, with an unadjusted prevalence ratio of 128 for the highest quintile (95%CI 17.9, 913.3, p< 0.001); and adjusted prevalence ratio of 147 for the highest quintile (95% CI 20.4, 1064.3, p<0.001) compared to the lowest. After a median follow up of 10 years (maximum of 16 years), there were 1,126 cases of incident AF (a rate of 2.2 per 100 person years). NT-proBNP was highly predictive of incident AF with an unadjusted hazard ratio of 5.2 (95% CI 4.3, 6.4, p < 0.001) for the development of AF for the highest quintile compared to the lowest; for the same contrast, NT-proBNP remained the strongest predictor of incident AF after adjustment for an extensive number of covariates, including age, sex, medication use, blood pressure, echocardiographic parameters, diabetes, and heart failure; with an adjusted hazard ratio of 4.0 (CI 3.2, 5.0, p< 0.001).
In a community based population of older adults, NT-pro BNP was a remarkable predictor of incident AF, independent of any other previously described risk factor.
B-type natriuretic peptide; atrial fibrillation; BNP; NT-proBNP
Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the “missing heritability” of complex traits. Here, we describe four independent analyses in 33,781 participants of European ancestry from ten cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%), and QT prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-SNP interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0×10−8). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.
QT interval; pharmacogenomics; gene-environment interaction
Atrial fibrillation (AF) prediction models have unclear clinical utility given the absence of AF prevention therapies and the immutability of many risk factors. Premature atrial contractions (PACs) play a critical role in AF pathogenesis and may be modifiable.
To investigate whether PAC count improves model performance for AF risk.
Prospective cohort study.
4 U.S. communities.
A random subset of 1260 adults without prevalent AF enrolled in the Cardiovascular Health Study between 1989 and 1990.
The PAC count was quantified by 24-hour electrocardiography. Participants were followed for the diagnosis of incident AF or death. The Framingham AF risk algorithm was used as the comparator prediction model.
In adjusted analyses, doubling the hourly PAC count was associated with a significant increase in AF risk (hazard ratio, 1.17 [95% CI, 1.13 to 1.22]; P < 0.001) and overall mortality (hazard ratio, 1.06 [CI, 1.03 to 1.09]; P < 0.001). Compared with the Framingham model, PAC count alone resulted in similar AF risk discrimination at 5 and 10 years of follow-up and superior risk discrimination at 15 years. The addition of PAC count to the Framingham model resulted in significant 10-year AF risk discrimination improvement (c-statistic, 0.65 vs. 0.72; P < 0.001), net reclassification improvement (23.2% [CI, 12.8% to 33.6%]; P < 0.001), and integrated discrimination improvement (5.6% [CI, 4.2% to 7.0%]; P < 0.001). The specificity for predicting AF at 15 years exceeded 90% for PAC counts more than 32 beats/h.
This study does not establish a causal link between PACs and AF.
The addition of PAC count to a validated AF risk algorithm provides superior AF risk discrimination and significantly improves risk reclassification. Further study is needed to determine whether PAC modification can prospectively reduce AF risk.
Primary Funding Source
American Heart Association, Joseph Drown Foundation, and National Institutes of Health.
Hypertension is an established risk factor for atrial fibrillation. Understanding the association of blood pressure (BP) levels and aortic distensibility with P wave indices (PWIs) and PR interval, intermediate phenotypes of atrial fibrillation, could provide insights into underlying mechanisms.
This analysis included 3180 men and women aged 45-84 participating in the Multi-Ethnic Study of Atherosclerosis, a community-based cohort in the United States. Aortic distensibility was evaluated in 2243 of these individuals using cardiac magnetic resonance imaging. PWIs and PR interval were automatically measured in standard 12-lead ECGs. Sitting BP and other cardiovascular risk factors were assessed using standardized protocols. Left ventricular mass was measured by magnetic resonance imaging.
Higher systolic and diastolic BP, and greater pulse pressure were associated with a significantly greater P wave terminal force. These associations, however, were markedly attenuated or disappeared after adjustment for left ventricular mass. Systolic BP, diastolic BP, and pulse pressure were not strongly associated with PR interval or maximum P wave duration. Reduced aortic distensibility was associated with a longer PR interval but not with PWIs: compared with individuals in the top quartile of aortic distensibility, participants in the lowest quartile had on average a 3.7 ms longer PR interval (95% CI: 0.7, 6.7, p=0.02), after multivariable adjustment.
In this large community-based sample, associations of BP and aortic distensibility with PWIs and PR interval differed. These results suggest that processes linking hypertension with the electrical substrate of atrial fibrillation, as characterized by these intermediate phenotypes, are diverse.
aorta; blood pressure; electrocardiography; epidemiology
Venous thromboembolism (VTE) is a common, heritable disease resulting in
high rates of hospitalization and mortality. Yet few associations between VTE
and genetic variants, all in the coagulation pathway, have been established. To
identify additional genetic determinants of VTE, we conducted a 2-stage
genome-wide association study (GWAS) among individuals of European ancestry in
the extended CHARGE VTE consortium. The discovery GWAS comprised 1,618 incident
VTE cases out of 44,499 participants from six community-based studies. Genotypes
for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to
~2.5 million SNPs in HapMap and association with VTE assessed using
study-design appropriate regression methods. Meta-analysis of these results
identified two known loci, in F5 and ABO. Top
1,047 tag SNPs (p≤0.0016) from the discovery GWAS were tested for
association in an additional 3,231 cases and 3,536 controls from three
case-control studies. In the combined data from these two stages, additional
genome-wide significant associations were observed on 4q35 at
F11 (top SNP rs4253399, intronic to F11)
and on 4q28 at FGG (rs6536024, 9.7 kb from
FGG) (p<5.0×10−13 for both).
The associations at the FGG locus were not completely explained
by previously reported variants. Loci at or near SUSD1 and
OTUD7A showed borderline yet novel associations
(p<5.0×10-6) and constitute new candidate genes. In
conclusion, this large GWAS replicated key genetic associations in
F5 and ABO, and confirmed the importance
of F11 and FGG loci for VTE. Future studies
are warranted to better characterize the associations with F11
and FGG and to replicate the new candidate associations.
venous thrombosis; genetics; genome-wide association; genetic epidemiology
Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.
We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.
The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 × 10-7). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 × 10-8) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.
In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD.
We assessed the association of lung function with 2,100 genes selected for cardiovascular diseases among 20,077 European-Americans and 6,900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with percent emphysema, and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with FEV1/FVC and percent emphysema.
We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10−6) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10−7). Both SNPs flank the gene for apolipoprotein M (apoM), a component of HDL. Both replicated in an independent cohort. SNPs in a second gene related to apoM and HDL, PCSK9, were associated with FEV1/FVC among African-Americans. rs707974 was associated with percent emphysema among European-Americans and African-Americans, and APOM expression was related to FEV1/FVC and percent emphysema. Higher HDL levels were associated with lower FEV1/FVC and greater percent emphysema.
These findings suggest a novel role for the APOM/HDL pathway in the pathogenesis of COPD and emphysema.
Apolipoproteins; Cholesterol; Percent Emphysema; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive
Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate–increasing and heart rate–decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
Newly-diagnosed atrial fibrillation (AF) during severe sepsis is associated with increased risks of in-hospital stroke and mortality. However, prevalence, incidence, and risk factors associated with AF during the sepsis syndromes are unclear.
We identified patients with preexisting, newly-diagnosed, or no AF in a nationally representative 5% sample of Medicare beneficiaries hospitalized with sepsis between 2004 and 2007. We identified multivariable-adjusted demographic and clinical characteristics associated with development of newly-diagnosed AF during a sepsis hospitalization.
A total of 60,209 beneficiaries had a sepsis hospitalization. Mean age was 80.2 years, 44.4% were men, and 83.1% were white. AF occurred during 25.5% (95% CI, 25.2–25.9) of sepsis hospitalizations, including 18.3% (18.0%–18.7%) with preexisting AF and 7.2% (7.0%–7.4%) with newly-diagnosed AF. Patients with sepsis requiring intensive care had a greater risk of newly-diagnosed AF (10.7%; 95% CI, 10.3–11.1%) compared with patients who did not require intensive care (4.4%; 4.2–4.5%; P < .001). In multivariable analysis, factors associated with newly-diagnosed AF during sepsis included older age, white race, acute organ dysfunction, intensive care unit admission, mechanical ventilation, right heart catheterization, diagnosis of endocarditis, and coronary artery bypass graft surgery. Cardiovascular comorbid conditions generally were not associated with increased risk for newly-diagnosed AF during sepsis.
AF is common among critically ill patients with sepsis. Acute factors, rather than preexisting cardiovascular comorbid conditions, are associated with increased risk for newly-diagnosed AF during sepsis, suggesting that mechanisms of newly-diagnosed AF during sepsis may differ from the general population of patients with AF.
Atrial Fibrillation; Hospitalization; Incidence; Prevalence; Sepsis
Pentraxin-3 (PTX3) is a protein mediator of innate immunity that is elevated in the setting of left heart disease and pulmonary arterial hypertension. The relationship between PTX3 and right ventricular (RV) structure and function is not known. We included men and women with magnetic resonance imaging assessment of RV structure and function and measurement of PTX3 from the Multi-Ethnic Study of Atherosclerosis, a study of individuals free of clinical cardiovascular disease. Multivariable linear regression estimated associations between PTX3 protein levels and RV measures after adjusting for demographic characteristics, anthropometrics, smoking status, diabetes mellitus, hypertension, and corresponding left ventricular (LV) parameters. Instrumental variable analysis exploiting Mendelian randomization was attempted using two-stage least squares regression. The study sample included 1,779 participants with available PTX3 levels, RV measures, and all covariables. Mean PTX3 level was 2.1 ng/mL. Higher PTX3 was independently associated with greater RV mass and larger RV end-diastolic volume with and without adjustment for the corresponding LV parameters or C-reactive protein (all P < .05). There was no association between PTX3 and RV ejection fraction or stroke volume. Single-nucleotide polymorphisms were not associated with PTX3 protein levels or RV measures after accounting for race. Instrumental variable analysis could not be reliably performed. Higher PTX3 protein levels were associated with greater RV mass and larger RV end-diastolic volume. These associations were independent of common cardiovascular risk factors and LV morphologic changes. Inflammation is associated with differences in the pulmonary circulation-RV axis in adults without clinical cardiovascular disease.
pulmonary hypertension; heart failure; inflammation; right ventricle; Mendelian randomization
Prior studies suggest that circulating fatty acids may influence the risk of atrial fibrillation (AF), but little is known about the associations of circulating saturated fatty acids with risk of AF.
Methods and Results
The study population included 2899 participants from the Cardiovascular Health Study, a community‐based longitudinal cohort of adults aged 65 years or older in the United States who were free of prevalent coronary heart disease and AF in 1992. Cox regression was used to assess the association of all the long‐chain saturated fatty acids—palmitic acid (16:0), stearic acid (18:0), arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0)—with incident AF. During a median of 11.2 years of follow‐up, 707 cases of incident AF occurred. After adjustment for other AF risk factors, higher levels of circulating 16:0 were associated with a higher risk of AF (hazard ratio comparing highest and lowest quartiles: 1.48; 95% CI: 1.18, 1.86). In contrast, higher levels of circulating 18:0, 20:0, 22:0, and 24:0 were each associated with a lower risk of AF. The hazard ratios (95% CI) for AF in the top and bottom quartiles were 0.76 (95% CI: 0.61, 0.95) for 18:0; 0.78 (95% CI: 0.63, 0.97) for 20:0; 0.62 (95% CI: 0.50, 0.78) for 22:0; and 0.68 (95% CI: 0.55, 0.85) for 24:0.
Results from this prospective cohort study of older adults demonstrate divergent associations of circulating 16:0 versus longer‐chain saturated fatty acids with incident AF, highlighting the need to investigate both determinants of these levels and potential pathways of the observed differential risk.
atrial fibrillation; epidemiology; fatty acid
The electrocardiographic PR interval reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation (AF). To identify underlying common genetic variation, we meta-analyzed genome-wide association results for PR interval from seven community-based studies of European-ancestry individuals in the CHARGE consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N=28,517). Statistically significant loci (P<5×10-8) were tested for association with AF (N=5,741 cases). We identified nine loci associated with PR interval. At chromosome 3p22.2, we observed two independent associations in voltage gated sodium channel genes SCN10A and SCN5A, while six loci were near cardiac developmental genes CAV1/CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5/TBX3. Another signal was at ARHGAP24, a locus without known relevance to the heart. Five of the nine loci, SCN5A, SCN10A, NKX2-5, CAV1/CAV2, and SOX5, were also associated with AF (P<0.0056). Common genetic variation, particularly in ion channel and developmental genes, contributes significantly to atrial and atrioventricular conduction and to AF risk.
genome-wide association study; quantitative trait; PR interval; PQ interval; developmental genes; voltage gated sodium channel; atrial fibrillation