Genome-wide association study of electrocardiographic and heart rate variability traits: the Framingham Heart Study

BACKGROUND: Heritable electrocardiographic (ECG) and heart rate variability (HRV) measures, reflecting pacemaking, conduction, repolarization and autonomic function in the heart have been associated with risks for cardiac arrhythmias. Whereas several rare monogenic conditions with extreme phenotypes have been noted, few common genetic factors contributing to interindividual variability in ECG and HRV measures have been identified. We report the results of a community-based genomewide association study of six ECG and HRV intermediate traits. METHODS: Genotyping using Affymetrix 100K GeneChip was conducted on 1345 related Framingham Heart Study Original and Offspring cohort participants. We analyzed 1175 Original and Offspring participants with ECG data (mean age 52 years, 52% women) and 548 Offspring participants with HRV data (mean age 48 years, 51% women), in relation to 70,987 SNPs with minor allele frequency ≥ 0.10, call rate ≥ 80%, Hardy-Weinberg p-value ≥ 0.001. We used generalized estimating equations to test association of SNP alleles with multivariable-adjusted residuals for QT, RR, and PR intervals, the ratio of low frequency to high frequency power (LF/HFP), total power (TP) and the standard deviation of normal RR intervals (SDNN). RESULTS: Associations at p < 10-3 were found for 117 (QT), 105 (RR), 111 (PR), 102 (LF/HF), 121 (TP), and 102 (SDNN) SNPs. Several common variants in NOS1AP (4 SNPs with p-values < 10-3; lowest p-value, rs6683968, p = 1 × 10-4) were associated with adjusted QT residuals, consistent with our previously reported finding for NOS1AP in an unrelated sample of FHS Offspring and other cohorts. All results are publicly available at NCBI's dbGaP at. CONCLUSION: In the community-based Framingham Heart Study none of the ECG and HRV results individually attained genomewide significance. However, the presence of bona fide QT-associated SNPs among the top 117 results for QT duration supports the importance of efforts to validate top results from the reported scans. Finding genetic variants associated with ECG and HRV quantitative traits may identify novel genes and pathways implicated in arrhythmogenesis and allow for improved recognition of individuals at high risk for arrhythmias in the general population.National Institutes of Health (K23 N01-HC25195); Doris Duke Charitable Foundation Clinical Scientist Developement Award; Pfizer; National Institutes of Health National Center for Research Resources Shared Instrumentation grant (1S10RR163736-01A1

A NOS1AP gene variant is associated with a paradoxical increase of the QT-interval shortening effect of digoxin

Digoxin is characterized by a small therapeutic window and a QT-interval shortening effect. Moreover, it has been shown that the genetic variants of the nitric oxide synthase-1 adaptor protein (NOS1AP) gene are associated with QT-interval prolongation. We investigated whether the rs10494366 variant of the NOS1AP gene decreases the QT-interval shortening effect of digoxin in patients using this drug. We included 10,057 individuals from the prospective population-based cohort of the Rotterdam Study during a median of 12.2 (interquartile range (IQR) 6.7-18.1) years of follow-up. At study entry, the mean age was 64 years and almost 59% of participants were women. A total of 23,179 ECGs were longitudinally recorded, of which 334 ECGs were from 249 individuals on digoxin therapy. The linear mixed model analysis was used to estimate the effect of the rs10494366 variant on the association between digoxin use and QT-interval duration, adjusted for age, sex, RR interval, diabetes, heart failure, and history of myocardial infarction. In non-users of digoxin, the GG genotype was associated with a significant 6.5 ms [95% confidence interval (CI) 5.5; 7.5] longer QT-interval duration than the TT variant. In current digoxin users, however, the GG variant was associated with a significantly -23.9 [95%CI -29.5; -18.5] ms shorter mean QT-interval duration than in those with the TT variant with -15.9 [95%CI -18.7; -13.1]. This reduction was strongest in the high digoxin dose category [≥0.250 mg/day] with the GG genotype group, with -40.8 [95%CI -52.5; -29.2] ms changes compared to non-users. Our study suggests that the minor homozygous GG genotype group of the NOS1AP gene rs10494366 variant is associated with a paradoxical increase of the QT-interval shortening effect of digoxin in a population of European ancestry

Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study

<p>Abstract</p> <p>Background</p> <p>Echocardiographic left ventricular (LV) measurements, exercise responses to standardized treadmill test (ETT) and brachial artery (BA) vascular function are heritable traits that are associated with cardiovascular disease risk. We conducted a genome-wide association study (GWAS) in the community-based Framingham Heart Study.</p> <p>Methods</p> <p>We estimated multivariable-adjusted residuals for quantitative echocardiography, ETT and BA function traits. Echocardiography residuals were averaged across 4 examinations and included LV mass, diastolic and systolic dimensions, wall thickness, fractional shortening, left atrial and aortic root size. ETT measures (single exam) included systolic blood pressure and heart rate responses during exercise stage 2, and at 3 minutes post-exercise. BA measures (single exam) included vessel diameter, flow-mediated dilation (FMD), and baseline and hyperemic flow responses. Generalized estimating equations (GEE), family-based association tests (FBAT) and variance-components linkage were used to relate multivariable-adjusted trait residuals to 70,987 SNPs (Human 100K GeneChip, Affymetrix) restricted to autosomal SNPs with minor allele frequency ≥0.10, genotype call rate ≥0.80, and Hardy-Weinberg equilibrium p ≥ 0.001.</p> <p>Results</p> <p>We summarize results from 17 traits in up to 1238 related middle-aged to elderly men and women. Results of all association and linkage analyses are web-posted at <url>http://ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007</url>. We confirmed modest-to-strong heritabilities (estimates 0.30–0.52) for several Echo, ETT and BA function traits. Overall, p < 10^-5in either GEE or FBAT models were observed for 21 SNPs (nine for echocardiography, eleven for ETT and one for BA function). The top SNPs associated were (GEE results): LV diastolic dimension, rs1379659 (<it>SLIT2</it>, p = 1.17*10^-7); LV systolic dimension, rs10504543 (<it>KCNB2</it>, p = 5.18*10^-6); LV mass, rs10498091 (p = 5.68*10^-6); Left atrial size, rs1935881 (<it>FAM5C</it>, p = 6.56*10^-6); exercise heart rate, rs6847149 (<it>NOLA1</it>, p = 2.74*10^-6); exercise systolic blood pressure, rs2553268 (<it>WRN</it>, p = 6.3*10^-6); BA baseline flow, rs3814219 (<it>OBFC1</it>, 9.48*10^-7), and FMD, rs4148686 (<it>CFTR</it>, p = 1.13*10^-5). Several SNPs are reasonable biological candidates, with some being related to multiple traits suggesting pleiotropy. The peak LOD score was for LV mass (4.38; chromosome 5); the 1.5 LOD support interval included <it>NRG2</it>.</p> <p>Conclusion</p> <p>In hypothesis-generating GWAS of echocardiography, ETT and BA vascular function in a moderate-sized community-based sample, we identified several SNPs that are candidates for replication attempts and we provide a web-based GWAS resource for the research community.</p

High-Dose versus Low-Dose Vitamin D Supplementation and Arterial Stiffness among Individuals with Prehypertension and Vitamin D Deficiency

Introduction:. Vitamin D deficiency is associated with the onset and progression of hypertension and cardiovascular disease (CVD). However, mechanisms underlying vitamin D deficiency-mediated increased risk of CVD remain unknown. We sought to examine the differential effect of high-dose versus low-dose vitamin D supplementation on markers of arterial stiffness among ~40 vitamin D deficient adults with prehypertension. Methods:. Participants were randomized to high-dose (4000 IU/d) versus low-dose (400 IU/d) oral vitamin D3 for 6 months. 24 hr ambulatory blood pressure (BP), carotid-femoral pulse wave velocity, and pulse wave analyses were obtained at baseline and after 6 months of vitamin D supplementation. Results:. There were no changes in resting BP or pulse wave velocity over 6 mo regardless of vitamin D dose (all p > 0.202). High-dose vitamin D decreased augmentation index and pressure by 12.3 ± 5.3% (p = 0.047) and 4.0 ± 1.5 mmHg (p = 0.02), respectively. However, these decreases in arterial stiffness were not associated with increases in serum 25-hydroxyvitamin D over 6 mo (p = 0.425). Conclusion:. High-dose vitamin D supplementation appears to lower surrogate measures of arterial stiffness but not indices of central pulse wave velocity. Clinical Trial Registration. This trial is registered with www.clinicaltrials.gov (Unique Identifier: NCT01240512)

Risk Profiles for Aortic Dissection and Ruptured or Surgically Treated Aneurysms: A Prospective Cohort Study

Background: Community screening to guide preventive interventions for acute aortic disease has been recommended in high‐risk individuals. We sought to prospectively assess risk factors in the general population for aortic dissection (AD) and severe aneurysmal disease in the thoracic and abdominal aorta. Methods and Results: We studied the incidence of AD and ruptured or surgically treated aneurysms in the abdominal (AAA) or thoracic aorta (TAA) in 30 412 individuals without diagnosis of aortic disease at baseline from a contemporary, prospective cohort of middle‐aged individuals, the Malmö Diet and Cancer study. During up to 20 years of follow‐up (median 16 years), the incidence rate per 100 000 patient‐years at risk was 15 (95% CI 11.7 to 18.9) for AD, 27 (95% CI 22.5 to 32.1) for AAA, and 9 (95% CI 6.8 to 12.6) for TAA. The acute and in‐hospital mortality was 39% for AD, 34% for ruptured AAA, and 41% for ruptured TAA. Hypertension was present in 86% of individuals who subsequently developed AD, was strongly associated with incident AD (hazard ratio [HR] 2.64, 95% CI 1.33 to 5.25), and conferred a population‐attributable risk of 54%. Hypertension was also a risk factor for AAA with a smaller effect. Smoking (HR 5.07, 95% CI 3.52 to 7.29) and high apolipoprotein B/A1 ratio (HR 2.48, 95% CI 1.73 to 3.54) were strongly associated with AAA and conferred a population‐attributable risk of 47% and 25%, respectively. Smoking was also a risk factor for AD and TAA with smaller effects. Conclusions: This large prospective study identified distinct risk factor profiles for different aortic diseases in the general population. Hypertension accounted for more than half of the population risk for AD, and smoking for half of the population risk of AAA

Genome-wide association with bone mass and geometry in the Framingham Heart Study

© 2007 Kiel et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution Licens

Increased power of mixed models facilitates association mapping of 10 loci for metabolic traits in an isolated population

The potential benefits of using population isolates in genetic mapping, such as reduced genetic, phenotypic and environmental heterogeneity, are offset by the challenges posed by the large amounts of direct and cryptic relatedness in these populations confounding basic assumptions of independence. We have evaluated four representative specialized methods for association testing in the presence of relatedness; (i) within-family (ii) within- and between-family and (iii) mixed-models methods, using simulated traits for 2906 subjects with known genome-wide genotype data from an extremely isolated population, the Island of Kosrae, Federated States of Micronesia. We report that mixed models optimally extract association information from such samples, demonstrating 88% power to rank the true variant as among the top 10 genome-wide with 56% achieving genome-wide significance, a >80% improvement over the other methods, and demonstrate that population isolates have similar power to non-isolate populations for observing variants of known effects. We then used the mixed-model method to reanalyze data for 17 published phenotypes relating to metabolic traits and electrocardiographic measures, along with another 8 previously unreported. We replicate nine genome-wide significant associations with known loci of plasma cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, thyroid stimulating hormone, homocysteine, C-reactive protein and uric acid, with only one detected in the previous analysis of the same traits. Further, we leveraged shared identity-by-descent genetic segments in the region of the uric acid locus to fine-map the signal, refining the known locus by a factor of 4. Finally, we report a novel associations for height (rs17629022, P< 2.1 × 10−8