Description of the Framingham Heart Study data for Genetic Analysis Workshop 13.
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Adult↗
Biomedical subjects
Daniel Levy
Publications and source records attributed to Daniel Levy.
Consistency of linkage results across exams and methods in the Framingham Heart Study.
BACKGROUND: The repeated measures in the Framingham Heart Study in the Genetic Analysis Workshop 13 data set allow us to test for consistency of linkage results within a study across time. We compared regression-based linkage to variance components linkage across time for six quantitative traits in the real data. RESULTS: The variance components approach found 11 significant linkages, the regression-based approach found 4. There was only one region that overlapped. Consistency between exams generally decreased as the time interval between exams increased. The regression-based approach showed higher consistency in linkage results across exams. CONCLUSION: The low consistency between exams and between methods may help explain the lack of replication between studies in this field.
Adult Children↗
Hormone therapy and cardiovascular disease.
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Cardiovascular Diseases↗
Case definitions for acute coronary heart disease in epidemiology and clinical research studies: a statement from the AHA Council on Epidemiology and Prevention; AHA Statistics Committee; World Heart Federation Council on Epidemiology and Prevention; the European Society of Cardiology Working Group on Epidemiology and Prevention; Centers for Disease Control and Prevention; and the National Heart, Lung, and Blood Institute.
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Acute Disease↗
Association between estrogen receptor alpha gene variation and cardiovascular disease.
CONTEXT: Estrogen and related hormone therapies activate estrogen receptors, which in turn regulate genes for several cardiovascular disease (CVD) risk factors. Relatively little is known, however, about the impact of genetic variation in estrogen receptor alpha (ESR1) on CVD risk. OBJECTIVE: To investigate whether the ESR1 c.454-397T>C polymorphism is associated with CVD risk. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 1739 unrelated men and women from the population-based offspring cohort of the Framingham Heart Study, who were followed up from 1971 to 1998. MAIN OUTCOME MEASURES: Total atherosclerotic CVD events, defined as recognized or unrecognized myocardial infarction (MI), angina pectoris, coronary insufficiency, intermittent claudication, coronary heart disease death, or atherothrombotic stroke (n = 178); major atherosclerotic CVD, defined as recognized acute MI, coronary insufficiency, coronary heart disease death, or atherothrombotic stroke (n = 83); and recognized acute MI (n = 59). RESULTS: Twenty percent of participants (n = 352) were homozygous for the ESR1 c.454-397C allele. After adjustment for covariates (age, sex, body mass index, hypertension, diabetes mellitus, total cholesterol, high-density lipoprotein cholesterol, and cigarette smoking), the CC genotype was significantly associated with major atherosclerotic CVD, with an odds ratio of 2.0 (95% confidence interval [CI], 1.3-3.2; P =.004) compared with individuals with the CT or TT genotypes. Participants with the CC genotype had 3.0-fold greater odds of MI (95% CI, 1.7-5.2; P<.001) compared with those with the CT or TT genotype. The results remained significant when analyses were restricted to men; too few women had events to study them separately. CONCLUSIONS: Individuals with the common ESR1 c.454-397CC genotype have a substantial increase in risk of MI. Whether ESR1 c.454-397T>C is causally related to MI risk or in linkage disequilibrium with 1 or more causal variants remains to be determined. These findings support the importance of estrogen receptors in CVD susceptibility, especially in men. Estrogen receptor variation also has potential to explain recent conflicting data regarding the effects of hormone therapy on CVD susceptibility in women.
Cardiovascular Diseases↗
Plasma homocysteine, hypertension incidence, and blood pressure tracking: the Framingham Heart Study.
Plasma homocysteine is cross-sectionally associated with blood pressure in large, community-based studies. It is unknown whether elevated plasma homocysteine predicts hypertension incidence. We investigated the relations of baseline plasma total homocysteine levels to hypertension incidence and blood pressure tracking in 2104 Framingham Heart Study participants (mean age, 57 years; 58% women), who were free of hypertension, myocardial infarction, heart failure, atrial fibrillation, or renal failure at baseline. Baseline mean+/-SD plasma homocysteine was 10.1+/-3.7 micromol/L. On follow-up 4 years from baseline, 360 persons (17.1%) had developed hypertension, and 878 persons (41.7%) had progressed to a higher blood pressure stage. In unadjusted analyses, a 1-SD higher log homocysteine value was associated with increased odds of developing hypertension (odds ratio [OR], 1.18; 95% confidence interval [CI], 1.05 to 1.32) and increased odds of blood pressure progression (OR, 1.17; 95% CI, 1.07 to 1.27). The relations of plasma homocysteine to the incidence of hypertension or blood pressure progression were statistically nonsignificant in age- and sex-adjusted logistic regression models (OR, 0.98; 95% CI, 0.87 to 1.11 and OR, 1.05; 95% CI, 0.96 to 1.16, respectively) and in multivariable models adjusted for age, sex, body mass index, diabetes, interim weight change, smoking, serum creatinine, baseline blood pressure, and blood pressure category (OR, 0.92; 95% CI, 0.81 to 1.06 and OR, 1.07; 95% CI, 0.97 to 1.18, respectively). In conclusion, we found no major relation of baseline plasma homocysteine levels to hypertension incidence or longitudinal blood pressure progression in a large, community-based cohort of nonhypertensive individuals after adjustment for age, sex, and other important covariates.
Blood Pressure↗
Serum insulin-like growth factor I and risk for heart failure in elderly individuals without a previous myocardial infarction: the Framingham Heart Study.
BACKGROUND: Several experimental investigations have emphasized the favorable effects of insulin-like growth factor I (IGF-I) on left ventricular remodeling, partly through its antiapoptotic effects. Cross-sectional clinical studies have reported that low serum IGF-I levels in patients with heart failure correlate with cachexia and severity of ventricular dysfunction. It is unclear whether low serum IGF-I is a risk factor for heart failure. OBJECTIVE: To prospectively study the association between serum IGF-I level and the incidence of congestive heart failure. DESIGN: Community-based, prospective cohort study. SETTING: Framingham, Massachusetts. PARTICIPANTS: 717 elderly individuals (mean age, 78.4 years; 67% women) who did not have myocardial infarction and congestive heart failure at baseline. MEASUREMENT: Incidence of a first episode of congestive heart failure on follow-up. RESULTS: During follow-up (mean, 5.2 years), 56 participants (35 women) developed congestive heart failure. In multivariable Cox regression models adjusting for established risk factors at baseline, there was a 27% decrease in risk for heart failure for every 1 standard deviation increment in log IGF-I. Individuals with serum IGF-I level at or above the median value (140 microg/L) had half the risk for heart failure (hazard ratio, 0.49 [95% CI, 0.26 to 0.92]) of those with serum IGF-I levels below the median. These comparisons were maintained in analyses adjusting for the occurrence of a myocardial infarction on follow-up. CONCLUSIONS: In our prospective, community-based investigation, serum IGF-I level was inversely related to the risk for congestive heart failure in elderly people without a previous myocardial infarction. Additional investigations are warranted to confirm these findings.
Aged↗
Cell surface expression and bile acid transport function of one topological form of m-epoxide hydrolase.
The bifunctional hepatic protein, microsomal epoxide hydrolase (mEH), plays a central role in the metabolism of many xenobiotics as well as mediating the Na(+)-dependent uptake of bile acids in parallel with the Na(+)-taurocholate co-transporting protein (ntcp). Previous studies have established that mEH is expressed in the endoplasmic reticulum with two topological orientations, where the type II form is targeted to the plasma membrane. In this report the topology and transport properties of mEH as a function of plasma membrane expression in cultured hepatocytes, transfected Madin-Darby canine kidney cells expressing mEH (MDCK[mEH]), and the human hepatoma cell line, HepG2, were studied using confocal fluorescence microscopy and substrate uptake measurements. Analysis of mEH localization with an anti-mEH monoclonal antibody demonstrated the expression of one topological form on the plasma membrane of hepatocytes and MDCK[mEH] cells where both systems exhibited Na(+)-dependent bile acid uptake. In contrast, Na(+)-dependent bile acid transport in HepG2 cells and hepatocytes in culture (72 h) was substantially reduced as was the expression of ntcp. Although the total mEH level was undiminished, the decrease of bile acid transport was associated with the loss of mEH surface expression possibly resulting from an alteration in mEH endoplasmic reticulum topology and/or the plasma membrane protein targeting system in these de-differentiated cells.
Animals↗
Is the relation of systolic blood pressure to risk of cardiovascular disease continuous and graded, or are there critical values?
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Adult↗
The ankle-brachial index in the elderly and risk of stroke, coronary disease, and death: the Framingham Study.
BACKGROUND: A low ankle-brachial index (ABI) is associated with an increased risk of death and cardiovascular disease. Limited data exist regarding the relation between a low ABI and stroke. We sought to examine the relation between a low ABI and stroke, coronary heart disease, and death in the elderly. METHODS: We examined 251 men and 423 women with a mean age of 80 years who had a Framingham Study examination from 1994 to 1995. A low ABI was defined as less than 0.9. Persons were followed up for 4 years for occurrence of stroke or transient ischemic attack, coronary disease, and death. Cox proportional hazards models were used to assess the relation between a low ABI and each outcome after adjusting for age, sex, and prevalent cardiovascular disease. RESULTS: A low ABI was detected in 20% of our sample. Only 18% of the participants with a low ABI reported claudication symptoms. One third of those with a normal ABI and 55% of those with a low ABI had cardiovascular disease at baseline. Results of multivariable Cox proportional hazards analysis demonstrated a statistically significant increase in the risk of stroke or transient ischemic attack in persons with a low ABI (hazards ratio, 2.0; 95% confidence interval, 1.1-3.7). No significant relation between a low ABI and coronary heart disease (hazards ratio, 1.2; 95% confidence interval, 0.7-2.1) or death (hazards ratio, 1.4; 95% confidence interval, 0.9-2.1) was observed. CONCLUSIONS: A low ABI is associated with risk of stroke or transient ischemic attack in the elderly. These results need to be confirmed in larger studies.
Aged↗
Lifetime risk of coronary heart disease by cholesterol levels at selected ages.
BACKGROUND: We sought to assess how cholesterol levels at different ages modify the remaining lifetime risk of coronary heart disease (CHD). METHODS: We included all Framingham Heart Study participants examined from 1971 through 1996 who did not have CHD and were not receiving lipid-lowering therapy. At index ages of 40, 50, 60, 70, and 80 years, participants were stratified by total cholesterol level and by cholesterol subfractions. Lifetime risk of CHD was calculated with death free of CHD as a competing event. RESULTS: Among 3269 men and 4019 women, 1120 developed CHD and 1365 died free of CHD during follow-up. At each index age, lifetime risk of CHD increased with higher cholesterol levels, and time to event decreased. At age 40 years, the lifetime risks of CHD through age 80 years for men with total cholesterol levels less than 200 mg/dL (<5.20 mmol/L), 200 to 239 mg/dL (5.20-6.19 mmol/L), and 240 mg/dL or greater (> or =6.20 mmol/L), respectively, were 31%, 43%, and 57%; for women, the lifetime risks were 15%, 26%, and 33%, respectively. Lifetime risks contrasted sharply with shorter-term risks: at age 40 years, the 10-year cumulative risks of CHD were 3%, 5%, and 12% for men, and 1%, 2%, and 5% for women, respectively. CONCLUSIONS: Lifetime risk of CHD increases sharply with higher total cholesterol levels for men and women at all ages. These data support an important role for cholesterol screening in younger patients, and they may help target high-risk patients for lifestyle modification or drug therapy.
Adult↗
Magnetoencephalographic study of the cortical activity elicited by human voice.
In an attempt to identify voice-specific neural activities in auditory cortex in humans, we recorded cortical magnetic responses. Volunteers were instructed to listen to vocal and instrumental sounds matched in fundamental-frequency, duration, temporal envelope and average root mean square power. The stimuli were sounds produced by four singers and four musical instruments at each of two fundamental frequencies: 220 Hz (musical note A3) and 261.9 Hz (C3). Two components of the evoked responses were analyzed, one at approximately 100 ms (N1m) and the other 400 ms after the stimulus onset (sustained field, SF). The source locations of equivalent current dipoles for both components were estimated around the Heschl's gyrus in both hemispheres. Compared with the instrumental sound, the source strength of the SF component for the voice was significantly larger.
Acoustic Stimulation↗
A risk score for predicting stroke or death in individuals with new-onset atrial fibrillation in the community: the Framingham Heart Study.
CONTEXT: Prior risk stratification schemes for atrial fibrillation (AF) have been based on randomized trial cohorts or Medicare administrative databases, have included patients with established AF, and have focused on stroke as the principal outcome. OBJECTIVE: To derive risk scores for stroke alone and stroke or death in community-based individuals with new-onset AF. DESIGN, SETTING, AND PARTICIPANTS: Prospective, community-based, observational cohort in Framingham, Mass. We identified 868 participants with new-onset AF, 705 of whom were not treated with warfarin at baseline. Risk scores for stroke (ischemic or hemorrhagic) and stroke or death were developed with censoring when warfarin initiation occurred during follow-up. Event rates were examined in low-risk individuals, as defined by the risk score and 4 previously published risk schemes. MAIN OUTCOME MEASURES: Stroke and the combination of stroke or death. RESULTS: During a mean follow-up of 4.0 years free of warfarin use, stroke alone occurred in 83 participants and stroke or death occurred in 382 participants. A risk score for stroke was derived that included the following risk predictors: advancing age, female sex, increasing systolic blood pressure, prior stroke or transient ischemic attack, and diabetes. With the risk score, 14.3% of the cohort had a predicted 5-year stroke rate < or =7.5% (average annual rate < or =1.5%), and 30.6% of the cohort had a predicted 5-year stroke rate < or =10% (average annual rate < or =2%). Actual stroke rates in these low-risk groups were 1.1 and 1.5 per 100 person-years, respectively. Previous risk schemes classified 6.4% to 17.3% of subjects as low risk, with actual stroke rates of 0.9 to 2.3 per 100 person-years. A risk score for stroke or death is also presented. CONCLUSION: These risk scores can be used to estimate the absolute risk of an adverse event in individuals with AF, which may be helpful in counseling patients and making treatment decisions.
Aged↗
Natural history of asymptomatic left ventricular systolic dysfunction in the community.
BACKGROUND: Information is limited regarding the rates of progression to congestive heart failure (CHF) and death in individuals with asymptomatic left ventricular systolic dysfunction (ALVD). We sought to characterize the natural history of ALVD, by studying unselected individuals with this condition in the community. METHODS AND RESULTS: We studied 4257 participants (1860 men) from the Framingham Study who underwent routine echocardiography. The prevalence of ALVD (visually estimated ejection fraction [EF] 50%, n=4128) and ALVD (n=129) were 0.7 and 5.8 per 100 person-years, respectively. After adjustment for cardiovascular disease risk factors, ALVD was associated with a hazards ratio (HR) for CHF of 4.7 (95% CI 2.7 to 8.1), compared with individuals without ALVD. An elevated risk of CHF after ALVD was observed even in individuals without prior myocardial infarction or valvular disease, with an adjusted HR of 6.5 (CI 3.1 to 13.5). Mild ALVD (EF 40% to 50%, n=78) and moderate-to-severe ALVD (EF <40%, n=51) were associated with adjusted HRs for CHF of 3.3 (CI 1.7 to 6.6) and 7.8 (CI 3.9 to 15.6), respectively. ALVD was also associated with an increased mortality risk (adjusted HR 1.6, CI 1.1 to 2.4). The median survival of ALVD subjects was 7.1 years. CONCLUSIONS: Individuals with ALVD in the community are at high risk of CHF and death, even when only mild impairment of EF is present. Additional studies are needed to define optimal therapy for mild ALVD.
Adult↗
Inhibition of human m-epoxide hydrolase gene expression in a case of hypercholanemia.
Microsomal epoxide hydrolase (mEH) is a bifunctional protein that plays a central role in carcinogen metabolism and is also able to mediate the sodium-dependent uptake of bile acids into hepatocytes. Studies have identified a subject (S-1) with extremely elevated serum bile salt levels in the absence of observable hepatocellular injury, suggesting a defect in bile acid uptake. In this individual, mEH protein and mEH mRNA levels were reduced by approximately 95% and 85%, respectively, whereas the expression and amino acid sequence of another bile acid transport protein (NTCP) was unaffected. Sequence analysis of the mEH gene (EPHX1) revealed a point mutation at an upstream HNF-3 site (allele I) and in intron 1 (allele II), which resulted in a significant decrease in EPHX1 promoter activity in transient transfection assays. Gel shift assays using a radiolabeled oligonucleotide from each region resulted in specific transcription factor binding patterns, which were altered in the presence of the mutation. These studies demonstrate that the expression of mEH is greatly reduced in a patient with hypercholanemia, suggesting that mEH participates in sodium-dependent bile acid uptake in human liver where its absence may contribute to the etiology of this disease.
Alleles↗
Heritability and genetic linkage of plasma natriuretic peptide levels.
BACKGROUND: Natriuretic peptides play a critical role in the maintenance of salt and water homeostasis and regulation of vascular tone. Thus, interindividual variation in plasma natriuretic peptide levels may contribute to variation in susceptibility to volume overload and hypertension. It is unknown to what extent genetic factors contribute to variation in plasma natriuretic peptide levels. METHODS AND RESULTS: We studied 1914 Framingham Study participants (mean age 57 years, 53% women) who underwent routine echocardiography and testing for plasma N-terminal proatrial natriuretic peptide (N-ANP) and brain natriuretic peptide (BNP). We estimated sex-specific multivariable models and used variance-components methods, implemented in SOLAR (Sequential Oligogenic Linkage Analysis Routines), to estimate heritability. Multipoint linkage analyses were performed using data from a 10-cM-density genome scan. Age, clinical, and echocardiographic variables accounted for 42% and 40% of the variation in log N-ANP and log BNP levels, respectively, in men. Corresponding values in women were 27% and 21%. Multivariable-adjusted heritabilities were 0.44 for log N-ANP and 0.35 for log BNP (P<0.0001). Genome-wide linkage analyses, based on 1142 participants from the 314 largest families, revealed 2 regions of suggestive linkage for log N-ANP and log BNP on chromosomes 2p25 (log-of-odds score 2.40) and 12p13 (log-of-odds score 2.13), respectively. CONCLUSIONS: In this community-based sample, a substantial proportion of the unexplained variation in plasma natriuretic peptide levels was attributable to additive genetic effects. Additional studies using candidate gene approaches may provide insight into the genetic loci that regulate plasma natriuretic peptide levels in humans.
Atrial Natriuretic Factor↗
The epidemiology of "asymptomatic" left ventricular systolic dysfunction: implications for screening.
Congestive heart failure is a progressive disorder that is frequently preceded by asymptomatic left ventricular systolic dysfunction. We reviewed the epidemiology, diagnosis, and natural history of asymptomatic left ventricular systolic dysfunction and evaluated community-wide screening for this condition as a potential strategy to reduce the incidence of heart failure. Asymptomatic left ventricular systolic dysfunction has an estimated prevalence of 3% to 6%, and is at least as common in the community as systolic heart failure. Because it often occurs in the absence of known cardiovascular disease, this condition may go unrecognized and undertreated. In randomized trials, individuals with asymptomatic left ventricular systolic dysfunction have high rates of incident heart failure and death. However, little is known about the prognosis of individuals with this condition in the community, who have a substantially lower prevalence of myocardial infarction, have milder degrees of systolic dysfunction, and are older than patients enrolled in clinical trials. Current evidence is inadequate to support community-wide screening for asymptomatic left ventricular systolic dysfunction, either with echocardiography or with assays for natriuretic peptides. Given the increasing prevalence of heart failure, additional studies are needed to develop effective strategies to detect and optimally manage individuals with asymptomatic left ventricular dysfunction in the community.
Angiotensin-Converting Enzyme Inhibitors↗
Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study.
BACKGROUND: Atrial fibrillation (AF) and congestive heart failure (CHF) frequently occur together, but there is limited information regarding their temporal relations and the combined influence of these conditions on mortality. METHODS AND RESULTS: We studied participants in the Framingham Study with new-onset AF or CHF. Multivariable Cox proportional hazards models with time-dependent variables were used to evaluate whether mortality after AF or CHF was affected by the occurrence and timing of the other condition. Hazard ratios (HRs) were adjusted for time period and cardiovascular risk factors. During the study period, 1470 participants developed AF, CHF, or both. Among 382 individuals with both conditions, 38% had AF first, 41% had CHF first, and 21% had both diagnosed on the same day. The incidence of CHF among AF subjects was 33 per 1000 person-years, and the incidence of AF among CHF subjects was 54 per 1000 person-years. In AF subjects, the subsequent development of CHF was associated with increased mortality (men: HR 2.7; 95% CI, 1.9 to 3.7; women: HR 3.1; 95% CI, 2.2 to 4.2). Similarly, in CHF subjects, later development of AF was associated with increased mortality (men: HR 1.6; 95% CI, 1.2 to 2.1; women: HR 2.7, 95% CI, 2.0 to 3.6). Preexisting CHF adversely affected survival in individuals with AF, but preexisting AF was not associated with adverse survival in those with CHF. CONCLUSIONS: Individuals with AF or CHF who subsequently develop the other condition have a poor prognosis. Additional studies addressing the pathogenesis, prevention, and optimal management of the joint occurrence of AF and CHF appear warranted.
Aged↗