Framingham Heart Study Population Research Articles

Development and validation of the HARMS2-AF lifestyle risk score to predict incident AF

Abstract Background Lifestyle risk factors (RFs) are a modifiable target in atrial fibrillation (AF) management. However, the relative contribution of individual lifestyle RFs to AF incidence has not been described. Purpose Development and validation of a novel AF-lifestyle risk score to determine AF risk in the general population. Methods The UK Biobank (UKB) is a large prospective cohort with outcomes measured >10 years. In the UKB, we performed regression analysis of AF lifestyle RFs which were then evaluated in a multivariable model and a weighted score was developed. Next, the risk score was externally validated in the Framingham Heart Study (FHS) population. Kaplan-Meier estimates ascertained the 10-year risk of AF development. Results In the UKB, AF incidence was 5.3% among 302,926 participants, with a median time to AF 7.3 years (IQR 4.3–9.8). Hypertension, sleep apnoea, male sex, age, obesity (BMI>30 kg/m2), alcohol and smoking were predictive variables (all p<0.001); physical inactivity (OR 1.02,95% CI 0.97–1.10, p=0.3), diabetes (OR 0.98,95% CI 0.91–1.06, p=0.2) and BMI 27–30 kg/m2 (OR 1.02, 95% CI 0.97–1.07, p=0.424) were not significant. The HARMS2-AF score (Figure 1) had similar predictive performance (AUC=0.782, LogLoss 0.178, Brier Score 0.046) to the unweighted regression model (AUC 0.808) in the UKB. Validation in the FHS (AF incidence 6.7% of 7206 participants) maintained excellent predictive performance with an AUC of 0.747 (95% CI 0.724–0.769, Figure 2). A higher HARMS2-AF score (>5 points) was associated with a heightened 10-year AF risk (score 5–9: OR 9.35, score 10–14: OR 33.34). Conclusions The HARMS2-AF score is a novel lifestyle risk score which may help identify individuals at risk of AF and assists in general population screening. Funding Acknowledgement Type of funding sources: None.

Paraseptal emphysema: Prevalence and distribution on CT and association with interstitial lung abnormalities

ObjectiveTo investigate the prevalence and distribution of paraseptal emphysema on chest CT images in the Framingham Heart Study (FHS) population, and assess its impact on pulmonary function. Also pursued was the association with interstitial lung abnormalities. Materials and methodsWe assessed 2633 participants in the FHS for paraseptal emphysema on chest CT. Characteristics of the participants, including age, sex, smoking status, clinical symptoms, and results of pulmonary function tests, were compared between those with and without paraseptal emphysema. The association between paraseptal emphysema and interstitial lung abnormalities was investigated. ResultsOf the 2633 participants, 86 (3%) had pure paraseptal emphysema (defined as paraseptal emphysema with no other subtypes of emphysema other than paraseptal emphysema or a very few centrilobular emphysema involved) in at least one lung zone. The upper zone of the lungs was almost always involved. Compared to the participants without paraseptal emphysema, those with pure paraseptal emphysema were significantly older, and were more frequently male and smokers (mean 64 years, 71% male, mean 36 pack-years, P<0.001) and had significantly decreased FEV1/FVC% (P=0.002), and diffusion capacity of carbon monoxide (DLCO) (P=0.002). There was a significant association between pure paraseptal emphysema and interstitial lung abnormalities (P<0.001). ConclusionsThe prevalence of pure paraseptal emphysema was 3% in the FHS population, predominantly affects the upper lung zone, and contributes to decreased pulmonary function. Cigarette smoking, aging, and male gender were the factors associated with the presence of paraseptal emphysema. Significant association between paraseptal emphysema and interstitial lung abnormalities was observed.

Predictive Value for the Rural Chinese Population of the Framingham Hypertension Risk Model: Results From Liaoning Province

A prediction model from the US Framingham Heart Study (FHS) population has been established to estimate an individual's risk of developing hypertension. However, this model has not been widely tested in other cohorts. In this study, we examined the predictive capability of the FHS prediction model in a rural Chinese population. A total of 24,434 rural Chinese adults aged ≥35 years, without prevalent hypertension, diabetes mellitus, stroke, and coronary heart disease at baseline, were followed for the incidence of hypertension. Standard clinical examinations of blood pressure, weight and height, smoking status, and parental history of hypertension were observed biennially. The mean age was 47.9 (SD = 10.2) years, and 49.5% of subjects were women. During a median 4.8 years of follow-up, we recorded a total of 8,675 incident hypertension cases. The cumulative 2-year and 4-year hypertension incidence rates were 7.7% and 25.6%, respectively. The C statistics for the 2-year and 4-year incidences of hypertension were 0.537 (95% confidence interval (CI) = 0.524-0.550) and 0.610 (95% CI = 0.602-0.618) for the FHS model, respectively. The Hosmer-Lemeshow χ(2) test results for 2-year and 4-year incidence of hypertension were 2,287.7 (P < 0.0001) and 8,227.1 (P < 0.0001), respectively. Sensitivity analysis indicates that the FHS prediction model still has a poor performance, although the predictive ability was better than for the overall population. The FHS hypertension prediction model is not a valid tool with which to estimate the risk of incidence of hypertension among the rural Chinese population. A new hypertension risk equation for the rural Chinese population is needed.

Heritability and Genetic Correlations Explained by Common SNPs for Metabolic Syndrome Traits

We used a bivariate (multivariate) linear mixed-effects model to estimate the narrow-sense heritability (h2) and heritability explained by the common SNPs (hg2) for several metabolic syndrome (MetS) traits and the genetic correlation between pairs of traits for the Atherosclerosis Risk in Communities (ARIC) genome-wide association study (GWAS) population. MetS traits included body-mass index (BMI), waist-to-hip ratio (WHR), systolic blood pressure (SBP), fasting glucose (GLU), fasting insulin (INS), fasting trigylcerides (TG), and fasting high-density lipoprotein (HDL). We found the percentage of h2 accounted for by common SNPs to be 58% of h2 for height, 41% for BMI, 46% for WHR, 30% for GLU, 39% for INS, 34% for TG, 25% for HDL, and 80% for SBP. We confirmed prior reports for height and BMI using the ARIC population and independently in the Framingham Heart Study (FHS) population. We demonstrated that the multivariate model supported large genetic correlations between BMI and WHR and between TG and HDL. We also showed that the genetic correlations between the MetS traits are directly proportional to the phenotypic correlations.

High Incidence of Arterial Thrombosis in Young Patients Treated for Multiple Myeloma:Results of a Prospective Cohort Study.

Abstract 149▪▪This icon denotes an abstract that is clinically relevant.It is well known that patients with multiple myeloma (MM) are at high risk for venous thromboembolism (VTE). Thrombotic complications are most frequently seen in patients treated with thalidomide based regimens. Several other risk factors for VTE have been identified including abnormalities in coagulation factors, such as high factor VIII levels, APC resistance and hypofibrinolysis. Recently a few cases of MM patients and arterial thromboembolism (ATE) have been reported. Therefore we prospectively studied the risk of ATE in 195 consecutive patients aged <66 years with previously untreated MM. All patients were treated according to the HOVON 50 study protocol, a prospective randomized phase III study on the effects of 3 courses of doxorubicin and dexamethasone with thalidomide (TAD) or vincristine (VAD) followed by high dose melphalan and thalidomide or interferon-alpha2 maintenance or the HOVON 65 study protocol, a prospective randomised phase III study on the effects of 3 courses doxorubicin and dexamethasone with vincristine (VAD) or bortezomib (PAD), followed by high dose melphalan and bortezomib or thalidomide maintenance. All patients treated with TAD courses received prophylaxis for VTE with low molecular-weight heparin. During a follow-up of 522.4 patient-years 11 patients (5.6%) developed ATE. Most events occurred within one year after start of treatment (64%). Median age at onset of ATE was 59 years (range 43–65). For myocardial infarction we demonstrated an annual incidence of 0.77% in men and 0.19% in women compared to an equal age group, 55–59 years, described by Parikh et al in the Framingham Heart Study population who reported annual incidences of 0.22% in men and 0.04% in women, respectively. For cerebral ischemic events we demonstrated an annual incidence of 0.77% in men and 0.19% in women compared to 0.29% in men and 0.22% in women in the general Dutch population, aged 55–59, as described by Gijsen and Poos. Of thrombophilic factors a statistically significant higher factor VIII:C (FVIII:C) was observed in symptomatic patients, 2.93 IU/ml (1.16–6.45) versus 2.15 (0.74–6.48) (p=0.03). FVIII:C correlated significantly with age (p=0.02) and ISS stage (p=0.001). Adjustment for age and ISS stage, revealed a RR for ATE of 11.67 (95% CI: 2.23–61.18) for hypertension, a RR of 15.17 (1.78–129.54) for smoking and a RR of 1.85 (0.99–3.47) for each IU/ml increase in FVIII level, respectively. In conclusion, MM patients are at high risk for arterial thrombotic events during and following induction chemotherapy. High factor VIII levels, which may reflect disease activity, contribute to the risk of ATE especially in patients with known risk factors for cardiovascular disease. Disclosures:Sonneveld:Johnson&Johnson: Consultancy.

Gitelman Syndrome

Gitelman Syndrome

Caffeinated Coffee Consumption, Cardiovascular Disease, and Heart Valve Disease in the Elderly (from the Framingham Study)

The relation between caffeinated coffee consumption and heart disease morbidity and mortality is of great interest given the extensive use of this beverage. A recent prospective epidemiologic study found a strong protective association in elderly subjects without moderate to severe hypertension in the NHANES. To test this association in the Framingham Heart Study population, in which cardiovascular risk factors and health behaviors were carefully documented, Cox regression analyses were conducted for 1,354 subjects aged 65.4 to 96.6 years at study entry. There were 210 deaths from cardiovascular disease and 118 from coronary heart disease (CHD) during 10.1 years of follow-up. A significant negative association between caffeinated coffee consumption and CHD mortality was observed for subjects with systolic blood pressure (BP) <160 mm Hg and diastolic BP <100 mm Hg. The decrease in risk of CHD mortality for any caffeinated coffee versus none was 43% (95% confidence interval 9 to 64). This decreased risk appeared to be caused primarily by an inverse prospective relation between caffeinated coffee consumption and the development or progression of heart valve disease. The decrease in risk of heart valve disease for subjects with systolic BP <160 mm Hg and diastolic BP <100 mm Hg for any caffeinated coffee versus none was 43% (95% confidence interval 4 to 66). In conclusion, caffeinated coffee consumption was associated with lower risk of CHD mortality and heart valve disease development or progression in older Framingham subjects without moderate or severe hypertension.

Blood pressure control and stroke mortality across populations

significantly reduced in the losartan-based treatment group compared with atenolol, stroke incidence was still higher as compared with coronary heart disease [7]. The devastating consequences and the burden of stroke urge implementation of evidence-based preventive strategies. An interesting approach could be based on estimation of individual risk. The unique scale for specific assessment of stroke risk is based in the Framingham Heart Study population [8]. This scale, which uses a Cox proportional risk model, allows 10-year stroke risk to be calculated using several variables (age, systolic BP values, tobacco use, diabetes, LVH, atrial fibrillation, and established cardiovascular disease), and has been adapted for use in treated hypertensive patients and in patients with new-onset atrial fibrillation [9]. Although its value for

Linkage and association studies in African- and Caucasian-American populations demonstrate that SHC3 is a novel susceptibility locus for nicotine dependence

Our previous linkage study demonstrated that the 9q22-q23 chromosome region showed a 'suggestive' linkage to nicotine dependence (ND) in the Framingham Heart Study population. In this study, we provide further evidence for the linkage of this region to ND in an independent sample. Within this region, the gene encoding Src homology 2 domain-containing transforming protein C3 (SHC3) represents a plausible candidate for association with ND, assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI) and the Fagerström Test for ND (FTND). We utilized 11 single-nucleotide polymorphisms within SHC3 to examine the association with ND in 602 nuclear families of either African-American (AA) or European-American (EA) origin. Individual SNP-based analysis indicated three SNPs for AAs and one for EAs were significantly associated with at least one ND measure. Haplotype analysis revealed that the haplotypes A-C-T-A-T-A of rs12519-rs3750399-rs4877042-rs2297313-rs1547696-rs1331188, with a frequency of 27.8 and 17.6%, and C-T-A-G-T of rs3750399-rs4877042-rs2297313-rs3818668-rs1547696, at a frequency of 44.7 and 30.6% in the AA and Combined samples, respectively, were significantly inversely associated with the ND measures. In the EA sample, another haplotype with a frequency of 10.6%, A-G-T-G of rs1331188-rs1556384-rs4534195-rs1411836, showed a significant inverse association with ND measures. These associations remained significant after Bonferroni correction. We further demonstrated the SHC3 contributed 40.1-59.2% (depending on the ND measures) of the linkage signals detected on chromosome 9. As further support, we found that nicotine administered through infusion increased the Shc3 mRNA level by 60% in the rat striatum, and decreased it by 22% in the nucleus accumbens (NA). At the protein level, Shc3 was decreased by 38.0% in the NA and showed no change in the striatum. Together, these findings strongly implicate SHC3 in the etiology of ND, which represents an important biological candidate for further investigation.

Association Between the UGT1A1*28 Allele, Bilirubin Levels, and Coronary Heart Disease in the Framingham Heart Study

Bilirubin is an antioxidant that suppresses lipid oxidation and retards atherosclerosis formation. An inverse association between serum bilirubin and coronary heart disease has been reported. Linkage studies have identified a major locus at the chromosome 2q telomere that affects bilirubin concentrations. A candidate gene in the linkage region encodes hepatic bilirubin uridine diphosphate-glucuronosyltransferase (UGT1A1). The insertion of a TA in the TATAA box of the gene, an allele designated UGT1A1*28, decreases gene transcription. Individuals homozygous for UGT1A1*28 (genotype 7/7) have increased serum bilirubin levels compared with carriers of the 6 allele. To date, no significant association between UGT1A1*28 and cardiovascular disease (CVD) events has been reported. We performed an association study in the Framingham Heart Study population to investigate whether UGT1A1*28 is associated with the risk of CVD events. The study population included 1780 unrelated individuals from the Offspring cohort (49% males, mean age 36 years at entry) who had been followed up for 24 years. Individuals with genotype 7/7 had significantly higher bilirubin levels (mean+/-SD 1.14+/-0.44 mg/dL) than those with genotypes 6/6 and 6/7 (mean+/-SD 0.69+/-0.27 mg/dL, P<0.01). Using the Cox proportional hazards model, we found significant associations between the UGT1A1*28 allele and decreased risk of CVD. Individuals with genotype 7/7 (population frequency of 11%) had approximately one third the risk for CVD and coronary heart disease as carriers of the 6 allele, which resulted in a hazard ratio (95% confidence interval) of 0.36 (0.18 to 0.74) and 0.30 (0.12 to 0.74), respectively. Homozygote UGT1A1*28 allele carriers with higher serum bilirubin concentrations exhibit a strong association with lower risk of CVD.

Heart Disease Risk Determines Menopausal Age Rather Than the Reverse

The purpose of this study was to investigate whether a harmful cardiovascular risk profile accelerates menopause. Women with an early menopause are at an increased risk of cardiovascular disease. Although increased cardiovascular risk has been proposed as consequence of menopause, the alternative hypothesis, that increased premenopausal cardiovascular risk promotes early menopause, needs to be examined. We used data from the Framingham Heart Study cohort. This study started in 1948 and has followed up participants biennially since then. Women who were premenopausal at study entry and who reached natural menopause after at least two examination rounds were included in the study (n = 695). Premenopausal age-independent levels of serum total cholesterol, relative weight, blood pressure, and Framingham risk score were determined, as well as premenopausal changes in cholesterol, body weight, and blood pressure. A higher premenopausal serum total cholesterol level was statistically significantly associated with an earlier age at menopause, as were increases in total serum cholesterol, relative weight, and blood pressure in the premenopausal period. A decrease in total serum cholesterol during premenopause was statistically significantly associated with later age at menopause. Decreasing blood pressure was associated with a later menopausal age, but this association was not statistically significant. A decrease in relative weight was associated with a significant earlier age at menopause. Each 1% higher premenopausal Framingham risk score was associated with a decrease in menopausal age of 1.8 years (95% confidence interval -2.72 to -0.92). The findings support the view that heart disease risk determines age at menopause. This offers a novel explanation for the inconsistent findings on cardiovascular disease rate and its relationship to menopausal age and effects of hormone replacement therapy.

The –174 IL-6 GG genotype is associated with a reduced risk of type 2 diabetes mellitus in a family sample from the National Heart, Lung and Blood Institute’s Framingham Heart Study

We evaluated the -174 IL-6 gene polymorphism as a risk factor for type 2 diabetes mellitus in a family-based analysis. We tested for associations between the -174 IL-6 G/C promoter polymorphism and fasting plasma glucose (FPG) and type 2 diabetes in a sample of 1,428 individuals from the largest 182 families in the National Heart, Lung and Blood Institute's Framingham Heart Study population. A significant association was found with FPG (p=0.01) and log (FPG) (p=0.005) using a modified family-based transmission disequilibrium test, the family-based association test (FBAT). The association between IL-6 genotype and FPG (p=0.035) and log (FPG) (p=0.03) was also found in the subset of families that were informative in FBAT using a mixed-effects regression model and strengthened after adjustment for potential confounders (p=0.008 for log [FPG]). The mean glucose level estimated from models with log (FPG) as the dependent variable for the GG genotype in the informative families was significantly lower (5.20+/-0.06 mmol/l) than for the GC (5.41+/-0.06 mmol/l) and CC (5.38+/-0.06 mmol/l) genotypes (p=0.03 for contrast between GG and GC genotypes). In the subset of informative families, the risk of type 2 diabetes associated with the GG genotype was lower relative to the GC and CC genotypes combined (potential confounder-adjusted, mixed-effects odds ratio 0.35, 95% CI 0.14-0.88, p=0.026, unaffected n=391, affected n=32). These results are consistent with a protective role for the -174 IL-6 G allele against type 2 diabetes and warrant further analysis of this polymorphism.

Haplotype analysis indicates an association between the DOPA decarboxylase (DDC) gene and nicotine dependence

DOPA decarboxylase (DDC; also known as L-amino acid decarboxylase; AADC) is involved in the synthesis of dopamine, norepinephrine and serotonin. Because the mesolimbic dopaminergic system is implicated in the reinforcing effects of many drugs, including nicotine, the DDC gene is considered a plausible candidate for involvement in the development of vulnerability to nicotine dependence (ND). Further, this gene is located within the 7p11 region that showed a 'suggestive linkage' to ND in our previous genome-wide scan in the Framingham Heart Study population. In the present study, we tested eight single nucleotide polymorphisms (SNPs) within DDC for association with ND, which was assessed by smoking quantity (SQ), the heaviness of smoking index (HSI) and the Fagerstrom test for ND (FTND) score, in a total of 2037 smokers and non-smokers from 602 nuclear families of African- or European-American (AA or EA, respectively) ancestry. Association analysis for individual SNPs using the PBAT-GEE program indicated that SNP rs921451 was significantly associated with two of the three adjusted ND measures in the EA sample (P=0.01-0.04). Haplotype-based association analysis revealed a protective T-G-T-G haplotype for rs921451-rs3735273-rs1451371-rs2060762 in the AA sample, which was significantly associated with all three adjusted ND measures after correction for multiple testing (min Z=-2.78, P=0.006 for HSI). In contrast, we found a high-risk T-G-T-G haplotype for a different SNP combination in the EA sample, rs921451-rs3735273-rs1451371-rs3757472, which showed a significant association after Bonferroni correction with the SQ and FTND score (max Z=2.73, P=0.005 for FTND). In summary, our findings provide the first evidence for the involvement of DDC in the susceptibility to ND and, further, reveal the racial specificity of its impact.

The Insulin Gene Variable Number Tandem Repeat and Risk of Type 2 Diabetes in a Population-Based Sample of Families and Unrelated Men and Women

Abnormalities in insulin regulation are central to the pathogenesis of type 2 diabetes. We assessed variation in the insulin gene variable number tandem repeat (INS VNTR) minisatellite (using the -23Hph1 A/T single nucleotide polymorphism) as a risk factor for 92 cases of incident type 2 diabetes in 883 unrelated Framingham Heart Study (FHS) subjects and in a separate sample of 698 members of 282 FHS nuclear families with 62 diabetes cases. In the unrelated sample, the -23Hph1 TT genotype frequency was 8.0% and was associated with a diabetes hazard ratio of 1.89 [95% confidence interval (CI), 1.01-3.52; P = 0.045] compared with the AA genotype using diabetes age of onset as the time failure variable in a proportional hazards model adjusted for age, offspring sex, body mass index, parental diabetes, and sex by parental diabetes interactions. In sex-stratified analyses, TT increased risk for diabetes in women (hazard ratio, 4.25; 95% CI, 1.76-10.3), but not men (hazard ratio, 1.01; 95% CI, 0.39-2.60). Using a family-based association test to assess transmission disequilibrium in the sample of related subjects, the age- and sex-adjusted z-score for diabetes associated with the T allele was 2.07 (P = 0.04), and a family-based association test using age of onset in a proportional hazards model was also statistically significant (P = 0.03), indicating that increased risk of diabetes was not attributable to population admixture. These data support the hypothesis that the INS VNTR is a genetic risk factor for type 2 diabetes, with the TT genotype accounting for about 6.6% of cases in the FHS population.

Asymptomatic cardiac disease following mediastinal irradiation

ObjectivesThis study was designed to evaluate the potential benefit of screening previously irradiated patients with echocardiography. BackgroundMediastinal irradiation is known to cause cardiac disease. However, the prevalence of asymptomatic cardiac disease and the potential for intervention before symptom development are unknown. MethodsWe recruited 294 asymptomatic patients (mean age 42 ± 9 years, 49% men, mean mantle irradiation dose 43 ± 0.3 Gy) treated with at least 35 Gy to the mediastinum for Hodgkin's disease. After providing written consent, each patient underwent electrocardiography and transthoracic echocardiography. ResultsValvular disease was common and increased with time following irradiation. Patients who had received irradiation more than 20 years before evaluation had significantly more mild or greater aortic regurgitation (60% vs. 4%, p < 0.0001), moderate or greater tricuspid regurgitation (4% vs. 0%, p = 0.06), and aortic stenosis (16% vs. 0%, p = 0.0008) than those who had received irradiation within 10 years. The number needed to screen to detect one candidate for endocarditis prophylaxis was 13 (95% confidence interval [CI] 7 to 44) for patients treated within 10 years and 1.6 (95% CI 1.3 to 1.9) for those treated at least 20 years ago. Compared with the Framingham Heart Study population, mildly reduced left ventricular fractional shortening (<30%) was more common (36% vs. 3%), and age- and gender-adjusted left ventricular mass was lower (90 ± 27 g/m vs. 117 g/m) in irradiated patients. ConclusionsThere is a high prevalence of asymptomatic heart disease in general, and aortic valvular disease in particular, following mediastinal irradiation. Screening echocardiography should be considered for patients with a history of mediastinal irradiation.

A genome-wide scan to identify loci for smoking rate in the Framingham Heart Study population.

BackgroundAlthough many years of genetic epidemiological studies have demonstrated that genetics plays a significant role in determining smoking behavior, little information is available on genomic loci or genes affecting nicotine dependence. Several susceptibility chromosomal regions for nicotine dependence have been reported, but few have received independent confirmation. To identify susceptibility loci for nicotine dependence, 313 extended pedigrees selected from the Framingham Heart Study population were analyzed by both the GENEHUNTER and S.A.G.E. programs.ResultsAfter performing linkage analyses on the 313 extended Framingham Heart Study families, the EM Haseman-Elston method implemented in GENEHUNTER provided evidence for significant linkage of smoking rate to chromosome 11 and suggestive linkage to chromosomes 9, 14, and 17. Multipoint sib-pair regression analysis using the SIBPAL program of S.A.G.E. on 1389 sib pairs that were split from the 313 extended families identified suggestive linkage of smoking rate to chromosomes 4, 7, and 17. Of these identified positive regions for nicotine dependence, loci on chromosomes 7, 11, and 17 were identified by both GENEHUNTER and S.A.G.E. programs.ConclusionOur genome-wide scan results on the Framingham Heart Study data provide evidence for significant linkage of smoking rate to chromosome 11 and suggestive linkage to chromosomes 4, 7, 9, 14, and 17. These findings suggest that some of these regions may harbor susceptibility loci for nicotine dependence, and warrant further investigation in this and other populations.

Mapping susceptibility loci for alcohol consumption using number of grams of alcohol consumed per day as a phenotype measure.

BackgroundThere is substantial evidence for a significant genetic component to the risk for alcoholism. However, susceptibility loci or genes for alcohol dependence remain largely unknown. To identify susceptibility loci for alcohol dependence, we selected 329 extended families from the Framingham Heart Study population in which at least one family member reported alcohol consumption during the interview in 1970–1971, and performed genome-wide linkage analyses using various analytical methods.ResultsMulti-point sib-pair regression analysis using the SIBPAL program of S.A.G.E. provided strong evidence for linkage of alcohol dependence to chromosomes 9 (p-value < 0.0001) and weak evidence to chromosomes 15 and 16 (p-value < 0.005). To confirm these findings, we re-analyzed the same data set by various methods implemented in GENEHUNTER and found that only one region was significant with a LOD score > 2.0 by the variance-component method. This region is located on chromosome 9 between markers GATA21F05 and GATA81C04.ConclusionAnalyses of the Framingham Heart Study population provided evidence of genetic susceptibility loci for alcohol dependence on chromosomes 9, 15, and 16. The genomic region identified on chromosome 9 was particularly interesting because the region has also been previously reported to be linked to alcohol dependence in the American Indian population by another group.

Cardiovascular risk assessment based on US cohort studies: findings from a National Heart, Lung, and Blood institute workshop.

This report was derived from a workshop on cardiovascular risk assessment sponsored by the National Heart, Lung, and Blood Institute, which addressed whether risk equations developed in the Framingham Heart Study (FHS) for predicting new-onset coronary heart disease (CHD) apply to diverse population groups. Preparation for the workshop included a reanalysis and comparison of prospective studies in several different populations in which risk factors were related to cardiovascular outcomes. Some studies included fatal and nonfatal CHD end points, whereas others contained only CHD mortality. Extensive collaboration provided as much uniformity as possible with respect to both risk factors and CHD end points. The FHS has led in defining the quantitative impact of risk factors.1 Many potential risk factors were measured and related to cardiovascular outcomes. Several risk factors proved to be strong, largely independent predictors of cardiovascular disease (CVD). These factors—advancing age, cigarette smoking, blood pressure (particularly systolic), cholesterol in total serum and HDL, and diabetes—served as the basis for the development of risk prediction equations.1 If FHS risk estimates are to be widely used, they must apply widely in the US population. To document their transportability, they must be compared with prospective studies in other populations. Although the FHS is the longest running prospective study, there are other major studies. The cardiovascular end points of these other studies have varied. Some include cardiovascular morbidity and mortality; others have only cardiovascular mortality. Among the end points, CHD is the most extensively reported; for this reason, CHD was the primary focus of the workshop. ### Multivariate Relative Risk Comparisons In preparation for the workshop, multivariate regression coefficients for each risk factor were compared in different populations with those of the FHS. Adjusted relative risk estimates make it possible to determine whether each independent risk factor confers a similar or different relative risk among different …

Explained and unexplained ischemic heart disease risk after renal transplantation.

Whether the high incidence of ischemic heart disease (IHD) among renal transplant patients can be attributed to the same risk factors that have been identified in the general population is unclear. The risk for major IHD events occurring >1 yr after transplantation among 1124 transplant recipients was estimated by using the risk calculated from the Framingham Heart Study (FHS). The FHS risk predicted IHD (relative risk, 1.28; 95% confidence interval, 1.20 to 1.40; P: < 0.001); however, the FHS risk tended to underestimate the risk of IHD for renal transplant recipients. This was largely attributable to increased risks associated with diabetes mellitus and, to a lesser extent, age and cigarette smoking for renal transplant recipients. For men, the relative risks for diabetes mellitus were 2.78 (1.73 to 4.49) and 1.53 for the transplant recipient and FHS populations, respectively; the relative risks for age (in years) were 1.06 (1.04 to 1.08) and 1.05, respectively, and those for smoking were 1.95 (1.20 to 3.19) and 1.69, respectively. For women, the relative risks for diabetes mellitus were 5.40 (2.73 to 10.66) and 1.82, respectively. There was a tendency for the risk associated with cholesterol levels to be higher for transplant recipients, compared with the FHS population, but the risks associated with high-density lipoprotein cholesterol levels and BP appeared to be comparable. Independent of these and other risk factors, the adjusted risk of IHD for the transplant recipient population has decreased. Compared with the era before 1986, transplantation between 1986 and 1992 was associated with a lower relative risk of 0.60 (0.39 to 0.92); transplantation after 1992 was associated with an even lower relative risk of 0.27 (0.11 to 0.63) for IHD. Of concern was the fact that dihydropyridine calcium channel antagonists were associated with an increased risk for IHD (relative risk, 2.26; 95% confidence interval, 1.24 to 4.12; P: = 0. 008), and this association was independent of other antihypertensive agents and risk factors. Therefore, although the FHS risk predicts IHD after renal transplantation, it tends to underestimate the risks, especially the risk associated with diabetes mellitus. The unexpected finding that dihydropyridine calcium channel antagonists were associated with an increased IHD risk merits further evaluation.

Direct Medical Costs of Coronary Artery Disease in the United States

To generate current incidence-based estimates of the direct medical costs of coronary artery disease (CAD) in the United States, a Markov model of the economic costs of CAD-related medical care was developed. Risks of initial and subsequent CAD events (sudden CAD death, fatal/nonfatal acute myocardial infarction [AMI], unstable angina, and stable angina) were estimated using new Framingham Heart Study risk equations and population risk profiles derived from national survey data. Costs were assumed to be those related to treatment of initial and subsequent CAD events (“event-related”) and follow-up care (“nonevent-related”), respectively. Cost estimates were derived primarily from national public-use databases. First-year direct medical costs of treating CAD events are estimated to be $17,532 for fatal AMI, $15,540 for nonfatal AMI, $2,569 for stable angina, $12,058 for unstable angina, and $713 for sudden CAD death. Nonevent-related direct costs of CAD treatment are estimated to be $1,051 annually. The annual incidence of CAD in the United States is estimated at 616,900 cases, with first-year costs of treatment totaling $5.54 billion. Five- and 10-year cumulative costs in 1995 dollars for patients who are initially free of CAD are estimated at $9.2 billion and $16.5 billion, respectively; for all patients with CAD, these costs are estimated to be $71.5 billion and $126.6 billion, respectively. The direct medical costs of CAD create a large economic burden for the United States health-care system.