Framingham Heart Study Cohort Research Articles

Powerful Bivariate Genome-Wide Association Analyses Suggest the SOX6 Gene Influencing Both Obesity and Osteoporosis Phenotypes in Males

BackgroundCurrent genome-wide association studies (GWAS) are normally implemented in a univariate framework and analyze different phenotypes in isolation. This univariate approach ignores the potential genetic correlation between important disease traits. Hence this approach is difficult to detect pleiotropic genes, which may exist for obesity and osteoporosis, two common diseases of major public health importance that are closely correlated genetically.Principal FindingsTo identify such pleiotropic genes and the key mechanistic links between the two diseases, we here performed the first bivariate GWAS of obesity and osteoporosis. We searched for genes underlying co-variation of the obesity phenotype, body mass index (BMI), with the osteoporosis risk phenotype, hip bone mineral density (BMD), scanning ∼380,000 SNPs in 1,000 unrelated homogeneous Caucasians, including 499 males and 501 females. We identified in the male subjects two SNPs in intron 1 of the SOX6 (SRY-box 6) gene, rs297325 and rs4756846, which were bivariately associated with both BMI and hip BMD, achieving p values of 6.82×10−7 and 1.47×10−6, respectively. The two SNPs ranked at the top in significance for bivariate association with BMI and hip BMD in the male subjects among all the ∼380,000 SNPs examined genome-wide. The two SNPs were replicated in a Framingham Heart Study (FHS) cohort containing 3,355 Caucasians (1,370 males and 1,985 females) from 975 families. In the FHS male subjects, the two SNPs achieved p values of 0.03 and 0.02, respectively, for bivariate association with BMI and femoral neck BMD. Interestingly, SOX6 was previously found to be essential to both cartilage formation/chondrogenesis and obesity-related insulin resistance, suggesting the gene's dual role in both bone and fat.ConclusionsOur findings, together with the prior biological evidence, suggest the SOX6 gene's importance in co-regulation of obesity and osteoporosis.

Von Willebrand Factor, Type 2 Diabetes Mellitus, and Risk of Cardiovascular Disease: The Framingham Offspring Study

Conclusion: Increased levels of von Willebrand factor (vWF) are associated with the risk of cardiovascular disease in patients with insulin resistance or type 2 diabetes mellitus. Summary: vWF is a large glycoprotein produced by endothelial cells that participates in the initial steps of thrombus formation by mediating platelet adhesion to injured endothelium. Because it interacts with endothelium, vWF may be a biomarker of endothelial damage. Because vWF is also known to be associated with insulin resistance and type 2 diabetes, vWF may be a risk factor for cardiovascular disease and may have increased significance in patients with insulin resistance or type 2 diabetes. The authors tested the hypothesis that vWF predicted the incidence cardiovascular disease in 3799 Framingham Offspring Study participants, focusing on those with insulin resistance or type 2 diabetes. The Framingham Offspring Study is a prospective observational study of cardiovascular disease and risk factors. It began in 1971 by enrolling children of the original Framingham Heart Study cohort and the children's spouses. During 11 years of follow-up, cardiovascular disease developed in 351 participants. Adjusting for age, sex, blood pressure, smoking, body mass index, and high-density lipoprotein levels as well as treatment with aspirin, insulin, antihypertensives, and lipid-lowering medications, the hazard ratio (HR) for cardiovascular disease was 0.94 in the second quartile of vWF distribution, 0.98 in the third quartile, and 1.32 in the highest quartile, using the lowest quartile as the reference (P = .04 for trend). Adjusting for type 2 diabetes or insulin resistance attenuated the association (HRs for top quartile 1.28, and 1.21, respectively). The model was also stratified for diabetes and insulin resistance distribution (top quartile vs lower three quartiles). vWF was associated with cardiovascular disease among participants with diabetes mellitus (HR for top quartile relative to bottom, 1.47; P = .04) but not among nondiabetic participants (HR, 1.15; P = .5). vWF was also associated with cardiovascular disease among those with insulin resistance (HR, 1.5; P = .01) but not among those who were insulin sensitive (HR, 1.02; P = .9). Comment: The data suggest vWF may be a risk factor unique in patients with type 2 diabetes mellitus or insulin resistance. Although diabetes mellitus and insulin resistance are clear risk factors for cardiovascular disease, patients with these risk factors have varying severities of clinical manifestations of atherosclerosis. This study offers the possibility of additional risk stratification among these patients based on levels of vWF.

Fractures Halved With Vitamin C

MONTREAL — Consumption of vitamin C at sufficiently high levels is associated with nearly a 50% decrease in the risk of hip and nonvertebral osteoporotic fractures in elderly men and women, according to a 15- to 17-year follow-up of participants in the Framingham Osteoporosis Study. Previous studies of menopausal and postmenopausal women have shown that dietary intake of vitamin C is associated with increased bone mineral density (BMD) and that a high vitamin C serum level is associated with a decreased prevalence of fracture, Marian T. Hannan, DSc, said at the annual meeting of the American Society for Bone and Mineral Research. Vitamin C, an antioxidant, plays an important role in the formation of collagen. Published evidence suggests that oxidative stress may result in increased osteoclast formation, resulting in greater bone resorption, said Dr. Hannan, who presented the study on behalf of Shivani Sahni of Tufts University, Boston. Of 5,209 men and women in the original Framingham Heart Study cohort, the investigators identified 958 individuals who had participated in the beginning of the osteoporosis study in 1988–1989, had answered a food-frequency questionnaire, and had no history of a hip fracture. These individuals had a mean age of 75 years and experienced 100 hip fractures and 180 nonvertebral osteoporotic fractures during the follow-up period, Dr. Hannan reported. For the study, participants were divided into three groups based on their intake of vitamin C. The relative risk of hip fracture was significantly lower for individuals who had the highest total intake of both dietary and supplemental vitamin C (a median of 305 mg/day) than it was for people with the lowest total intake (median of 97 mg/day). This translated into a 44% decrease in relative risk of hip fracture, according to Dr. Hannan of Harvard Medical School's Institute for Aging Research, Boston. Those with the highest total intake of vitamin C also had a 36% lower relative risk of having a nonvertebral osteoporotic fracture than did individuals with the lowest total intake. When the investigators looked at supplemental vitamin C intake alone, the highest users (median of 260 mg/day) had a 70% lower relative risk of hip fracture than did nonusers. Supplements accounted for about 28% of the individuals' total vitamin C intake, Dr. Hannan said. The investigators found no effect for dietary intake of vitamin C alone. All of the comparisons were adjusted for age, sex, body mass index, height, smoking status, estrogen use in women, physical activity, alcohol use, multivitamin use, femoral neck BMD, and total intake of energy, calcium, vitamin D, and potassium. One audience member suggested that the discrepancy between the effects of supplemental and dietary vitamin C intake could mean that there are residual confounding effects from factors that were not accounted for in the study, such that supplemental use of vitamin C may be a marker for people who care more about their health and take better care of themselves. This is a problem that can only be answered with a randomized, controlled trial, Dr. Hannan noted. “We were intrigued by the lack of a BMD effect on [the association between] vitamin C and fracture, and we believe that it implies that vitamin C may affect a different pathway or other fracture risk factors, for example, fall risk factors or mobility risk factors,” Dr. Hannan said Jeff Evans is a senior writer with Elsevier Global Medical News.

Clinical and genetic factors associated with lipoprotein-associated phospholipase A 2 in the Framingham Heart Study

Objective To conduct an investigation of clinical and genetic correlates of lipoprotein-associated phospholipase (Lp-PLA 2) activity and mass in a large community-based cohort. Higher circulating Lp-PLA 2 predicts cardiovascular disease risk, but sources of inter-individual variability are incompletely understood. Methods We conducted stepwise regression of clinical correlates of Lp-PLA 2 in four Framingham Heart Study cohorts ( n = 8185; mean age 50 ± 14 years, 53.8% women, 9.8% ethnic/racial minority cohort). We also conducted heritability and linkage analyses in Offspring and Generation 3 cohorts ( n = 6945). In Offspring cohort participants we performed association analyses ( n = 1535 unrelated) with 1943 common tagging SNPs in 233 inflammatory candidate genes. Results Sixteen clinical variables explained 57% of the variability in Lp-PLA 2 activity; covariates associated with Lp-PLA 2 mass were similar but only explained 27% of the variability. Multivariable-adjusted heritability estimates for Lp-PLA 2 activity and mass were 41% and 25%, respectively. A linkage peak was observed for Lp-PLA 2 activity (chromosome 6, LOD score 2.4). None of the SNPs achieved experiment-wide statistical significance, though 12 had q values <0.50, and hence we expect at least 50% of these associations to be true positives. The strongest multivariable-association with Lp-PLA 2 activity was found for MEF2A (rs2033547; nominal p = 3.20 × 10 −4); SNP rs1051931 in PLA2G7 was nominally associated ( p = 1.26 × 10 −3). The most significant association to Lp-PLA 2 mass was in VEGFC (rs10520358, p = 9.14 × 10 −4). Conclusions Cardiovascular risk factors and genetic variation contribute to variability in Lp-PLA 2 activity and mass. Our genetic association analyses need replication, which will be facilitated by web posting of our genetic association results.

Effect of Current and Midlife Obesity Status on Mortality Risk in the Elderly

The primary purpose of this study was to determine whether current and midlife obesity status provide independent information on mortality risk in elderly persons. Analyses were based on 3,238 participants from the original Framingham Heart Study (FHS) cohort who lived to at least 70 years of age and who had BMI measures from when they were in their 50s. Within this group of 70-year olds, obesity based on current BMI was associated with a 21% increased risk of mortality (P = 0.019) whereas obesity in 70-year olds based on BMI measures obtained at around 50 years of age was associated with a 55% increased risk of mortality (P < 0.0001). Compared to 70-year olds who were nonobese at both 50 and 70 years of age, mortality risk was increased by 47% (P < 0.001) in those who were obese at both 50 and 70 years of age, increased by 56% (P < 0.001) in those who were obese at 50 years of age and nonobese at 70 years of age, and not significantly different (P > 0.9) in those who were nonobese at 50 years of age and obese at 70 years of age. In summary, in this cohort of elderly adults, midlife and current BMI had independent effects on mortality risk. Specifically, although mortality risk was increased in obese older adults who were already obese at midlife, this was not the case for newly obese older adults. Conversely, nonobese older adults who were obese at midlife had an increased mortality risk. These observations imply that it is imperative to consider an elderly adult's BMI in context of their BMI at midlife.

Relation of Corneal Arcus to Cardiovascular Disease (from the Framingham Heart Study Data Set)

Corneal arcus is a lipid-rich deposit at the corneoscleral limbus that shares some similarities with the lipid deposition of atherosclerosis. Epidemiologic studies examining the association between corneal arcus and coronary artery disease (CAD) have yielded mixed results. This study was conducted to determine if corneal arcus is an independent risk factor for cardiovascular disease (CVD) and CAD. A prospective analysis was performed using Cox proportional-hazards regression models in the Framingham Heart Study Original Cohort and Offspring Cohort database. This cohort included 23,376 patient-examinations, during 3,890 (17%) of which corneal arcus was identified. Corneal arcus was a predictor of CVD and CAD at 4 years (hazard ratios [HRs] 2.28 and 1.99, respectively) and 8 years (HRs 2.52 and 2.35, respectively) of follow-up (p <0.0001 for all). Corneal arcus was no longer predictive of either CVD or CAD, however, after adjustment for age and gender at 4 years (HRs 1.07 and 1.01, respectively) and 8 years (HRs 1.18 and 1.17, respectively) of follow-up (p >0.05 for all). In conclusion, corneal arcus predicted CVD and CAD in the community-based Framingham Heart Study cohort because of the strong association of corneal arcus with increasing age. To date, this is the largest and lengthiest population-based cohort study examining the direct association between corneal arcus and CVD and CAD.

Advanced Illness Care in Older Adults: Many Lessons Yet To Be Learned

OLDER adults comprise the vast majority of those contending with multiple medical problems and the burden of chronic illnesses and symptoms. They are the preponderance of those facing the final stages of life: about 70% are aged 65 years and older. Thus, it is fundamental that all health care providers understand the unique and diverse issues experienced by older adults with advanced illness. Studies from this issue’s Special Section on Advanced Illness Care highlight how much we have to learn about treatment preferences and symptom burden among older adults with advanced illness. In a follow-up study of the original Framingham Heart Study cohort, McCarthy and colleagues (1) shed light on care preferences of these participants now predominantly in their 80s. Although most reported that they preferred comfort measures at the end of life, when presented with specific clinical scenarios, almost half of all participants stated that they would be willing to endure a chronic ventilator or tube feeding to avoid death, and over half stated they would be willing to live out their life in a great deal of pain or confused rather than die. The desire to avoid death is, of course, not surprising; as Somerset Maugham said of death, ‘‘my advice to you is to have nothing whatever to do with it.’’ Nevertheless, McCarthy’s study highlights the complexity associated with end-of-life decision-making and methods used to elicit preferences. Many older adults who want ‘‘comfort care’’ still are willing to undergo the discomfort of life-prolonging interventions to avoid death. Because so few had conversations with their providers about their wishes, it is likely that the participants’ treatment preferences would not be fully understood should they develop an acute, life-threatening event. As in McCarthy and colleagues’ study, Rose and colleagues demonstrate the rare occurrence of goals of care discussions with providers, even among older adults with advanced-stage cancer (2). The authors also demonstrate less connection between the health care team and older adults, despite older adults’ increased comorbidity burden. These findings highlight the importance of consistent, planned interactions with older adults and careful goals of care discussions that go beyond questions related to comfort care alone. Others also offer insights into symptom burden and management in older adults with advanced illness. In Rose’s study of cancer patients, older patients were less likely to report severe pain or be prescribed opioids (2). Pain was present in half of all nursing home residents studied by Cadogan and colleagues (3). However, pain severity and its impact on function varied greatly, suggesting that pain is multidimensional and that pain severity alone is inadequate for evaluating the true impact of pain on quality of life and function. Although pain in older patients is underappreciated and not well understood, strategies can be implemented to enhance pain management in this population. In Bailey and colleagues’ study of pain and dyspnea management in an inpatient setting, staff education and a decision-support tool to facilitate symptom management doubled orders for and quadrupled administration of opioids for patients with high symptom burden at the end of life (4). Each of these studies provide important clues for better ways to address treatment preferences and assess and manage symptoms. They also elicit more questions—how do we encourage conversations about end-of-life care? How do we best facilitate decision-making about treatment choices in advanced illness, especially when many older adults have limitations in health literacy and cognitive capacity brought on by multiple chronic illnesses? What is the best way to evaluate and treat symptoms such as pain and dyspnea at the end of life, when many of our treatment choices are associated with adverse effects that impact

Liver fat is reproducibly measured using computed tomography in the Framingham Heart Study

Fatty liver is the hepatic manifestation of obesity, but community-based assessment of fatty liver among unselected patients is limited. We sought to determine the feasibility of and optimal protocol for quantifying fat content in the liver in the Framingham Heart Study using multidetector computed tomography (MDCT) scanning. Participants (n = 100, 49% women, mean age 59.4 years, mean body mass index 27.8 kg/m(2)) were drawn from the Framingham Heart Study cohort. Two readers measured the attenuation of the liver, spleen, paraspinal muscles, and an external standard from MDCT scans using multiple slices in chest and abdominal scans. The mean measurement variation was larger within a single axial computed tomography (CT) slice than between multiple axial CT slices for the liver and spleen, whereas it was similar for the paraspinal muscles. Measurement variation in the liver, spleen, and paraspinal muscles was smaller in the abdomen than in the chest. Three versus six measures of attenuation in the liver and two versus three measures in the spleen gave reproducible measurements of tissue attenuation (intraclass correlation coefficient [ICCC] of 1 in the abdomen). Intra reader and interreader reproducibility (ICCC) of the liver-to-spleen ratio was 0.98 and 0.99, the liver-to-phantom ratio was 0.99 and 0.99, and the liver-to-muscle ratio was 0.93 and 0.86, respectively. One cross-sectional slice is adequate to capture the majority of variance of fat content in the liver per individual. Abdominal scan measures as compared to chest scan measures of fat content in the liver are more precise. The measurement of fat content in the liver on MDCT scans is feasible and reproducible.

Maternal influence on blood pressure suggests involvement of mitochondrial DNA in the pathogenesis of hypertension: the Framingham Heart Study

To investigate the contribution of the mitochondrial genome to hypertension and quantitative blood pressure (BP) phenotypes in the Framingham Heart Study cohort, a randomly ascertained, community-based sample. Longitudinal BP values of 6421 participants (mean age, 53 years; 46% men) from 1593 extended families were used for analyses. In analyses of BP as a continuous trait, a variance components model with a variance component for maternal effects was used to estimate the mitochondrial heritability of the long-term average BP adjusted for age, sex, body mass index, and hypertension treatment. For analyses of BP as a categorical trait, a nonparametric test sensitive to excessive maternal inheritance was used to test for mitochondrial effect on long-term hypertension, defined as systolic BP of at least 140 mmHg or diastolic BP of at least 90 mmHg or use of antihypertensive medication in one-half or more of qualifying examinations. This test was based on 353 pedigrees comprised of 403 individuals informative for mitochondrial DNA contribution. The estimated fraction of hypertensive pedigrees potentially due to mitochondrial effects was 35.2% (95% confidence interval, 27-43%, P < 10). The mitochondrial heritabilities for multivariable-adjusted long-term average systolic BP and diastolic BP were, respectively, 5% (P < 0.02) and 4% (P = 0.11). Our data provide support for a maternal effect on hypertension status and quantitative systolic BP, consistent with mitochondrial influence. Additional studies are warranted to identify mitochondrial DNA variant(s) affecting BP.

Characteristics of Framingham Offspring Participants With Long-lived Parents

Prior research has suggested that delay or avoidance of cardiovascular disease and cardiovascular disease risk factors plays an important role in longevity. We studied 1697 Framingham Heart Study (FHS) offspring members 30 years or older, whose parents (1) participated in the original FHS cohort and (2) achieved age 85 years or died before January 1, 2005. Offspring participants (mean +/- SD age, 40 +/- 7 years; 51% women) were grouped according to whether neither (n = 705), one (n = 804), or both parents (n = 188) survived to 85 years or older. We examined offspring risk factors at examination cycle 1 (1971-1975) including age, sex, education, cigarette smoking, systolic and diastolic blood pressures, total-high-density lipoprotein cholesterol ratio, body mass index, and Framingham Risk Score. Participants returning for examination cycle 3 (1983-1987; n = 1319) were eligible for inclusion in longitudinal analyses evaluating risk factor progression from baseline to a higher follow-up risk category. For all factors studied, except body mass index, we observed statistically significant linear trends for lower offspring examination 1 risk factor levels with increasing parental survival category. The mean Framingham Risk Score was most favorable in offspring with both parents surviving to 85 years or older and was progressively worse in those with one or no long-lived parent (0.55, 1.08, and 1.71, respectively; P value for trend, <.001). Longitudinally, offspring of parents who lived longer had lower risk of blood pressure and Framingham Risk Score progression. Our findings suggest that individuals with long-lived parents have advantageous cardiovascular risk profiles in middle age compared with those whose parents died younger. The risk factor advantage persists over time.

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.

Spectrum of Calcific Aortic Valve Disease

Received October 26, 2004; revision received January 13, 2005; accepted February 4, 2005. Calcific aortic valve disease is a slowly progressive disorder with a disease continuum that ranges from mild valve thickening without obstruction of blood flow, termed aortic sclerosis, to severe calcification with impaired leaflet motion, or aortic stenosis (Figure 1). In the past, this process was thought to be “degenerative” because of time-dependent wear-and-tear of the leaflets with passive calcium deposition. Now, there is compelling histopathologic and clinical data suggesting that calcific valve disease is an active disease process akin to atherosclerosis with lipoprotein deposition, chronic inflammation, and active leaflet calcification. The overlap in the clinical factors associated with calcific valve disease and atherosclerosis and the correlation between the severity of coronary artery and aortic valve calcification provide further support for a shared disease process. Figure 1. Gross specimen of minimally diseased aortic valve (left) and severely stenotic aortic valve (right). In the severely stenotic valve, there are prominent lipocalcific changes on aortic side of valve cusps (arrow), with sparing of commissures. ### Anatomy of Normal Aortic Valve The normal aortic valve comprises 3 layers. The ventricularis, on the ventricular side of the leaflet, is composed of elastin-rich fibers that are aligned in a radial direction, perpendicular to the leaflet margin. The fibrosa, on the aortic side of the leaflet, comprises primarily fibroblasts and collagen fibers arranged circumferentially, parallel to the leaflet margin. The spongiosa is a layer of loose connective tissue at the base of the leaflet, between the fibrosa and ventricularis, composed of fibroblasts, mesenchymal cells, and a mucopolysaccharide-rich matrix. These layers work in concert to provide tensile strength and pliability for decades of repetitive motion. ### Early Lesion of Aortic Sclerosis Histopathologic studies of aortic sclerosis show focal subendothelial plaquelike lesions on the aortic side of the leaflet that extend to the adjacent fibrosa layer. Similarities to …

Anticardiolipin antibodies and risk of ischemic stroke and transient ischemic attack: the Framingham cohort and offspring study.

The role of anticardiolipin antibodies (aCLs) as novel risk factors for ischemic stroke and transient ischemic attacks (TIAs) has been a matter of debate. Prior cohort studies included only selected subjects, mostly men. We related serum concentrations of aCLs to incident first ischemic stroke/TIA among men and women in the Framingham Heart Study cohort and offspring. There were a total of 2712 women (mean age, 59.3 years) and 2262 men (mean age, 58.3 years) free of stroke/TIA at the time of their baseline examinations. An enzyme immunoassay was used to measure aCLs. Optical density of the sample serum compared with the reference serum was defined as the aCL screening ratio (aCL SR). Analyses were based on sex-specific aCL SR quartiles and individual ratios. During the 11-year follow-up, 222 ischemic strokes/TIAs occurred. In multivariate analysis, after adjustment for age, prior cardiovascular disease, systolic blood pressure, diabetes, smoking, C-reactive protein, and total and high-density lipoprotein cholesterol levels, an aCL SR of >0.4 (78% of sample) was significantly associated with an increased risk of ischemic stroke/TIA for women (hazard ratio [HR], 2.6; 95% confidence interval [CI], 1.3 to 5.4; absolute risk, 3.2%, 95% CI, 2.2 to 4.3) but not in men (HR, 1.3; 95% CI, 0.7 to 2.4; absolute risk, 4.5%; 95% CI, 3.0 to 6.0). Similar results were obtained when the higher 3 aCL SR quartiles were compared with the lowest. Elevated serum concentrations of aCLs, independently of other cardiovascular risk factors, significantly predict the risk of future ischemic stroke and TIA in women but not in men.

Improvements in treatment of coronary heart disease and cessation of stroke mortality rate decline.

Many countries observed rapidly declining stroke mortality rates during 1970-1990, followed by a slowing or a cessation of this decline. This slowing was seen for both sexes and all ages. Here we test the hypothesis that improvements in coronary heart disease (CHD) survival can explain this slowing through an increase in the number of CHD survivors at an increased risk for stroke. We created multistate life-table models based on the survival experience of 46 years of follow-up of the Framingham Heart Study cohort. Improvements in survival after CHD were modeled by decreasing mortality rates for those with CHD. We analyzed whether improved CHD survival could result in a >3% increase in annual stroke mortality rates, which would be enough to eliminate the previously observed decline. CHD survival improvements led to an increase in the number of stroke deaths but also a concomitant increase in the total population size. Under no circumstances was there an annual increase in stroke mortality rates approaching 3% for both sexes and for younger and older age groups. The hypothesis that increases in the numbers of people with CHD, as a consequence of improvements in CHD survival, explain the observed slowing of the stroke mortality rate decline must be rejected. The true explanation is also likely to be a factor that changed markedly around 1990, but with more direct effects on stroke mortality.

Polymorphisms in the insulin-degrading enzyme gene are associated with type 2 diabetes in men from the NHLBI Framingham Heart Study.

Linkage studies have mapped a susceptibility gene for type 2 diabetes to the long arm of chromosome 10, where we have previously identified a quantitative trait locus that affects fasting blood glucose within the Framingham Heart Study cohort. One candidate gene in this region is the insulin-degrading enzyme (IDE), which, in the GK rat model, has been associated with nonobese type 2 diabetes. Single nucleotide polymorphisms (SNPs) were used to map a haplotype block in the 3' end of IDE, which revealed association with HbA(1c), fasting plasma glucose (FPG), and mean fasting plasma glucose (mFPG) measured over 20 years. The strongest associations were found in a sample of unrelated men. The lowest trait values were associated with a haplotype (TT, f approximately 0.32) containing the minor allele of rs2209772 and the major allele of the rs1887922 SNP (FPG P < 0.001, mFPG P < 0.003, HbA(1c) P < 0.025). Another haplotype (CC, f approximately 0.16) was associated with elevated HbA(1c) (P < 0.002) and type 2 diabetes (P < 0.001, odds ratio 1.96, 95% CI 1.28-3.00). The evidence presented supports the possibility that IDE is a susceptibility gene for diabetes in populations of European descent.

Dietary factors associated with the risk of high iron stores in the elderly Framingham Heart Study cohort

High body iron stores may increase the risk of several chronic diseases. Whether dietary factors contribute to the risk of high iron stores is unknown. We assessed the relation between dietary factors and the risk of high iron stores in the elderly Framingham Heart Study cohort. We examined the relation between the usual intake of dietary factors (food-frequency questionnaire) and the risk of high iron stores (serum ferritin >300 and 200 micro g/L in men and women, respectively) in 614 subjects aged 68-93 y. The risk of high iron stores was significantly higher 1) in subjects who took > or =30 mg supplemental Fe/d than in nonusers [odds ratio (OR): 4.32; 95% CI: 1.63, 11.47], 2) in subjects who consumed >21 servings of fruit/wk than in those who consumed < or =14 servings/wk (OR: 2.88; 95% CI: 1.26, 6.61), and 3) in subjects who consumed >4 but <7 or > or=7 servings of red meat/wk than in those who consumed < or =4 servings/wk (ORs: 2.94 and 3.61, respectively; 95% CIs: 1.33, 6.47 and 1.57, 8.27, respectively). Whole-grain intake (>7 servings/wk) was inversely associated (OR: 0.23; 95% CI: 0.07, 0.75). Among elders, intakes of highly bioavailable forms of iron (supplemental iron and red meat) and of fruit, a dietary source of an enhancer of nonheme-iron absorption (vitamin C), promote high iron stores, whereas foods containing phytate (whole grains) decrease these stores. Individual dietary patterns may be important modulators of high iron stores.

The association of seropositivity to Helicobacter pylori, Chlamydia pneumoniae, and cytomegalovirus with risk of cardiovascular disease: A prospective study

ObjectivesWe sought to determine whether seropositivity to Helicobacter pylori, Chlamydia pneumoniae, and cytomegalovirus (CMV) is an independent predictor of incident cardiovascular disease. BackgroundRecent reports have suggested that infections may contribute to risk of cardiovascular disease. However, prospective studies of these associations in a free-living population are lacking. MethodsWe measured serum H. pylori IgG, C. pneumoniae IgG and IgA, and CMV IgG levels in Framingham Heart Study cohort participants. Blood samples were drawn during the 16th biennial examination cycle (1979 to 1982) from 1,187 participants free of cardiovascular disease (mean age 69 years) and stored at −20°C. A pooled primary end point of myocardial infarction, atherothrombotic stroke, and coronary heart disease deaths was studied in relation to serology. Using a Cox model, hazard ratios (HR) and 95% confidence intervals (CI) were calculated, adjusting for age, gender, and established risk factors. ResultsSeropositivity to H. pylori IgG, C. pneumoniae IgG, C. pneumoniae IgA, and CMV IgG was 60%, 45%, 11%, and 69%, respectively. During 10 years of follow-up, incident cardiovascular disease occurred in 199 participants (16.8%). In age- and gender-adjusted models, H. pylori IgG (HR 1.09, 95% CI 0.81 to 1.46), C. pneumoniae IgG (HR 0.91, 95% CI 0.68 to 1.20), C. pneumoniae IgA (HR 0.65, 95% CI 0.39 to 1.07), and CMV IgG (HR 0.84, 95% CI 0.62 to 1.12) were not associated with incident cardiovascular disease. These associations were further attenuated after adjustment for risk factors including body mass index, total and high-density lipoprotein cholesterol, diabetes mellitus, smoking, and hypertension. These estimates did not change for the individual components of cardiovascular disease, and seropositivity to more than one organism did not alter these risk estimates substantially. ConclusionsIn this elderly cohort, chronic H. pylori, C. pneumoniae, and CMV infections, as evidenced by seropositivity, were not associated with increased risk for cardiovascular disease. Additional studies are needed to determine the relations of chronic infections to cardiovascular disease risk in younger persons.

Evidence for heritability of abdominal aortic calcific deposits in the Framingham Heart Study.

Atherosclerosis is a systemic disease that underlies clinical cardiovascular disease. The radiographic finding of abdominal aortic calcific deposits is an indicator of the presence of aortic atherosclerosis and an independent predictor of cardiovascular disease events. Little is known about the heritability of aortic calcification. Original Framingham Heart Study cohort participants (2151) in 1109 extended pedigrees had a lateral lumbar radiograph. The presence and severity of abdominal aortic calcific (AAC) deposits at the levels of the first through fourth lumbar vertebrae was graded by a previously validated rating scale. Correlation coefficients were calculated in pairs of siblings, parent-offspring, and spouses. Age-, sex-, and multivariable-adjusted correlation coefficients for AAC were 0.52 for parent-offspring pairs and 0.20 for sibling pairs. In contrast, the multivariable-adjusted correlation for AAC in spouse pairs was -0.02. Using variance component methods implemented in SOLAR, the estimated heritability for age-, sex-, and multivariable-adjusted AAC was 0.49 (P<0.001). Thirty-one percent of the overall variance in AAC deposits was due to measured covariates, and 49% to heritable factors. In our large, population-based sample, heritable factors play a role in the presence and extent of abdominal aortic calcification. Thus, a substantial proportion of the variation in AAC is due to additive effects of genes, which have yet to be characterized. Measures of aortic atherosclerosis may provide heritable quantitative phenotypes for the genetic dissection of the complex condition of atherosclerosis in human populations.

A cardiovascular life history. A life course analysis of the original Framingham Heart Study cohort.

AIMS The objective of this paper is to measure the potential burden of cardiovascular disease within the original Framingham Heart Study cohort by transforming its well-described epidemiological measures into time-based health policy measures, such as life years lost to or lived with the disease. METHODS AND RESULTS We constructed multi-state life tables of the Framingham Heart Study cohort to calculate dwelling times with a history of cardiovascular disease. Age-specific probabilities determined transitions from healthy through disease to death. For this synthetic cohort, from age 50 men (women) live on average 26 (32) years; 20 (26) free of cardiovascular disease. Allowing occupancy of more than one disease state, 50-year-old males (females) live 2 X 9 (1 X 2) years with a history of myocardial infarction, 0 X 93 (1 X 2) with a history of stroke, and 0 X 67 (0 X 93) with congestive heart failure. Having ever suffered acute myocardial infarction, stroke or congestive heart failure, life expectancy is reduced by 9 (13), 12 (15) or 16 (16) years, respectively in 60-year-old men (women). CONCLUSIONS Transforming occurrence probabilities into time-based health measures, the prevalence of cardiovascular disease is remarkable: from age 50, 20% of remaining life expectancy is lived with the disease. Such measures are integral to appropriate health planning and assessment of the potential population health value of various treatment and prevention strategies.

Central auditory dysfunction may precede the onset of clinical dementia in people with probable Alzheimer's disease.

To document the prognostic significance of a central auditory speech-processing deficit for the subsequent onset of probable Alzheimer's disease. Prospective cohort study. Framingham Heart Study. Seven hundred forty dementia-free volunteers from the Framingham Heart Study cohort with symmetric hearing thresholds at biennial examination 15 (1983-1985). The diagnosis of probable Alzheimer's disease was made prospectively using the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease Related Disorder Association criteria. A central auditory speech-processing deficit was defined as a score of 50% of less correct on the Synthetic Sentence Identification with Ipsilateral Competing Message test in at least one ear with normal word recognition ability in both ears. Cox proportional hazards regression assessed the relationship between a central auditory speech-processing deficit and the age at diagnosis of probable Alzheimer's disease. Forty subjects (5.4%) received a diagnosis of probable Alzheimer's disease during an average of 8.4 years (range 3-12) of follow-up; seven (17.5%) of these had a central auditory speech-processing deficit. The presence of a central auditory speech-processing deficit had an age-adjusted risk ratio for probable Alzheimer's disease of 10.8 (95% CI = 4.6-25.2), and the estimated risk ratio adjusted for age, gender, education level, apolipoprotein allele E4 presence, and hearing level was 23.3 (95% CI =6.6-82.7). A central auditory speech-processing deficit had a positive predictive value for subsequent probable Alzheimer's disease of 47% but the sensitivity was only 17.5%. Central auditory speech-processing deficits may be an early manifestation of probable Alzheimer's disease and may precede the onset of dementia diagnosis by many years.