Framingham Heart Study Cohort Research Articles

Arterial stiffness and hypertension: chicken or egg?

Hypertension is highly prevalent in the United States and worldwide. In the United States, 1 in 3 adults (≈73 million people) have hypertension. The financial and human costs of hypertension are substantial. The estimated costs attributable to hypertension in the United States alone in 2010 were $70 billion direct costs for medical treatments and $24 billion indirect costs because of lost productivity.1 Awareness and treatment of hypertension have improved considerably during the past several decades: >80% of all people with hypertension are aware of the condition and 75% are using antihypertensive medications.2,3 However, despite enormous effort and treatment-related expenditures, only 53% of those with documented hypertension have their blood pressure controlled.3 Older age (Figure 1), left ventricular hypertrophy, and obesity are important risk factors for uncontrolled or drug-resistant hypertension.4 Importantly, the foregoing are also risk factors for increased aortic stiffness.5 Figure 1. Hypertension prevalence and control rates as a function of age in the National Health and Nutrition Examination Survey 2003 to 2004. Data derived from Wong et al.44 During the past 2 decades, measures of aortic stiffness have emerged as important risk factors for progression of blood pressure and incident cardiovascular disease. Carotid femoral pulse wave velocity (CFPWV), a measure of aortic wall stiffness, increases markedly with age, particularly after midlife. For example, Framingham Heart Study investigators have shown that the prevalence of CFPWV ≥12 m/s increases from a few percentage before 50 years of age to ≥60% after 70 years of age (Figure 2A). Importantly, elevated CFPWV is associated with high risk for incident hypertension (Figure 2B) and cardiovascular disease (Figure 2C). Figure 2C should be interpreted within the context that a normal value (<95th percentile) for CFPWV in a healthy Framingham Heart Study reference sample <50 years of age was 8.1 …

Age, Gender, and Cancer but Not Neurodegenerative and Cardiovascular Diseases Strongly Modulate Systemic Effect of the Apolipoprotein E4 Allele on Lifespan

Enduring interest in the Apolipoprotein E (ApoE) polymorphism is ensured by its evolutionary-driven uniqueness in humans and its prominent role in geriatrics and gerontology. We use large samples of longitudinally followed populations from the Framingham Heart Study (FHS) original and offspring cohorts and the Long Life Family Study (LLFS) to investigate gender-specific effects of the ApoE4 allele on human survival in a wide range of ages from midlife to extreme old ages, and the sensitivity of these effects to cardiovascular disease (CVD), cancer, and neurodegenerative disorders (ND). The analyses show that women's lifespan is more sensitive to the e4 allele than men's in all these populations. A highly significant adverse effect of the e4 allele is limited to women with moderate lifespan of about 70 to 95 years in two FHS cohorts and the LLFS with relative risk of death RR = 1.48 (p = 3.6×10−6) in the FHS cohorts. Major human diseases including CVD, ND, and cancer, whose risks can be sensitive to the e4 allele, do not mediate the association of this allele with lifespan in large FHS samples. Non-skin cancer non-additively increases mortality of the FHS women with moderate lifespans increasing the risks of death of the e4 carriers with cancer two-fold compared to the non-e4 carriers, i.e., RR = 2.07 (p = 5.0×10−7). The results suggest a pivotal role of non-sex-specific cancer as a nonlinear modulator of survival in this sample that increases the risk of death of the ApoE4 carriers by 150% (p = 5.3×10−8) compared to the non-carriers. This risk explains the 4.2 year shorter life expectancy of the e4 carriers compared to the non-carriers in this sample. The analyses suggest the existence of age- and gender-sensitive systemic mechanisms linking the e4 allele to lifespan which can non-additively interfere with cancer-related mechanisms.

Comparison of testosterone fractions between Framingham Heart Study participants and Japanese participants

To determine testosterone fractions in Japanese men and to compare these values with those of Framingham Heart Study participants. We enrolled 498 healthy Japanese men. Total testosterone was assayed by liquid chromatography tandem mass spectrometry, sex hormone-binding globulin was assayed by immunoassay and free testosterone was calculated by a laboratory at the Boston Medical Center. Analog-based free testosterone and immunoassay-based total testosterone were determined by immunoassay. We compared mass spectrometry assay-based total testosterone and calculated free testosterone values in the Japanese participants with values in the American Framingham Heart Study third generation cohort. The mean serum mass spectrometry assay-based total testosterone, sex hormone-binding globulin, and calculated free testosterone values were 439.4 ± 167 ng/dL, 65.34 ± 30.61 nmol/L, and 58.75 ± 20.0 pg/mL, respectively. The correlation coefficients with age for mass spectrometry assay-based total testosterone, sex hormone-binding globulin, and calculated free testosterone were 0.0010, 0.5041, and -0.496, respectively. There were no age-related changes in mass spectrometry assay-based total testosterone values in healthy men (P = 0.981), whereas sex hormone-binding globulin and calculated free testosterone levels showed similar age-related changes (P < 0.0001). Serum analog-based free testosterone levels (8.24 ± 2.9 pg/mL) showed age-related changes (P < 0.0001) regardless of immunoassay-based total testosterone levels (P = 0.828). Serum immunoassay-based total testosterone values (486.1 ± 162.5 ng/dL) correlated with serum mass spectrometry assay-based total testosterone values (r = 0.740, 95% confidence interval 0.6965-0.7781, P < 0.0001). Similarly, analog-based free testosterone and calculated free testosterone values showed a highly significant correlation (r = 0.706, 95% confidence interval 0.6587-0.7473, P < 0.0001). The analog-based free testosterone values were approximately 10% of the calculated free testosterone values. In contrast to the Framingham Heart Study cohort, total testosterone values in Japanese men are not associated with advancing age; thus, they cannot be used to diagnose late-onset hypogonadism in Japan. The analog-based free testosterone value can be considered instead as a suitable biochemical determinant for diagnosing late-onset hypogonadism syndrome.

A systems analysis of age-related changes in some cardiac aging traits

Aging process or senescence affects the expression of a wide range of phenotypic traits throughout the life span of organisms. These traits often show modular, synergistic, and even antagonistic relationships, and are also influenced by genomic, developmental, physiological and environmental factors. The cardiovascular system (CVS) in humans represents a major modular system in which the relationships among physiological, anatomical and morphological traits undergo continuous remodeling throughout the life span of an individual. Here we extend the concept of developmental plasticity in order to study the relationships among 14 traits measured on 3,412 individuals from the Framingham Heart Study cohort, relative to age and gender, using exploratory structural equation modeling-a form of systems analysis. Our results reveal differing patterns of association among cardiac traits in younger and older persons in both sexes, indicating that physiological and developmental factors may be channeled differentially in relation to age and gender during the remodeling process. We suggest that systems approaches are necessary in order to understand the coordinated functional relationships among traits of the CVS over the life course of individuals.

Validation of a new predictive risk model for mortality using Framingham Heart Study data

BackgroundThe Institute for Health Metrics and Evaluation (IHME) developed a risk model to estimate 10-year mortality risk compared with a population with optimum risk factors in adults aged 30 years and older. IHME used data on exposure distributions of 12 behavioural and biometric risks in the US population, mortality rates by cause, and estimates of the proportional hazards of risk factor exposure from systematic reviews. The model has been validated using National Health and Nutrition Examination Survey (NHANES) data collected during 1988–94 and 1999–2004 (n=8331). MethodsWe will use data from participants attending the Framingham Heart Study (FHS) Offspring Examination 7 (1998–2001) and the Original Cohort Examination 20 (1986–90) to further validate the 10-year mortality risk model. These examinations were chosen since risk factors used in the IHME development mortality risk model were measured in these examinations. FHS participants aged 30 years and older at the time of examination will be included. Model performance will be assessed by (a) area under the curve to assess the ability of the model to discriminate between FHS participants who did and did not die within 10 years; and (b) Hosmer-Lemeshow goodness-of-fit tests comparing the FHS-observed mortality rate with the model-predicted mortality risk. FindingsThe FHS validation cohort consists of 3500 participants (mean age 62·4 years); 55% are women. Unlike NHANES, the FHS cohort sample is predominantly white. The FHS cohort is approximately 10·6 years (95% CI 10·1–11·1) older than NHANES, on average; FHS and NHANES have 55% and 53% females, respectively. The observed mortality rate is 14·3% (95% CI 13·2–15·5) in FHS and 8·4% (7·8–9·0) in NHANES cohort samples. We will present the findings of the validation on the FHS participants and compare with NHANES validation results. InterpretationAdequate performance of the risk model when applied to FHS, a sample with characteristics somewhat different from NHANES, will further support its validity and usefulness in the US population. FundingNational Heart, Lungs and Blood Institute at the National Institutes of Health (2 N01-HC-25195-06).

A combined epidemiologic and metabolomic approach improves CKD prediction.

Metabolomic approaches have begun to catalog the metabolic disturbances that accompany CKD, but whether metabolite alterations can predict future CKD is unknown. We performed liquid chromatography/mass spectrometry-based metabolite profiling on plasma from 1434 participants in the Framingham Heart Study (FHS) who did not have CKD at baseline. During the following 8 years, 123 individuals developed CKD, defined by an estimated GFR of <60 ml/min per 1.73 m(2). Numerous metabolites were associated with incident CKD, including 16 that achieved the Bonferroni-adjusted significance threshold of P≤0.00023. To explore how the human kidney modulates these metabolites, we profiled arterial and renal venous plasma from nine individuals. Nine metabolites that predicted CKD in the FHS cohort decreased more than creatinine across the renal circulation, suggesting that they may reflect non-GFR-dependent functions, such as renal metabolism and secretion. Urine isotope dilution studies identified citrulline and choline as markers of renal metabolism and kynurenic acid as a marker of renal secretion. In turn, these analytes remained associated with incident CKD in the FHS cohort, even after adjustment for eGFR, age, sex, diabetes, hypertension, and proteinuria at baseline. Addition of a multimarker metabolite panel to clinical variables significantly increased the c-statistic (0.77-0.83, P<0.0001); net reclassification improvement was 0.78 (95% confidence interval, 0.60 to 0.95; P<0.0001). Thus, the addition of metabolite profiling to clinical data may significantly improve the ability to predict whether an individual will develop CKD by identifying predictors of renal risk that are independent of estimated GFR.

The role of lipid‐related genes, aging‐related processes, and environment in healthspan

The inherent complexity of aging-related traits can temper progress in unraveling the genetic origins of healthspan. We focus on two generations in the Framingham Heart Study, the original (FHS) and offspring (FHSO) cohorts, to determine whether aging-related processes in changing environments can substantially impact the role of lipid-related genes discovered in candidate gene (the apolipoprotein E (APOE) e2/3/4 polymorphism) and genome-wide (the APOB rs1042034 (C/T)) studies, in regulation of total cholesterol (TC) and onset of cardiovascular disease (CVD). We demonstrate that the APOE e4 allele and APOB CC genotype can play detrimental, neutral, and protective sex-specific roles in the etiology of CVD at different ages and in different environments. We document antagonistic roles for the e4 allele in the onset of CVD characterized by detrimental effects at younger ages (RR≤ 75 years = 1.49, P = 7.5 × 10(-4) ) and protective effects at older ages (RR76+years = 0.77, P = 0.044) for FHS participants. We found that disregarding the role of aging erroneously nullifies the significant effects of the e4 allele in this sample (RR = 0.92, P = 0.387). The leading biogenetic pathways mediating genetic effects on CVD may be more relevant to lipid metabolism for APOB than APOE. Aging-related processes can modulate the strength of genetic associations with TC in the same individuals at different chronological ages. We found substantial differences in the effects of the same APOE and APOB alleles on CVD and TC across generations. The results suggest that aging-related processes in changing environments may play key roles in the genetics of healthspan. Detailed systemic integrative analyses may substantially advance the progress.

Living the Good Life? Mortality and Hospital Utilization Patterns in the Old Order Amish

Lifespan increases observed in the United States and elsewhere throughout the developed world, have been attributed in part to improvements in medical care access and technology and to healthier lifestyles. To differentiate the relative contributions of these two factors, we have compared lifespan in the Old Order Amish (OOA), a population with historically low use of medical care, with that of Caucasian participants from the Framingham Heart Study (FHS), focusing on individuals who have reached at least age 30 years.Analyses were based on 2,108 OOA individuals from the Lancaster County, PA community born between 1890 and 1921 and 5,079 FHS participants born approximately the same time. Vital status was ascertained on 96.9% of the OOA cohort through 2011 and through systematic follow-up of the FHS cohort. The lifespan part of the study included an enlargement of the Anabaptist Genealogy Database to 539,822 individuals, which will be of use in other studies of the Amish. Mortality comparisons revealed that OOA men experienced better longevity (p<0.001) and OOA women comparable longevity than their FHS counterparts.We further documented all OOA hospital discharges in Lancaster County, PA during 2002–2004 and compared OOA discharge rates to Caucasian national rates obtained from the National Hospital Discharge Survey for the same time period. Both OOA men and women experienced markedly lower rates of hospital discharges than their non-Amish counterparts, despite the increased lifespan.We speculate that lifestyle factors may predispose the OOA to greater longevity and perhaps to lesser hospital use. Identifying these factors, which might include behaviors such as lesser tobacco use, greater physical activity, and/or enhanced community assimilation, and assessing their transferability to non-Amish communities may produce significant gains to the public health.

Association of Female Reproductive Factors with Body Composition: The Framingham Heart Study

Identifying reproductive risk factors in women offers a life course approach to obesity and cardiovascular disease prevention. The association of female reproductive factors with measures of regional body fat distribution has not been comprehensively studied. We examined the association of female reproductive factors (age at menarche, parity, age at natural menopause, menopausal status) in association with body composition data from women who participated in the Offspring and the Third Generation Framingham Heart Study cohorts. Visceral adipose tissue (VAT) and sc adipose tissue (SAT) were measured volumetrically by multidetector computerized tomography. We modeled the relationship between each fat depot and female reproductive factors after adjusting for various factors such as age, smoking status, alcohol intake, physical activity index, hormone replacement therapy, and menopausal status. Earlier age at menarche was associated with increased body mass index (BMI), waist circumference (WC), VAT, and SAT (P < 0.0001). This association of earlier menarche with adiposity measures was attenuated after adjusting for BMI (all P > 0.70). We observed no association between parity and all parameters of adiposity measurements (all P > 0.24). Similarly, age at natural menopause was not associated with measures of body composition. Despite higher mean BMI among the post- (BMI 27.3 kg/m(2)) compared with the premenopausal women (BMI 25.9 kg/m(2)) in an age-matched analysis, mean VAT was not different between the two groups (P = 0.30). Earlier menarche is associated with overall obesity but not with VAT or SAT after accounting for measures of generalized adiposity. Parity and menopausal age were not associated with adiposity measures. Although postmenopausal women had increased BMI, VAT, and SAT, the association was predominantly due to age.

Burden of Rare Sarcomere Gene Variants in the Framingham and Jackson Heart Study Cohorts

Rare sarcomere protein variants cause dominant hypertrophic and dilated cardiomyopathies. To evaluate whether allelic variants in eight sarcomere genes are associated with cardiac morphology and function in the community, we sequenced 3,600 individuals from the Framingham Heart Study (FHS) and Jackson Heart Study (JHS) cohorts. Out of the total, 11.2% of individuals had one or more rare nonsynonymous sarcomere variants. The prevalence of likely pathogenic sarcomere variants was 0.6%, twice the previous estimates; however, only four of the 22 individuals had clinical manifestations of hypertrophic cardiomyopathy. Rare sarcomere variants were associated with an increased risk for adverse cardiovascular events (hazard ratio: 2.3) in the FHS cohort, suggesting that cardiovascular risk assessment in the general population can benefit from rare variant analysis.

Cardiometabolic Correlates and Heritability of Fetuin-A, Retinol-Binding Protein 4, and Fatty-Acid Binding Protein 4 in the Framingham Heart Study

Fetuin-A, retinol-binding protein 4 (RBP4), and fatty-acid binding protein 4 (FABP4) are novel biomarkers that may link adiposity to insulin resistance and the metabolic syndrome (MetSyn). The aim of this study was to investigate the correlates of these three adiposity biomarkers in a large community-based sample. DESIGN, SETTING, PARTICIPANTS, AND OUTCOMES: Serum concentrations of fetuin-A, RBP4, and FABP4 were assayed in 3658 participants of the Third Generation Framingham Heart Study cohort (mean age 40 yr, 54% women). We used multivariable regression to cross-sectionally relate biomarkers to insulin resistance, cardiovascular risk factors, and the MetSyn. The genetic contribution to inter-individual variation in biomarker levels was assessed using variance-components analysis. All three biomarkers exhibited sexual dimorphisms (levels higher in women for fetuin-A and FABP4 but greater in men for RBP4) and were associated positively with insulin resistance assessed using the homeostasis model, with high-sensitivity C-reactive protein, and with prevalent MetSyn (P<0.01 for all). The biomarkers showed distinct patterns of association with metabolic risk factors. RBP4 levels were correlated with body mass index only in unadjusted but not in adjusted models. None of the biomarkers were associated with prevalent diabetes in multivariable models. Circulating fetuin-A, RBP4, and FABP4 levels showed modest heritability, ranging from 15-44% (all P<0.0001). In our large young- to middle-aged community-based sample, we observed that circulating levels of fetuin-A, RBP4, and FABP4 are associated with insulin resistance and with distinct components of MetSyn consistent with the multifactorial pathogenesis of metabolic dysregulation.

Abstract MP032: Greater Physical Activity Assessed by Accelerometry is Associated with Favorable Adipokine Profile in the Community: Cross-sectional Observations from The Framingham Third Generation Cohort

Background: Adipokines, produced by adipose tissues, contribute to the development of obesity-related metabolic traits. It is unclear, however, if greater physical activity favorably affects cardiometabolic profiles by influencing levels of key adipokines. We related physical activity, as measured by accelerometry, to circulating levels of novel adipokines, including retinol binding protein-4 (RBP4), adipocyte-fatty acid binding protein (A-FABP), adiponectin, leptin and leptin-receptor (LEP-R), in a large community-based sample. Methods: We evaluated 2063 participants in the 3rd generation Framingham Heart Study cohort (mean age 47 years, 55% female) who underwent objective assessment of moderate-to-vigorous physical activity (MVPA) by an accelerometer. MVPA was measured in total minutes, and in bouts ≥10 minutes (MVPA10) and nonbouts (MVPA&lt;10 minutes). Blood adipokine levels were log-transformed and related to MVPA, using separate regression models for each adipokine, adjusted for age, sex, smoking, and season. Results: On average, participants engaged in 28 minutes/day of MVPA, 19 minutes/day of nonbout MVPA and 9 minutes/day of MVPA10. Mean adipokine levels were 40.7 ± 10.7 ng/ml for RBP-4, 18.6 ± 10.3 ng/ml for A-FABP, 11.4 ± 12.9 ng/ml for leptin, 19.6 ± 8.6 ng/ml for LEP-R, and 8.7 ± 5.5 ng/ml for adiponectin. Total MVPA, as well as MVPA10 and nonbout MVPA, were inversely related to leptin and A-FABP and positively associated with levels of adiponectin (See Table). The directionality of the observed associations - positive for adiponectin and negative for leptin and A-FABP- were consistent with greater physical activity being related to a more favorable cardiometabolic profile. Conclusions: In our cross-sectional study of a large community-based sample, both bout and nonbout MVPA were significantly related to a favorable adipokine profile. Additional longitudinal observations are warranted to assess if physical activity influences cardiometabolic health through alterations in adipokine levels.

A genome-wide association study of plasma total IgE concentrations in the Framingham Heart Study

Atopy and plasma IgE concentration are genetically complex traits, and the specific genetic risk factors that lead to IgE dysregulation and clinical atopy are an area of active investigation. We sought to ascertain the genetic risk factors that lead to IgE dysregulation. A genome-wide association study (GWAS) was performed in 6819 participants from the Framingham Heart Study (FHS). Seventy of the top single nucleotide polymorphisms (SNPs) were selected based on P values and linkage disequilibrium among neighboring SNPs and evaluated in a meta-analysis with 5 independent populations from the Cooperative Health Research in the Region of Augsburg cohort, the British 1958 Birth Cohort, and the Childhood Asthma Management Program cohort. Thirteen SNPs located in the region of 3 genes, FCER1A, signal transducer and activator of transcription 6 (STAT6), and IL13, were found to have genome-wide significance in the FHS cohort GWAS. The most significant SNPs from the 3 regions were rs2251746 (FCER1A, P= 2.11 × 10(-12)), rs1059513 (STAT6, P= 2.87 × 10(-8)), and rs1295686 (IL13, P= 3.55 × 10(-8)). Four additional gene regions, HLA-G, HLA-DQA2, HLA-A, and Duffy blood group, chemokine receptor (DARC), reached genome-wide statistical significance in a meta-analysis combining the FHS and replication cohorts, although the DARC association did not appear independent of SNPs in the nearby FCER1A gene. This GWAS of the FHS cohort has identified genetic loci in HLA genes that might have a role in the pathogenesis of IgE dysregulation and atopy. It also confirmed the association of the known susceptibility loci FCER1A, STAT6, and IL13 for the dysregulation of total IgE.

Lipoprotein(a) levels, apo(a) isoform size, and coronary heart disease risk in the Framingham Offspring Study

The aim of this study was to assess the independent contributions of plasma levels of lipoprotein(a) (Lp(a)), Lp(a) cholesterol, and of apo(a) isoform size to prospective coronary heart disease (CHD) risk. Plasma Lp(a) and Lp(a) cholesterol levels, and apo(a) isoform size were measured at examination cycle 5 in subjects participating in the Framingham Offspring Study who were free of CHD. After a mean follow-up of 12.3 years, 98 men and 47 women developed new CHD events. In multivariate analysis, the hazard ratio of CHD was approximately two-fold greater in men in the upper tertile of plasma Lp(a) levels, relative to those in the bottom tertile (P < 0.002). The apo(a) isoform size contributed only modestly to the association between Lp(a) and CHD and was not an independent predictor of CHD. In multivariate analysis, Lp(a) cholesterol was not significantly associated with CHD risk in men. In women, no association between Lp(a) and CHD risk was observed. Elevated plasma Lp(a) levels are a significant and independent predictor of CHD risk in men. The assessment of apo(a) isoform size in this cohort does not add significant information about CHD risk. In addition, the cholesterol content in Lp(a) is not a significant predictor of CHD risk.

Distribution, size, shape, growth potential and extent of abdominal aortic calcified deposits predict mortality in postmenopausal women

BackgroundAortic calcification is a major risk factor for death from cardiovascular disease. We investigated the relationship between mortality and the composite markers of number, size, morphology and distribution of calcified plaques in the lumbar aorta.Methods308 postmenopausal women aged 48-76 were followed for 8.3 ± 0.3 years, with deaths related to cardiovascular disease, cancer, or other causes being recorded. From lumbar X-rays at baseline the number (NCD), size, morphology and distribution of aortic calcification lesions were scored and combined into one Morphological Atherosclerotic Calcification Distribution (MACD) index. The hazard ratio for mortality was calculated for the MACD and for three other commonly used predictors: the EU SCORE card, the Framingham Coronary Heart Disease Risk Score (Framingham score), and the gold standard Aortic Calcification Severity score (AC24) developed from the Framingham Heart Study cohorts.ResultsAll four scoring systems showed increasing age, smoking, and raised triglyceride levels were the main predictors of mortality after adjustment for all other metabolic and physical parameters. The SCORE card and the Framingham score resulted in a mortality hazard ratio increase per standard deviation (HR/SD) of 1.8 (1.51-2.13) and 2.6 (1.87-3.71), respectively. Of the morphological x-ray based measures, NCD revealed a HR/SD >2 adjusted for SCORE/Framingham. The MACD index scoring the distribution, size, morphology and number of lesions revealed the best predictive power for identification of patients at risk of mortality, with a hazard ratio of 15.6 (p < 0.001) for the 10% at greatest risk of death.ConclusionsThis study shows that it is not just the extent of aortic calcification that predicts risk of mortality, but also the distribution, shape and size of calcified lesions. The MACD index may provide a more sensitive predictor of mortality from aortic calcification than the commonly used AC24 and SCORE/Framingham point card systems.

Hypertension Risk Prediction

Hypertension has been recognized for decades as a major predictor of adverse outcomes, including stroke, heart failure, end-stage renal disease, heart disease, and peripheral vascular disease. These disease risk estimates are the key components for the development and implementation of prevention, treatment, and control guidelines with a general theme of lower blood pressure levels associated with less adverse events.1 The public health burden from high blood pressure and the process to design interventions are further complicated by the high proportion of the population affected (≈1 in 3 adults), a linear increase with age, and disproportionally higher rates for segments of the population, such as blacks and Hispanics.2 Changes in awareness, treatment, and control of hypertension can be assessed and monitored in the population with a series of cross-sectional observational studies. Although these prevalence rates can be determined from single measurements in time, hypertension management and prevention strategies are dependent on incidence rates and the disease progression. These evidence-based guidelines are dependent on incidence and progression rates of …

Consent for genetic research in the Framingham Heart Study

Extensive efforts have been aimed at understanding the genetic underpinnings of complex diseases that affect humans. Numerous genome-wide association studies have assessed the association of genes with human disease, including the Framingham Heart Study (FHS), which genotyped 550,000 SNPs in 9,000 participants. The success of such efforts requires high rates of consent by participants, which is dependent on ethical oversight, communications, and trust between research participants and investigators. To study this we calculated percentages of participants who consented to collection of DNA and to various uses of their genetic information in two FHS cohorts between 2002 and 2009. The data included rates of consent for providing a DNA sample, creating an immortalized cell line, conducting research on various genetic conditions including those that might be considered sensitive, and for notifying participants of clinically significant genetic findings were above 95%. Only with regard to granting permission to share DNA or genetic findings with for-profit companies was the consent rate below 95%. We concluded that the FHS has maintained high rates of retention and consent for genetic research that has provided the scientific freedom to establish collaborations and address a broad range of research questions. We speculate that our high rates of consent have been achieved by establishing frequent and open communications with participants that highlight extensive oversight procedures. Our approach to maintaining high consent rates via ethical oversight of genetic research and communication with study participants is summarized in this report and should be of help to other studies engaged in similar types of research. Published 2010 Wiley-Liss, Inc.

Coronary Heart Disease and Stroke Risk in Patients with Psoriasis: Retrospective Analysis

Background Past studies suggest an association between psoriasis and the risk of developing coronary heart disease. The objectives of this study were to estimate the 10-year risks of coronary heart disease and stroke in patients with moderate to severe psoriasis, to compare risks between patients and the general population, and to determine whether risk profiles are affected by disease severity. Methods Data were pooled from patients with moderate to severe psoriasis (Psoriasis Area and Severity Index [PASI] score ≥ 10) who were enrolled in Phase II (M02-528) or Phase III trials ( Comparative Study of HUMIR A vs Methotrexate vs Placebo In Ps Oriasis Patie Nts[CHAMPION], Randomized Controlled EValuation of Adalimumab Every Other Week Dosing in Moderate to Severe Psoriasis Tri AL[REVEAL]) evaluating adalimumab. Risks of coronary heart disease and stroke were estimated using the Framingham risk score algorithm and a stroke risk function based on the Framingham Heart Study cohorts. To compare risks between patients with psoriasis and the general population, average population risks were imputed on the basis of age and gender. Wilcoxon rank-sum tests evaluated risk differences between patients with psoriasis and the general population and between patients with moderate psoriasis and patients with severe psoriasis. Results A total of 1591 patients were identified, including 1082 patients with PASI scores ≥ 10 and ≤ 20 and 509 patients with PASI scores > 20. Patients with PASI scores from 10 to 20 and PASI scores > 20 had similar 10-year risks of coronary heart disease (12.3% and 12.2%; P = .49) and stroke (8.3% and 8.7%; P = .28). Compared with the general population, 10-year risks of patients with psoriasis were 28% greater for coronary heart disease ( P < .001) and 11.8% greater for stroke ( P = .02). Conclusion Patients with moderate to severe psoriasis had increased risks of coronary heart disease and stroke compared with the general population.

Hypertension Resistance Polymorphisms in ROMK Alter Channel Function by Different Mechanisms

The ROMK potassium channel plays a critical role in renal sodium handling. Genome sequencing efforts in the Framingham Heart Study cohort recently revealed an association between suspected loss‐of‐function polymorphisms in ROMK and resistance to hypertension, suggesting that ROMK activity is also a determinant of blood pressure in the general population. Here, we examine whether these sequence variants do, in fact, alter ROMK function and explore the mechanisms. As assessed by two‐microelectrode voltage clamp in Xenopus Oocytes, 3/5 of the variants (R193P, H251Y and T313FS) displayed an almost complete attenuation of whole‐cell ROMK channel activity. Surface antibody binding to external epitope tagged channels and analysis of glycosylation‐state maturation revealed that these variants prevent channel expression at the plasmalemma, likely as a consequence of ER retention. The other variants (P166S, R169H) had no obvious effect on the basal channel activity or surface expression but, instead, displayed a regulated‐gating defect. Apparent PIP2 binding affinity of the variants was reduced, causing channels to become susceptible to inhibition by GPCR‐mediated stimulation of PIP2 hydrolysis. In summary, hypertension resistance sequence variants inhibit ROMK channel function by different mechanisms, providing new insights into the role of the channel in blood pressure control.

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.