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Framingham Center, MA, United States

Chen H.,Boston University | Meigs J.B.,Massachusetts General Hospital | Meigs J.B.,Harvard University | Dupuis J.,Boston University | Dupuis J.,Lung and Blood Institutes Framingham Heart Study
Genetic Epidemiology | Year: 2013

A large number of rare genetic variants have been discovered with the development in sequencing technology and the lowering of sequencing costs. Rare variant analysis may help identify novel genes associated with diseases and quantitative traits, adding to our knowledge of explaining heritability of these phenotypes. Many statistical methods for rare variant analysis have been developed in recent years, but some of them require the strong assumption that all rare variants in the analysis share the same direction of effect, and others requiring permutation to calculate the P-values are computer intensive. Among these methods, the sequence kernel association test (SKAT) is a powerful method under many different scenarios. It does not require any assumption on the directionality of effects, and statistical significance is computed analytically. In this paper, we extend SKAT to be applicable to family data. The family-based SKAT (famSKAT) has a different test statistic and null distribution compared to SKAT, but is equivalent to SKAT when there is no familial correlation. Our simulation studies show that SKAT has inflated type I error if familial correlation is inappropriately ignored, but has appropriate type I error if applied to a single individual per family to obtain an unrelated subset. In contrast, famSKAT has the correct type I error when analyzing correlated observations, and it has higher power than competing methods in many different scenarios. We illustrate our approach to analyze the association of rare genetic variants using glycemic traits from the Framingham Heart Study. © 2012 WILEY PERIODICALS, INC.

Wang H.,Tufts University | Livingston K.A.,Tufts University | Fox C.S.,Lung and Blood Institutes Framingham Heart Study | Meigs J.B.,Massachusetts General Hospital | Jacques P.F.,Tufts University
Nutrition Research | Year: 2013

The evidence-based Dietary Guidelines for Americans recommends increasing the intake of fat-free or low-fat milk and milk products. However, yogurt, a nutrient-dense milk product, has been understudied. This cross-sectional study examined whether yogurt consumption was associated with better diet quality and metabolic profile among adults (n = 6526) participating in the Framingham Heart Study Offspring (1998-2001) and Third Generation (2002-2005) cohorts. A validated food frequency questionnaire was used to assess dietary intake, and the Dietary Guidelines Adherence Index (DGAI) was used to measure overall diet quality. Standardized clinical examinations and laboratory tests were conducted. Generalized estimating equations examined the associations of yogurt consumption with diet quality and levels of metabolic factors. Approximately 64% of women (vs 41% of men) were yogurt consumers (ie, consumed >0 servings/week). Yogurt consumers had a higher DGAI score (ie, better diet quality) than nonconsumers. Adjusted for demographic and lifestyle factors and DGAI, yogurt consumers, compared with nonconsumers, had higher potassium intakes (difference, 0.12 g/d) and were 47%, 55%, 48%, 38%, and 34% less likely to have inadequate intakes (based on Dietary Reference Intake) of vitamins B2 and B12, calcium, magnesium, and zinc, respectively (all P ≤ .001). In addition, yogurt consumption was associated with lower levels of circulating triglycerides, glucose, and lower systolic blood pressure and insulin resistance (all P < .05). Yogurt is a good source of several micronutrients and may help to improve diet quality and maintain metabolic well-being as part of a healthy, energy-balanced dietary pattern. © 2013 Elsevier Inc.

Hanna E.B.,Louisiana State University | Chen A.Y.,Duke University | Roe M.T.,Duke University | Wiviott S.D.,Brigham and Womens Hospital | And 3 more authors.
JACC: Cardiovascular Interventions | Year: 2011

Objectives: This study sought to evaluate the characteristics, therapies, and outcomes of patients with chronic kidney disease (CKD) presenting with nonST-segment elevation myocardial infarction (NSTEMI) and managed with percutaneous coronary intervention (PCI). This specific population has not been evaluated previously. Background: Among patients with acute coronary syndrome, the presence of renal dysfunction is associated with an increased risk of death and major bleeding. Methods: We examined data on 40,074 NSTEMI patients managed with PCI who were captured by the ACTION (Acute Coronary Treatment and Intervention Outcomes Network) registry. Patients were divided according to baseline renal function in 4 groups: no CKD and CKD stages 3, 4, and 5. Results: Overall, 31.1% (n = 12,045) of patients with NSTEMI undergoing PCI had CKD. Compared with patients with normal renal function, CKD patients managed with PCI had significantly more history of myocardial infarction, heart failure, and more 3-vessel coronary artery disease. They received fewer antithrombotic therapies but were treated more frequently with bivalirudin. In addition, they had significantly higher rates of in-hospital mortality and major bleeding. CKD stage 4 was associated with the highest risk of adverse events relative to no CKD. The multivariable adjusted odds ratios of in-hospital mortality for CKD stages 3, 4, and 5 relative to no CKD were 2.0, 2.8, and 2.6, respectively (global p value <0.0001), and the analogous adjusted odds ratios of major bleeding were 1.5, 2.8, and 1.8, respectively (global p value <0.0001). Conclusions: CKD patients presenting with NSTEMI and managed with PCI have more comorbidities and receive guideline-recommended therapies less frequently than do patients without CKD. CKD is strongly associated with in-hospital mortality and bleeding in NSTEMI patients undergoing PCI. © 2011 American College of Cardiology Foundation.

Domire J.S.,Ohio State University | Green J.A.,Ohio State University | Lee K.G.,Ohio State University | Johnson A.D.,Lung and Blood Institutes Framingham Heart Study | And 2 more authors.
Cellular and Molecular Life Sciences | Year: 2011

Primary cilia are nearly ubiquitous cellular appendages that provide important sensory and signaling functions. Ciliary dysfunction underlies numerous human diseases, collectively termed ciliopathies. Primary cilia have distinct functions on different cell types and these functions are defined by the signaling proteins that localize to the ciliary membrane. Neurons throughout the mammalian brain possess primary cilia upon which certain G protein-coupled receptors localize. Yet, the precise signaling proteins present on the vast majority of neuronal cilia are unknown. Here, we report that dopamine receptor 1 (D1) localizes to cilia on mouse central neurons, thereby implicating neuronal cilia in dopamine signaling. Interestingly, ciliary localization of D1 is dynamic, and the receptor rapidly translocates to and from cilia in response to environmental cues. Notably, the translocation of D1 from cilia requires proteins mutated in the ciliopathy Bardet-Biedl syndrome (BBS), and we find that one of the BBS proteins, Bbs5, specifically interacts with D1. © 2010 Springer Basel AG.

Abraham T.M.,Harvard University | Pencina K.M.,Boston University | Pencina M.J.,Duke University | Fox C.S.,Harvard University | And 2 more authors.
Diabetes Care | Year: 2015

OBJECTIVE Obesity and type 2 diabetes continue to increase in prevalence in the U.S. Whether diabetes incidence continues to increase in recent times is less well documented. We examined trends in diabetes incidence over the previous four decades. RESEARCH DESIGN AND METHODS Framingham Heart Study participants ages 40-55 years and free of diabetes at baseline (n = 4,795; mean age 45.3 years; 51.6% women) were followed for the development of diabetes in the 1970s, 1980s, 1990s, and 2000s. Diabetes was defined as either fasting glucose ≥126 mg/dL or use of antidiabetes medication. Poisson regression was used to calculate sex-specific diabetes incidence rates for a 47-year-old individual in each decade. Rates were also calculated among obese, overweight, and normal weight individuals. RESULTS The annualized rates of diabetes per 1,000 individuals were 2.6, 3.8, 4.7, and 3.0 (women) and 3.4, 4.5, 7.4, and 7.3 (men) in the 1970s, 1980s, 1990s, and 2000s, respectively. Compared with the 1970s, the age- And sex-adjusted relative risks of diabetes were 1.37 (95% CI 0.87-2.16; P = 0.17), 1.99 (95% CI 1.30-3.03; P = 0.001), and 1.81 (95% CI 1.16-2.82; P = 0.01) in the 1980s, 1990s, and 2000s, respectively. Compared with the 1990s, the relative risk of diabetes in the 2000s was 0.85 (95% CI 0.61-1.20; P = 0.36). CONCLUSIONS In our community-based sample, the risk of new-onset diabetes continued to be higher in the 2000s compared with the 1970s. In the past decade, diabetes incidence remained steady despite the ongoing trend of rising adiposity. © 2015 by the American Diabetes Association.

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