Clinically relevant variants identified in thoracic aortic aneurysm patients by research exome sequencing

Thoracic aortic aneurysm (TAA) is a genetically heterogeneous disease involving subclinical and progressive dilation of the thoracic aorta, which can lead to life-threatening complications such as dissection or rupture. Genetic testing is important for risk stratification and identification of at risk family members, and clinically available genetic testing panels have been expanding rapidly. However, when past testing results are normal, there is little evidence to guide decision-making about the indications and timing to pursue additional clinical genetic testing. Results from research based genetic testing can help inform this process. Here we present 10 TAA patients who have a family history of disease and who enrolled in research-based exome testing. Nine of these ten patients had previous clinical genetic testing that did not identify the cause of disease. We sought to determine the number of rare variants in 23 known TAA associated genes identified by research-based exome testing. In total, we found 10 rare variants in six patients. Likely pathogenic variants included a TGFB2 variant in one patient and a SMAD3 variant in another. These variants have been reported previously in individuals with similar phenotypes. Variants of uncertain significance of particular interest included novel variants in MYLK and MFAP5, which were identified in a third patient. In total, clinically reportable rare variants were found in 6/10 (60%) patients, with at least 2/10 (20%) patients having likely pathogenic variants identified. These data indicate that consideration of re-testing is important in TAA patients with previous negative or inconclusive results

Calcium, magnesium and potassium intake and mortality in women with heart failure: The Women\u27s Health Initiative

Although diet is thought to affect the natural history of heart failure (HF), nutrient intake in HF patients has not been well studied. Based on prior research linking high intake of Ca, Mg and K to improved cardiovascular health, we hypothesised that these nutrients would be inversely associated with mortality in people with HF. Of the 161 808 participants in the Women\u27s Health Initiative (WHI), we studied 3340 who experienced a HF hospitalisation. These participants were followed for post-hospitalisation all-cause mortality. Intake was assessed using questionnaires on food and supplement intake. Hazard ratios (HR) and 95 % CI were calculated using Cox proportional hazards models adjusted for demographics, physical function, co-morbidities and dietary covariates. Over a median of 4·6 years of follow-up, 1433 (42·9 %) of the women died. HR across quartiles of dietary Ca intake were 1·00 (referent), 0·86 (95 % CI 0·73, 1·00), 0·88 (95 % CI 0·75, 1·04) and 0·92 (95 % CI 0·76, 1·11) (P for trend = 0·63). Corresponding HR were 1·00 (referent), 0·86 (95 % CI 0·71, 1·04), 0·88 (95 % CI 0·69, 1·11) and 0·84 (95 % CI 0·63, 1·12) (P for trend = 0·29), across quartiles of dietary Mg intake, and 1·00 (referent), 1·20 (95 % CI 1·01, 1·43), 1·06 (95 % CI 0·86, 1·32) and 1·16 (95 % CI 0·90, 1·51) (P for trend = 0·35), across quartiles of dietary K intake. Results were similar when total (dietary plus supplemental) nutrient intakes were examined. In summary, among WHI participants with incident HF hospitalisation, intakes of Ca, Mg and K were not significantly associated with subsequent mortality

Exome Sequencing Identifies Candidate Genetic Modifiers of Syndromic and Familial Thoracic Aortic Aneurysm Severity

Thoracic aortic aneurysm (TAA) is a genetic disease predisposing to aortic dissection. It is important to identify the genetic modifiers controlling penetrance and expressivity to improve clinical prognostication. Exome sequencing was performed in 27 subjects with syndromic or familial TAA presenting with extreme phenotypes (15 with severe TAA; 12 with mild or absent TAA). Family-based analysis of a subset of the cohort identified variants, genes, and pathways segregating with TAA severity among three families. A rare missense variant in ADCK4 (p.Arg63Trp) segregated with mild TAA in each family. Genes and pathways identified in families were further investigated in the entire cohort using the optimal unified sequence kernel association test, finding significance for the gene COL15A1 (p = 0.025) and the retina homeostasis pathway (p = 0.035). Thus, we identified candidate genetic modifiers of TAA severity by exome-based study of extreme phenotypes, which may lead to improved risk stratification and development of new medical therapies

Are the 2005 Dietary Guidelines for Americans Associated With Reduced Risk of Type 2 Diabetes and Cardiometabolic Risk Factors?: Twenty-year findings from the CARDIA study

OBJECTIVE To examine the prospective association between accordance with the 2005 Dietary Guidelines for Americans (DGA) and subsequent diabetes incidence and changes in cardiometabolic risk factors

Dietary Intake, D3Cr Muscle Mass, and Appendicular Lean Mass in a Cohort of Older Men.

BackgroundWe examined cross-sectional associations between dietary patterns, macronutrient intake, and measures of muscle mass and lean mass in older men.MethodsParticipants in the Osteoporotic Fractures in Men (MrOS) cohort (n = 903; mean ± SD age 84.2 ± 4 years) completed brief Block food frequency questionnaires (May 2014-May 2016); factor analysis was used to derive dietary patterns. The D3-creatine (D3Cr) dilution method was used to measure muscle mass; dual-energy x-ray absorptiometry (DXA) was used to measure appendicular lean mass (ALM). Generalized linear models were used to report adjusted means of outcomes by dietary pattern. Multiple linear regression models were used to determine associations between macronutrients and D3Cr muscle mass and DXA ALM. Multivariable models were adjusted for age, race, clinic site, education, depression, total energy intake, height, and percent body fat.ResultsGreater adherence to a Western dietary pattern (high factor loadings for red meat, fried foods, and high-fat dairy) was associated with higher D3Cr muscle mass (p-trend = .026). Adherence to the Healthy dietary pattern (high factor loadings for fruit, vegetables, whole grains, and lean meats) was not associated with D3Cr muscle mass or DXA ALM. Total protein (β = 0.09, 95% CI = 0.03, 0.14) and nondairy animal protein (β = 0.16, 95% CI = 0.10, 0.21) were positively associated with D3Cr muscle mass. Nondairy animal protein (β = 0.06, 95% CI = 0.002, 0.11) was positively associated with DXA ALM. Associations with other macronutrients were inconsistent.ConclusionsNondairy animal protein intake (within a Western dietary pattern and alone) was positively associated with D3Cr muscle mass in older men

Lack of Association Between 25(OH)D Levels and Incident Type 2 Diabetes in Older Women

Objective: To examine whether lower serum levels of serum 25-hydroxyvitamin (OH) D [25(OH)D] are associated with increased risk of developing type 2 diabetes. Research Design and Methods: A post hoc analysis of three nested case-control studies of fractures, colon cancer, and breast cancer that measured serum 25(OH)D levels in women participating in the Women’s Health Initiative (WHI) Clinical Trials and Observational Study who were free of prevalent diabetes at baseline. Diabetes was defined as self-report of physician diagnosis or receiving insulin or oral hypoglycemic medication. We used inverse probability weighting to make the study population representative of the WHI population as a whole. Weighted logistic regression models compared 25(OH)D levels (divided into quartiles, clinical cut points [<50, 50–<75, $\geq$75 nmol/L], or as a continuous variable) using the distribution of control subjects and adjusted for multiple confounding factors. Results: Of 5,140 women (mean age 66 years) followed for an average of 7.3 years, 317 (6.2%) developed diabetes. Regardless of the cut points used or as a continuous variable, 25(OH)D levels were not associated with diabetes incidence in either age or fully adjusted models. Nor was any relationship found between 25(OH)D and incident diabetes when evaluated by strata of BMI, race/ethnicity, or randomization status in the Calcium Vitamin D trial. Conclusions: Lower serum 25(OH)D levels were not associated with increased risk of developing type 2 diabetes in this racially and ethnically diverse population of postmenopausal women

Dietary Patterns and Fractures in Postmenopausal Women: Results From the Women\u27s Health Initiative

IMPORTANCE: Considerable efforts have been undertaken to relate single nutrients to bone health. To this point, results are inconsistent. Suboptimal single nutrient intake does not occur in isolation but rather reflects a poor diet quality. OBJECTIVE: To assess the association between adherence to a diet quality index constructed on the basis of dietary recommendations or existing healthy dietary patterns and fractures in postmenopausal women. DESIGN, SETTING, AND PARTICIPANTS: Post hoc analysis was conducted of longitudinal data from 40 clinical centers throughout the United States included in the Women\u27s Health Initiative (WHI) observational study. Participants in the prospective cohort included 93676 women who were eligible for the WHI if they were aged 50 to 79 years. Recruitment was conducted from October 1, 1993, to December 31, 1998, with the study ending August 29, 2014. The WHI food frequency questionnaire was used to derive nutrient and food intake at baseline. Diet quality and adherence were assessed by scores on the alternate Mediterranean Diet (aMED), a 9-category measure of adherence to a Mediterranean dietary pattern; the Healthy Eating Index 2010 (HEI-2010), a 100-point measure of 12 food components; the 11-item Alternate Healthy Eating Index 2010 (AHEI-2010); or the 8-component Dietary Approaches to Stop Hypertension (DASH) diet score. MAIN OUTCOMES AND MEASURES: Outcome measures included incident total and hip fractures. Hazard ratios (HRs) by quintiles of dietary index scores were estimated using Cox proportional hazards regression analyses. RESULTS: Of the 93676 participants, 90014 were included in the analysis (mean [SD] age, 63.6 [7.4]) years. During a median follow-up time of 15.9 years, there were 2121 cases of hip fractures and 28718 cases of total fractures. Women scoring in the highest quintile (Q5) of the aMED index had a lower risk for hip fractures (HR, 0.80; 95% CI, 0.66-0.97), with an absolute risk reduction of 0.29% and a number needed to treat of 342 (95% CI, 249-502). No association between the aMED score and total fractures was observed (Q5 HR, 1.01; 95% CI, 0.95-1.07). Higher HEI-2010 or DASH scores tended to be inversely related to hip fracture risk, but the results were nonsignificant (Q5 HR, 0.87; 95% CI, 0.75-1.02; and Q5 HR, 0.89; 95% CI, 0.75-1.06, respectively). The AHEI-2010 score was associated with neither hip nor total fractures. CONCLUSIONS AND RELEVANCE: Higher adherence to a Mediterranean diet is associated with a lower risk for hip fractures. These results support that a healthy dietary pattern may play a role in maintaining bone health in postmenopausal women

Food Price and Diet and Health Outcomes: 20 Years of the CARDIA Study

Despite surging interest in taxation as a policy to address poor food choice, US research directly examining the association of food prices with individual intake is scarce

Fish oil, selenium and mercury in relation to incidence of hypertension: a 20-year follow-up study: Fish, selenium, mercury and incidence of hypertension

Long-chain omega-3 polyunsaturated fatty acids (LCω3PUFAs), selenium (Se) and mercury (Hg) are three important components in fish. The cardioprotective effect of LCω3PUFA intake has been recognized; however, the hypothesis that this benefit may be greatest with high Se and low Hg levels has not been investigated

Folate intake and incidence of hypertension among American young adults: a 20-y follow-up study

Background: Laboratory studies suggest that folate intake may decrease blood pressure (BP) through increasing nitric oxide synthesis in endothelial cells and/or reducing plasma homocysteine concentrations. However, human studies, particularly longitudinal data, are limited