Left ventricular (LV) hypertrophy is a common condition that profoundly affects morbidity and mortality from cardiovascular diseases, including myocardial infarction, congestive heart failure, and ...stroke. Noninvasive imaging methods have greatly expanded our ability to evaluate cardiac structural and functional characteristics, and enhanced our understanding of the natural history of LV hypertrophy. The etiology of LV hypertrophy is likely due to the effects of multiple genes interacting with other genes and the environment. Although hypertension is recognized as a strong determinant of LV hypertrophy, blood pressure explains only a limited amount of the interindividual variation in LV mass. Moreover, LV hypertrophy occurs in the absence of hypertension, and in some cases precedes its development. Genes encoding proteins involved in the structure of the LV, as well as genes encoding cell signal transduction, hormones, growth factors, calcium homeostasis, and blood pressure, are likely candidates for the development of common forms of LV hypertrophy. An overview of the epidemiology and pathophysiology of LV hypertrophy and dysfunction is provided, in addition to evidence of the genetic basis for LV hypertrophy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
492.
The US Cancer Moonshot initiative Aelion, C Marjorie; Airhihenbuwa, Collins O; Alemagno, Sonia ...
The lancet oncology,
05/2016, Volume:
17, Issue:
5
Journal Article
Peer reviewed
Open access
Since the beginning of the so-called war on cancer, the most notable cancer successes have been due to the power and effectiveness of prevention.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted ...single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome sequencing data.
Cases were defined as individuals treated for hypertension (HTN) taking three different AHT classes, with average systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg, or four or more medications regardless of BP (
= 1,705). A normotensive control group was defined as individuals with BP < 140/90 mmHg (
= 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP < 140/ 90 mmHg (
= 5,424). Logistic regression with kinship adjustment using the Scalable and Accurate Implementation of Generalized mixed models (SAIGE) was performed, adjusting for age, sex, and genetic ancestry. We assessed variants using SKAT-O in rare-variant analyses. Single-variant and gene-based tests were conducted in a pooled multi-ethnicity stratum, as well as self-reported ethnic/racial strata (European and African American).
One variant in the known HTN locus,
, was a top finding in the multi-ethnic analysis (
= 8.23E-07) for the normotensive control group rs12476527, odds ratio (95% confidence interval) = 0.80 (0.74-0.88). This variant was replicated in the Vanderbilt University Medical Center's DNA repository data. Aggregate gene-based signals included the genes
and
.
Additional work validating these loci in larger, more diverse populations, is warranted to determine whether these regions influence the pathobiology of aTRH.
Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the ...contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability (Formula: see text) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability (Formula: see text, 0.18-0.34). In the African ancestry samples, Formula: see text was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.
It has been suggested that the trophic effects of insulin may contribute to left ventricular (LV) hypertrophy in hypertension, but few population-based data exist to assess the potential impact of ...insulin level on LV structure or systolic function.
Fasting plasma insulin levels (log-transformed) in 1542 nondiabetic African American or white hypertensive participants in the
Hypertension
Genetic
Epidemiology
Network (HyperGEN) study were compared to indices of LV geometry and function, with adjustment for potential confounders (age, sex, ethnicity, blood pressure (BP), body mass index, height and antihypertensive drugs).
In simple correlation analysis, a weak positive relation (
r = 0.078,
P = .002) was found between LV mass and insulin, principally due to positive correlations (
r = 0.22 and 0.50) of both variables to body mass index. Multivariate analysis, adjusting for age, sex, ethnicity, body size, systolic BP, and antihypertensive drugs revealed a modest negative relation between insulin and LV mass (
r = −0.08,
P = .001) due to a negative relationship between insulin with LV chamber size (
r = − 0.10,
P < .001) and no significant relation to LV wall thicknesses. These results were confirmed in additional analysis controlling for a positive relation (
r = .19,
P < .0001) of insulin to heart rate, and the relation with insulin became slightly more negative when LV mass was indexed for height
2.7 (
r = −0.13,
P < .001). After adjustment for covariates, there were no significant relations of insulin to LV ejection fraction or stress-corrected midwall shortening; however, insulin was negatively related to stroke volume (
r = −0.12, p < 0.001) and was weakly related positively to relative wall thickness (
r = .053) (
P = .04).
After adjustment for body mass index and other covariates, insulin in nondiabetic hypertensive individuals has weak negative relations to LV chamber size, mass, and stroke volume, and also has weak positive relations to relative wall thickness but not to measures of LV systolic function. Thus, native plasma insulin level may not play a major independent role in the pathogenesis of hypertensive LV hypertrophy or dysfunction.
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GEOZS, IJS, NUK, OILJ, PNG, SBCE, UL, UM, UPUK
Previous studies of the association between the use of appetite suppressants and valvular heart disease have not accounted for the effects of valvular structure and aortic root diameter, which are ...associated with obesity. We assessed whether the use of the appetite suppressants fenfluramine/dexfenfluramine, either alone or with phentermine, was associated with aortic regurgitation while adjusting for these variables.
The sample included 2524 adult participants in the population-based Hypertension Genetic Epidemiology Network study. Information regarding current drug use was assessed during a clinical examination. Medication use was continued at the time of echocardiographic study. Expert readers blinded to current therapy read echocardiograms centrally at Cornell Medical Center. Analyses of the associations between use of fenfluramine/dexfenfluramine (alone or with phentermine) and aortic regurgitation adjusted for potential confounders, including aortic root dilatation and valve fibrocalcification.
Nineteen participants, all of whom had hypertension, were being treated with fenfluramine or dexfenfluramine (5 on these agents alone, 14 also with phentermine). Aortic regurgitation was present in 32% (n = 6) of those taking fenfluramine or dexfenfluramine versus 6% (162/2505) of remaining subjects (P = 0.001). In multivariate-adjusted analyses, treatment with fenfluramine or dexfenfluramine was associated with aortic regurgitation (odds ratio OR = 4.9; 95% confidence interval CI: 1.7 to 14) and aortic fibrocalcification (OR = 5.2; 95% CI: 1.9 to 15).
In a population-based sample, use of fenfluramine or dexfenfluramine, alone or in combination with phentermine, was associated with aortic regurgitation independent of aortic dilatation or fibrocalcification.
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GEOZS, IJS, NUK, OILJ, UL, UM
Abstract only Introduction: Dietary fatty acids have a role in many physiological mechanisms that influence cardiovascular health. An emerging body of evidence suggests that dietary fats may interact ...with genetic variants in regulating tissue levels of fatty acids, thus impacting disease risk. Epigenetic changes such as DNA methylation are a promising mechanism underlying such interactions. However, no studies to date have investigated the relationship between DNA methylation and tissue fatty acids at the genome-wide level. Methods: We have performed the first epigenome-wide association study (EWAS) of erythrocyte concentrations of polyunsaturated, monounsaturated, saturated, and trans fatty acids in 958 participants of the Genetics of Diet and Lipid Lowering Drugs Network (GOLDN). We assayed the methylation status of approximately 450,000 CpG sites in CD4+ T-cells. To investigate the associations between methylation of each CpG site and red blood cell fatty acids, we fit linear mixed models adjusted for age, sex, cell purity, and family structure. Results: The strongest association was observed between the methylation status of a CpG site in PDE4D, previously linked to systemic inflammation and stroke, and red blood cell trans fatty acids (P=4x10-7). In the analysis of polyunsaturated fatty acids, we found inverse associations with the methylation status of two CpG sites in BRSK2 (P=9x10-6 and P=1x10-5 respectively), as well as with a CpG site located in a “gene desert” on chromosome 14 proximally to VRK1 (P=5x10-7). BRSK2 encodes a kinase previously shown to control epigenetic programs that determine T-cell function. The top hits for monounsaturated and saturated fatty acids were located in ATL2 (P=1x10-6) and FGD2 (P=1x10-5), respectively. Conclusions: We present preliminary evidence of cross-sectional association between the methylation status of several biologically relevant genomic regions and erythrocyte concentrations of polyunsaturated, trans, monounsaturated, and saturated fatty acids. Upon successful validation, these findings further current understanding of gene-fatty acid interactions in human health and disease.
Traditional Cardiovascular Risk Factors in Relation to Left Ventricular Mass, Volume, and Systolic Function by Cardiac Magnetic Resonance Imaging: The Multiethnic Study of Atherosclerosis
Susan R. ...Heckbert, Wendy Post, Gregory D. N. Pearson, Donna K. Arnett, Antoinette S. Gomes, Michael Jerosch-Herold, W. Gregory Hundley, Joao A. Lima, David A. Bluemke
We examined the cross-sectional associations of cardiovascular risk factors with left ventricular (LV) geometry and systolic function measured by magnetic resonance imaging. We studied 4,869 participants without clinical cardiovascular disease in the Multiethnic Study of Atherosclerosis. After adjustment for sociodemographic variables and height, higher systolic blood pressure and body mass index were associated with larger LV mass and volumes, and current smoking and diabetes were associated with greater LV mass and lower stroke volume, although on average the differences were small. Additional study of these modifiable risk factors and their treatment in relation to the new development or progression of LV dysfunction is needed.
The goal of this study was to examine the cross-sectional associations of cardiovascular risk factors with left ventricular (LV) geometry and systolic function measured by cardiac magnetic resonance imaging (MRI) in the Multiethnic Study of Atherosclerosis (MESA).
Cardiovascular risk factors including hypertension, smoking, and obesity are known to be associated with increased LV mass, but less is known about the association of risk factors with LV systolic function, particularly in populations without clinical cardiovascular disease.
Participants were from 4 racial/ethnic groups and were free of clinical cardiovascular disease. Blood pressure, health habits, body mass index, lipid levels, and glucose abnormalities were assessed and MRI exams performed at baseline (n = 4,869). Multivariable linear regression was used to model the association of risk factors with LV mass, end-diastolic volume, stroke volume, ejection fraction, and cardiac output.
The mean age was 62 years, and 52% of the participants were women. After adjustment for sociodemographic variables and height, higher systolic blood pressure and body mass index were associated with larger LV mass and volumes. Current smoking and diabetes were associated with greater LV mass (+7.7 g, 95% confidence interval CI +5.5 to +9.9 and +3.5 g, 95% CI +1.2 to +5.8, respectively), and with lower stroke volume (−1.9 ml, 95% CI −3.3 to −0.5 and −4.5 ml, 95% CI −6.0 to −3.0, respectively) and lower ejection fraction (−1.6%, 95% CI −2.1 to −1.0 and −0.8%, 95% CI −1.5 to −0.2, respectively).
In this cohort free of clinical cardiovascular disease, modifiable risk factors were associated with subclinical alterations in LV size and systolic function as detected by cardiac MRI.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: S100 calcium-binding protein A9 (S100A9) has previously been identified as a type 2 diabetes (T2D) gene. However, this finding requires independent validation and more in-depth analyses ...in other populations and ancestries.
Objectives: We aimed to replicate the associations between an S100A9 variant and insulin resistance and T2D and to initiate an investigation of potential interactions with the habitual diet in several independent populations.
Design: We investigated the association of the S100A9 variant rs3014866 with insulin resistance and T2D risk and its interactions with diet in 3 diverse populations as follows: the CORDIOPREV (Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention; n = 711), which consisted of Spanish white adults; the GOLDN (Genetics of Lipids Lowering Drugs and Diet Network; n = 818), which involved North American non-Hispanic white adults; and Hispanic adults who participated in the BPRHS (Boston Puerto Rican Health Study; n = 1155).
Results: Meta-analysis indicated that T carriers presented a lower risk of T2D than CC carriers (pooled OR: 0.714; 95% CI: 0.584, 0.845; P = 0.002). In all 3 populations (CORDIOPREV, GOLDN, and BPRHS), we showed a significant interaction between the rs3014866 single nucleotide polymorphism and dietary SFA:carbohydrate ratio intake for the homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.028, P = 0.017, and P = 0.026, respectively). CC carriers had a significantly higher HOMA-IR only when SFA:carbohydrate intake was high (P = 0.045 for the CORDIOPREV, P = 0.033 for the GOLDN, and P = 0.046 for the BPRHS) but not when SFA:carbohydrate ratio intake was low.
Conclusions: The minor allele (T) of the S100A9 variant rs3014866 is associated with lower T2D risk in 3 populations of different ancestries. Note that individuals with the high-risk CC genotype may be more likely to benefit from a low SFA:carbohydrate ratio intake to improve insulin resistance as evaluated with the use of the HOMA-IR. These trials were registered at clinicaltrials.gov as NCT00924937 (CORDIOPREV), NCT00083369 (GOLDN), and NCT01231958 (BPRHS).
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CMK, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A genome scan was performed for low-density lipoprotein cholesterol concentration (LDL-C) in white subjects who were ascertained through the NHLBI Family Heart Study (FHS). The NIH Mammalian ...Genotyping Service (Marshfield, Wis.) genotyped 401 autosomal markers spaced at approximate 10-cM intervals. Additional FHS families were genotyped by the FHS Molecular Laboratory at the University of Utah for 243 markers; 645 subjects were typed in both laboratories so that a combined map of the 644 markers from the two screening sets (average distance of 5.46 cM) could be produced. Analyses were done on 2,799 genotyped subjects in 500 families where at least two genotyped persons in the family had measured LDL-C levels (average number of genotyped family members=5.95). The variance components method was used as implemented in GeneHunter (Kruglyak et al. 1996). Prior to analysis, each phenotype was adjusted, within sex, for age, age squared, body mass index, waist-hip ratio, alcohol, smoking, medication status for diabetes and hypertension, estrogen use, and field center location. Linkage analyses were performed, first excluding 305 subjects on lipid-lowering medications, then again including the data from these subjects. The highest peak was on chromosome 11 at 56.3-56.4 cM, with a maximum lod score of 3.72. Two genome scans of lipid traits in other populations have found peaks in this region. Other scores at or above 1.9 occurred on chromosomes 5 (lod=1.89 at 1.6 cM), 10 (lod=2.47 at 127.1 cM), 17 (lod=2.33 at 116.3 cM), and 21 (lod=2.74 at 45.2 cM).
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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