Martin G Larson

..abstract:..

..The study of 70,987 single nucleotide polymorphisms (SNPs) in 1,010 FHS participants provides a list of SNPs showing the strongest associations with renal traits which need to be verified in independent study samples...

..Hundreds of statistical tests may be performed for a single SNP, thereby complicating interpretation of results and inhibiting identification of patterns of association...

..We also apply the three-stage approach to the GWA analyses of uric acid in Framingham Heart Study's SNP Health Association Resource (SHARe) project...

..Prior investigations have reported several single gene variants associated with CHD, stroke, HF, and AF. We report a community-based genome-wide association study of major CVD outcomes...

..Prior research yielded conflicting results about the magnitude of the association between body mass index (BMI) and chronic kidney disease (CKD)...

..Serum C-reactive protein (CRP) level is a heritable complex trait that predicts incident cardiovascular disease. We investigated the clinical and genetic sources of interindividual variability in serum CRP...

..Knowledge about the pathophysiological processes that determine arterial stiffness may help guide therapeutic approaches...

..Long-term blood pressure (BP) progression and its importance as a predictor of clinical outcome have not been well characterized across different periods...

..There are no data, however, on the incremental utility of a parsimonious set of biomarkers (reflecting pathways implicated in HF) for predicting HF risk in the community...

..Several biological pathways are activated concomitantly during left ventricular (LV) remodeling. However, the relative contribution of circulating biomarkers representing these distinct pathways to LV geometry is unclear...

..Neither cysC nor MA was significantly associated with AAC in age- and gender- or multivariable-adjusted models. In conclusion, CKD, cysC, and MA are not associated with CAC or AAC when accounting for cardiovascular disease risk factors...

..In conclusion, serum C-reactive protein concentrations are higher in nonhypertensive offspring of parents with hypertension. These data suggest that inflammation may partly mediate the familial influences on hypertension risk...

..In conclusion, circulating homocysteine, aldosterone, and BNP provide incremental information regarding risk for incident CKD and MA beyond traditional risk factors...

..We evaluated the relative contributions of circulating biomarkers representing distinct biological pathways to the incidence of MetS and to longitudinal changes of its constituent risk factors...

..Visceral (VAT) and subcutaneous adipose tissue (SAT) may confer differential metabolic risk profiles. The relations of VAT and SAT were analyzed with CKD as estimated by creatinine- and cystatin-based estimating equations...

..Experimental evidence identified the osteoprotegerin (OPG)/receptor activator of nuclear factor-kappaB (RANK)/RANK ligand (RANKL) pathway as a candidate system modulating vascular remodeling and cardiovascular disease (CVD)...

..Excess risk was apparent at natriuretic peptide levels well below current thresholds used to diagnose heart failure...

..Systemic oxidative stress causes insulin resistance in rodents. We tested the hypothesis that oxidative stress and insulin resistance are associated in humans...

..In conclusion, inflammatory markers were elevated in patients with valvular calcium. Our findings suggest that much of the observed association between systemic inflammatory markers and valvular calcium may be due to shared risk factors...

..Few studies relating vitamin D deficiency to obesity have included direct measures of adiposity. Furthermore, the degree to which vitamin D is associated with metabolic traits after adjusting for adiposity measures is unclear...

..Recent experimental studies have highlighted the potential role of the natriuretic peptides and aldosterone in mediating salt sensitivity...

..We conducted a genome-wide association study (GWAS) in the community-based Framingham Heart Study...

..We report the results of a community-based genomewide association study of six ECG and HRV intermediate traits...

..In conclusion, there were modest associations of inflammatory markers, particularly IL-6, with carotid atherosclerosis. This association appears more pronounced in current smokers than in former smokers and nonsmokers...

..We related validated parental premature CVD with the subclinical measures of coronary artery (CAC) and abdominal aortic (AAC) calcification in the community...

..To evaluate if biomarkers reflecting left ventricular/vascular extracellular matrix remodeling are associated with cardiovascular disease (CVD) and death in the community...

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..In conclusion, our observations are consistent with the hypothesis that MS and insulin resistance impair vascular function predominantly through the influence of the component metabolic abnormalities that comprise MS...

..In conclusion, subjects with prolonged QRS durations, even without bundle branch block, are at increased risk for future pacemaker implantation. Such individuals may warrant monitoring for progressive conduction disease...

..Additional studies addressing the pathogenesis, prevention, and optimal management of the joint occurrence of AF and CHF appear warranted...

..Baseline arterial measures did not associate with incident CKD or incident microalbuminuria. In summary, arterial stiffness correlates with albuminuria but not with mild-to-moderate CKD...

..18, 95% confidence interval 0.98 to 1.43, p = 0.09). In conclusion, circulating osteoprotegerin concentration was significantly associated with incident AF in our community-based sample, possibly mediated by interim cardiovascular events...

..EBCT AV calcium was associated with calcium deposits in the coronary arteries and the thoracic aorta, but these associations were confounded by age and risk factors...

..We hypothesized that this paradox is due partly to the advent of increasingly sensitive biomarkers for AMI diagnosis...

..Higher circulating Lp-PLA(2) predicts cardiovascular disease risk, but sources of inter-individual variability are incompletely understood...

..85-0.95, P = 2 x 10(-4), respectively). Common genetic variants at the NPPA-NPPB locus found to be associated with circulating natriuretic peptide concentrations contribute to interindividual variation in blood pressure and hypertension...

..Additional studies are needed to determine whether variation in inflammatory marker genes is associated with tonometry measures...

..Elevated PAI-1 levels may be associated with an increased risk for diabetes as a marker for underlying endothelial dysfunction rather than by a direct effect of genetically mediated elevated levels...

..Although impaired vascular function is hypothesized to influence the BP response during exercise, limited data exist on the association of vascular function with exercise BP in the community...

..Increased arterial stiffness is a key factor in the pathogenesis of systolic hypertension and cardiovascular disease. Substantial heritability of blood-pressure (BP) and arterial-stiffness suggests important genetic contributions...

..This study does not support a link between SDB and endothelial dysfunction as measured by brachial artery flow-mediated dilation...

..Whether inflammatory biomarkers are associated with kidney function and albuminuria after accounting for traditional CVD risk factors is not completely understood...

..Sequence variants at the endothelial nitric oxide synthase (NOS3) locus have been associated with endothelial function measures, but replication has been limited...

..Biomarkers of multiple pathophysiological pathways have been related to incident atrial fibrillation (AF), but their predictive ability remains controversial...

..Our data emphasize the contribution of familial factors to the heart-failure burden in the community...

..In the family-based Framingham Heart Study, we investigated heritability and candidate gene associations of systemic inflammatory biomarkers...

..Multiple markers of inflammation and oxidative stress correlated with pericardial and intrathoracic fat volumes, extending the known association between regional adiposity and inflammation and oxidative stress...

..Although it has been shown that obese individuals have reduced natriuretic peptide levels, conflicting data exist on the relation of natriuretic peptide levels to other metabolic risk factors...

..265), above and beyond traditional risk factors. VAT, but not SAT was associated with FMD% after adjusting for clinical covariates. Nevertheless, the differential association with VAT as compared to SAT was minimal...

..In conclusion, in a community-based sample, correlations among subclinical atherosclerosis test results are low, and a substantial proportion has high levels of subclinical atherosclerosis detected on >or=2 imaging tests...

..Congestive heart failure (CHF) is an increasing public health problem...

..Genome-wide association studies (GWAS) provide mechanisms to investigate the genetic contributions to biomarker variability unconstrained by current knowledge of physiological relations...

..We sought to investigate the hypothesis that smoking is accompanied by systemic inflammation...

..Further research is warranted to understand whether traditional and novel vascular risk factor burden, as well as metabolic derangements found in early kidney disease, can account for the CKD-MAC association...

..We undertook a linkage disequilibrium (LD)-based genetic approach to investigate the hypothesis that common sequence variants in 5 thrombosis genes influence plasma hemostatic protein levels or risk of cardiovascular disease (CVD)...

..16; 95% CI: 1.00 to 1.33). ARR is a heritable trait influenced by clinical and genetic factors. There is a continuous gradient of increasing risk of BP progression across ARR levels in nonhypertensive individuals...

..These data support the premise that abnormalities in multiple biological pathways antedate the onset of overt hypertension...

..Few investigations have evaluated the incremental usefulness of multiple biomarkers from distinct biologic pathways for predicting the risk of cardiovascular events...

..CONCLUSION: Lack of association of natriuretic peptides with OSAH indices suggests that undiagnosed OSAH may not be associated with major alterations in left ventricular function, as reflected in morning natriuretic peptide levels...

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..These studies identify a relationship between lipid acyl chain content and diabetes risk and demonstrate how lipid profiling could aid in clinical risk assessment...

..35 (p <0.001). In conclusion, high CysC is associated with CVD risk factors even in the absence of CKD. The strong associations between CysC and CVD risk factors may partially explain why CysC is a strong predictor of incident CVD...

..The blood pressure (BP) and heart rate responses to exercise treadmill testing predict incidence of cardiovascular disease, but the genetic determinants of hemodynamic and chronotropic responses to exercise are largely unknown...

..Little is known about the relations of natriuretic peptides and homocysteine to arterial wall stiffness in the community...

..It has been suggested that obesity promotes a relative natriuretic peptide deficiency, but this has been a variable finding in prior studies and the cause is unknown...

..Our data suggest that blood levels may not adequately reflect the important role of heat shock proteins in prevalent CVD...

..Greater emphasis is needed on achieving blood pressure control in all patients but particularly among older subjects and those with systolic hypertension...

..The possibility that inflammatory markers may be potential mediators between social integration and coronary heart disease merits further investigation...

..Information is limited on the longitudinal tracking of left ventricular (LV) mass over the adult life course and the determinants of such change...

..Additional investigations are warranted to confirm these findings...

..Prior studies were limited by small sample sizes and selection bias and none compared the diagnostic performance of these peptides in men and women...

..To examine the association between variation in estrogen-related genes and cross-sectional and longitudinal blood pressure in men and women...

..The purpose of this study is to determine the usefulness of exercise treadmill testing (ETT) among asymptomatic persons in predicting coronary heart disease (CHD) events over and above the Framingham CHD risk score...

..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...

..5% of the variation in QT interval. These results, together with an accompanying paper, offer insights into myocardial repolarization and suggest candidate genes that could predispose to sudden cardiac death and drug-induced arrhythmias...

..Given the high prevalence of obesity in the United States, strategies to promote optimal body weight may reduce the population burden of heart failure...

..Insulin resistance was associated with increased LV mass in women alone, but this relation was largely accounted for by obesity...

..The reference limits derived from this large, healthy community-based sample will aid in the identification of elevated natriuretic peptide levels in clinical practice...

..The purpose of this study was to investigate the impact of age, sex, and hypertension (HTN) on aortic atherosclerotic burden using cardiovascular MRI (CMR) in a free-living longitudinally followed cohort...

..Excess adiposity is associated with greater systemic inflammation. Whether visceral adiposity is more proinflammatory than subcutaneous abdominal adiposity is unclear...

..Additional investigations are warranted to elucidate the mechanisms underlying the observed associations...

..Additional investigations are warranted to confirm these findings and elucidate the basis for these gender-related differences...

..Recognition of the genetic determinants of HRV may provide additional insights into the pathophysiology of the autonomic nervous system and offer clues to its modulation...

..Cross-sectional twin and family studies have shown a moderate-to-substantial genetic component for BMI. However, the contribution of genetics to the long-term average, variability, or change over time in BMI is less clear...

..It remains unknown what role, if any, is played by other genetic variants in the inter-individual variability in levels of fibrinogen in the general population...

..19; P = 2.3 x 10(-7)). We replicated this association in an independent cohort from the German AF Network (odds ratio = 1.44; P = 1.6 x 10(-11); combined RR = 1.25; combined P = 1.8 x 10(-15))...

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..58). In conclusion, we have demonstrated a substantial genetic component to PP and have identified 4 chromosomal regions that may harbor genes influencing vascular stiffness...

..Genome wide SNP heterozygosity may be used to understand the phenomenon of dominance as well as the evolutionary basis of many quantitative traits in humans...

..These findings are supported by four practical examples from the Framingham Heart Study...

..The association provides evidence suggestive of a biologic pathway by which socioeconomic position may predispose to coronary heart disease...

..Aortic stiffness and small-artery structure and function share various risk factors; however, relations between these 2 measures of vascular function are complex and incompletely understood...

..The same method could be applied to evidence synthesis of other quantitative traits, whenever the typed SNPs vary among studies, and to assist fine mapping of causal variants...

..09) less than 5cM from the interleukin-10 (IL10) gene. Multiple genes on chromosome 1 may influence inflammatory biomarker levels and may have a potential role in development of CVD...

..Our findings support the concept that dynamic BP provides incremental information to BP at rest and suggest that exercise diastolic BP may be a better predictor than exercise systolic BP in this age group...

..However, few prior community-based studies have evaluated the genetics of arterial stiffness and separate mean and pulsatile components of blood pressure...

..The present study was suggestive of modest relations between common genetic variants at the NOS3 locus and arterial stiffness...

..CONCLUSIONS: Our region of interest on chromosome 9 has been implicated by two prior studies. Variance components analysis appeared to be sensitive to pedigree structures as well as the method of IBD computation used...