232 research outputs found
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Plasma Levels of FetuinâA and Risk of Coronary Heart Disease in US Women: The Nurses' Health Study
Background: FetuinâA may be involved in the etiology of coronary heart disease (CHD) through opposing pathways (ie, promoting insulin resistance and inhibiting ectopic calcification). We aimed to explicitly examine whether systemic inflammation, a factor leading to elevated vascular calcification, may modify the association between fetuinâA and CHD risk. Method and Results During 16 years of followâup (1990â2006), we prospectively identified and confirmed 466 incident fatal or nonfatal CHD case in the Nurses' Health Study. For each case, 1 healthy control was selected using riskâset sampling from 26 245 eligible participants. Cases and controls were matched for age, smoking status, fasting status, and date of blood draw. After multivariate adjustment for lifestyle factors, body mass index, diet, and blood lipids, fetuinâA levels were not associated with CHD risk in the whole population: odds ratio (OR) (95% CI) comparing extreme quintiles of fetuinâA was 0.79 (0.44 to 1.40). However, a significant inverse association was observed among participants with higher Câreactive protein levels (Pinteraction=0.04). The OR (95% CI) comparing highest versus lowest quintiles of fetuinâA was 0.50 (0.26 to 0.97; Ptrend=0.004) when Câreactive protein levels were above population median (0.20 mg/dL), whereas among the remainder of the participants, the corresponding OR (95% CI) was 1.09 (0.58 to 2.05; Ptrend=0.75). Conclusions: In this population of US women, fetuinâA levels were associated with lower CHD risk when Câreactive protein levels were high, but null association was observed among participants with lower Câreactive protein levels. This divergent pattern of association needs replication in future studies
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Identifying Metabolomic Profiles of Insulinemic Dietary Patterns
The food-based empirical dietary index for hyperinsulinemia (EDIH) score assesses the insulinemic potential of diet. This cross-sectional study evaluated associations between EDIH scores from food frequency questionnaires with c-peptide concentrations and with 448 metabolites, from fasting plasma samples, in multivariable linear regression analyses. Metabolites were measured with liquid chromatography tandem mass spectroscopy. Using a robust two-stage study design, discovery of metabolite associations was conducted among 1109 Womenâs Health Initiative (WHI) Hormone Therapy (HT) trial participants and results replicated in an independent dataset of 810 WHI Observational Study (OS) participants. In both discovery and replication datasets, statistical significance was based on the false-discovery rate adjusted P \u3c 0.05. In the multivariable-adjusted analyses, EDIH was significantly associated with c-peptide concentrations among 919 women (HT & OS) with c-peptide data. On average, c-peptide concentrations were 18% higher (95% CI, 6%, 32%; P-trend \u3c 0.0001) in EDIH quintile 5 compared to quintile 1. Twenty-six metabolites were significantly associated with EDIH in the discovery dataset, and 19 of these were replicated in the validation dataset. Nine metabolites were found to decrease in abundance with increasing EDIH scores and included: C14:0 CE, C16:1 CE, C18:1 CE, C18:3 CE, C20:3 CE, C20:5 CE, C36:1 PS plasmalogen, trigonelline, and eicosapentanoate, whereas the 10 metabolites observed to increase with increasing EDIH scores were: C18:2 SM, C36:3 DAG, C36:4 DAG-A, C51:3 TAG, C52:3 TAG, C52:4, TAG, C54:3 TAG, C54:4 TAG, C54:6 TAG, and C10:2 carnitine. Cholesteryl esters, phospholipids, acylglycerols, and acylcarnitines may constitute circulating metabolites that are associated with insulinemic dietary patterns
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Dietary fiber intake and mortality among survivors of myocardial infarction: prospective cohort study
Objective: To evaluate the associations of dietary fiber after myocardial infarction (MI) and changes in dietary fiber intake from before to after MI with all cause and cardiovascular mortality. Design: Prospective cohort study. Setting: Two large prospective cohort studies of US women and men with repeated dietary measurements: the Nursesâ Health Study and the Health Professionals Follow-Up Study. Participants: 2258 women and 1840 men who were free of cardiovascular disease, stroke, or cancer at enrollment, survived a first MI during follow-up, were free of stroke at the time of initial onset of MI, and provided food frequency questionnaires pre-MI and at least one post-MI. Main outcome measures Associations of dietary fiber post-MI and changes from before to after MI with all cause and cardiovascular mortality using Cox proportional hazards models, adjusting for drug use, medical history, and lifestyle factors. Results: Higher post-MI fiber intake was significantly associated with lower all cause mortality (comparing extreme fifths, pooled hazard ratio 0.75, 95% confidence interval 0.58 to 0.97). Greater intake of cereal fiber was more strongly associated with all cause mortality (pooled hazard ratio 0.73, 0.58 to 0.91) than were other sources of dietary fiber. Increased fiber intake from before to after MI was significantly associated with lower all cause mortality (pooled hazard ratio 0.69, 0.55 to 0.87). Conclusions: In this prospective study of patients who survived MI, a greater intake of dietary fiber after MI, especially cereal fiber, was inversely associated with all cause mortality. In addition, increasing consumption of fiber from before to after MI was significantly associated with lower all cause and cardiovascular mortality
Haptoglobin Genotype Is a Consistent Marker of Coronary Heart Disease Risk Among Individuals With Elevated Glycosylated Hemoglobin
ObjectivesThis study sought to investigate into the biologically plausible interaction between the common haptoglobin (Hp) polymorphism rs#72294371 and glycosylated hemoglobin (HbA1c) on risk of coronary heart disease (CHD).BackgroundStudies of the association between the Hp polymorphism and CHD report inconsistent results. Individuals with the Hp2-2 genotype produce Hp proteins with an impaired ability to prevent oxidative injury caused by elevated HbA1c.MethodsHbA1c concentration and Hp genotype were determined for 407 CHD cases matched 1:1 to controls (from the NHS [Nurses' Health Study]) and in a replication cohort of 2,070 individuals who served as the nontreatment group in the ICARE (Prevention of Cardiovascular Complications in Diabetic Patients With Vitamin E Treatment) study, with 29 CHD events during follow-up. Multivariate models were adjusted for lifestyle and CHD risk factors as appropriate. A pooled analysis was conducted of NHS, ICARE, and the 1 previously published analysis (a cardiovascular disease case-control sample from the Strong Heart Study).ResultsIn the NHS, Hp2-2 genotype (39% frequency) was strongly related to CHD risk only among individuals with elevated HbA1c (â„6.5%), an association that was similar in the ICARE trial and the Strong Heart Study. In a pooled analysis, participants with both the Hp2-2 genotype and elevated HbA1c had a relative risk of 7.90 (95% confidence interval: 4.43 to 14.10) for CHD compared with participants with both an Hp1 allele and HbA1c <6.5% (p for interaction = 0.004), whereas the Hp2-2 genotype with HbA1c <6.5% was not associated with risk (relative risk: 1.34 [95% confidence interval: 0.73 to 2.46]).ConclusionsHp genotype was a significant predictor of CHD among individuals with elevated HbA1c
Lifetime physical activity and risk of breast cancer
We conducted a caseâcontrol study of 394 women with breast cancer and 788 control women (91% response) to investigate the association of lifetime physical activity with mainly menopausal breast cancer risk. After controlling for potential confounders, the odds ratios (95% confidence intervals) for increasing quartiles of lifetime physical activity were 1.00 (referent), 0.91 (0.60â1.37), 0.91 (0.60â1.39), and 1.10 (0.73â1.67), respectively;P, trend = 0.47. We also separately examined physical activity at ages 12â18, 19â34, 35â49 and â„50 years; no significant trends were observed in any age group. These data do not support a role of physical activity in preventing breast cancer. © 2001 Cancer Research Campaignhttp://www.bjcancer.co
Adiposity has differing associations with incident coronary heart disease and mortality in the Scottish population: cross-sectional surveys with follow-up
Objective:
Investigation of the association of excess adiposity with three different outcomes: all-cause mortality, coronary heart disease (CHD) mortality and incident CHD.
Design:
Cross-sectional surveys linked to hospital admissions and death records.
Subjects:
19â329 adults (aged 18â86 years) from a representative sample of the Scottish population.
Measurements:
Gender-stratified Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause mortality, CHD mortality and incident CHD. Separate models incorporating the anthropometric measurements body mass index (BMI), waist circumference (WC) or waistâhip ratio (WHR) were created adjusted for age, year of survey, smoking status and alcohol consumption.
Results:
For both genders, BMI-defined obesity (greater than or equal to30âkgâmâ2) was not associated with either an increased risk of all-cause mortality or CHD mortality. However, there was an increased risk of incident CHD among the obese men (hazard ratio (HR)=1.78; 95% confidence interval=1.37â2.31) and obese women (HR=1.93; 95% confidence interval=1.44â2.59). There was a similar pattern for WC with regard to the three outcomes; for incident CHD, the HR=1.70 (1.35â2.14) for men and 1.71 (1.28â2.29) for women in the highest WC category (men greater than or equal to102âcm, women greater than or equal to88âcm), synonymous with abdominal obesity. For men, the highest category of WHR (greater than or equal to1.0) was associated with an increased risk of all-cause mortality (1.29; 1.04â1.60) and incident CHD (1.55; 1.19â2.01). Among women with a high WHR (greater than or equal to0.85) there was an increased risk of all outcomes: all-cause mortality (1.56; 1.26â1.94), CHD mortality (2.49; 1.36â4.56) and incident CHD (1.76; 1.31â2.38).
Conclusions:
In this study excess adiposity was associated with an increased risk of incident CHD but not necessarily death. One possibility is that modern medical intervention has contributed to improved survival of first CHD events. The future health burden of increased obesity levels may manifest as an increase in the prevalence of individuals living with CHD and its consequences
Are Bone and Muscle Changes from POWER PE, an 8-month In-school Jumping Intervention, Maintained at Three Years?
Our aim was to determine if the musculoskeletal benefits of a twice-weekly, school-based, jumping regime in healthy adolescent boys and girls were maintained three years later. Subjects of the original POWER PE trial (nâ=â99) were contacted and asked to undergo retesting three years after cessation of the intervention. All original measures were completed including: sitting height, standing height, weight, calcaneal broadband ultrasound attenuation (BUA), whole body, hip and spine bone mineral content (BMC), lean tissue mass, and fat mass. Physical activity was recorded with the bone-specific physical activity questionnaire (BPAQ) and calcium intake was estimated with a calcium-focussed food questionnaire. Maturity was determined by Tanner staging and estimation of the age of peak height velocity (PHV). Twenty-nine adolescents aged 17.3±0.4 years agreed to participate. Three years after the intervention, there were no differences in subject characteristics between control and intervention groups (p>0.05). Three-year change in weight, lean mass, and fat mass were similar between groups (p>0.05). There were no significant group differences in three-year change in BUA or BMC at any site (p>0.05), although the between-group difference in femoral neck BMC at follow-up exceeded the least significant change. While significant group differences were not observed three years after cessation of the intervention, changes in bone parameters occurred in parallel for intervention and control groups such that the original benefits of the intervention observed within the treatment group were sustained
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Low Carbohydrate Diet From Plant or Animal Sources and Mortality Among Myocardial Infarction Survivors
Background: The healthiest dietary pattern for myocardial infarction (MI) survivors is not known. Specific longâterm benefits of a lowâcarbohydrate diet (LCD) are unknown, whether from animal or vegetable sources. There is a need to examine the associations between postâMI adherence to an LCD and allâcause and cardiovascular mortality. Methods and Results: We included 2258 women from the Nurses' Health Study and 1840 men from the Health Professional FollowâUp Study who had survived a first MI during followâup and provided a preâMI and at least 1 postâMI food frequency questionnaire. Adherence to an LCD high in animal sources of protein and fat was associated with higher allâcause and cardiovascular mortality (hazard ratios of 1.33 [95% CI: 1.06 to 1.65] for allâcause mortality and 1.51 [95% CI: 1.09 to 2.07] for cardiovascular mortality comparing extreme quintiles). An increase in adherence to an animalâbased LCD prospectively assessed from the preâ to postâMI period was associated with higher allâcause mortality and cardiovascular mortality (hazard ratios of 1.30 [95% CI: 1.03 to 1.65] for allâcause mortality and 1.53 [95% CI: 1.10 to 2.13] for cardiovascular mortality comparing extreme quintiles). An increase in adherence to a plantâbased LCD was not associated with lower allâcause or cardiovascular mortality. Conclusions: Greater adherence to an LCD high in animal sources of fat and protein was associated with higher allâcause and cardiovascular mortality postâMI. We did not find a health benefit from greater adherence to an LCD overall after MI
Circulating Levels of Resistin and Risk of Type 2 Diabetes in Men and Women: Results From Two Prospective Cohorts
OBJECTIVEâThe purpose of this study was to investigate the role of circulating resistin levels in the development of type 2 diabetes using two prospective cohorts of well-characterized men and women
Effects of two common polymorphisms in the 3' untranslated regions of estrogen receptor ÎČ on mRNA stability and translatability
Estrogen signaling is mediated by estrogen receptors (ERs), ERα and ERÎČ. Aberrant
estrogen signaling is involved in breast cancer development. ERα is one of the key
biomarkers for diagnosis and treatment of breast cancer. Unlike ERα, ERÎČ is still not
introduced as a marker for diagnosis and established as a target of therapy. Numerous
studies suggest antiproliferative effects of ERÎČ, however its role remains to be fully
explored. Albeit important, ERα is not a perfect marker, and some aspects of ERα
function are still unclear. This thesis aims to characterize distinct molecular facets of
ER action relevant for breast cancer and provide valuable information for ER-based
diagnosis and treatment design.
In PAPER I, we analyzed the functionality of two common single
nucleotide polymorphisms in the 3â untranslated regions of ERÎČ, rs4986938 and
rs928554, which have been extensively investigated for association with various
diseases. A significant difference in allelic expression was observed for rs4986938 in
breast tumor samples from heterozygous individuals. However, no difference in mRNA
stability or translatability between the alleles was observed.
In PAPER II, we provided a more comprehensive understanding of ERÎČ
function independent of ERα. A global gene expression analysis in a HEK293/ERÎČ cell
model identified a set of ERÎČ-regulated genes. Gene Ontology (GO) analysis showed
that they are involved in cell-cell signaling, morphogenesis and cell proliferation.
Moreover, ERÎČ expression resulted in a significant decrease in cell proliferation.
In PAPER III, using the human breast cancer MCF-7/ERÎČ cell model,
we demonstrated, for the first time, the binding of ERα/ÎČ heterodimers to various
DNA-binding regions in intact chromatin.
In PAPER IV, we investigated a potential cross-talk between estrogen
signaling and DNA methylation by identifying their common target genes in MCF-7
cells. Gene expression profiling identified around 150 genes regulated by both 17ÎČ-
estradiol (E2) and a hypomethylating agent 5-aza-2â-deoxycytidine. Based on GO
analysis, CpG island prediction analysis and previously reported ER binding regions,
we selected six genes for further analysis. We identified BTG3 and FHL2 as direct
target genes of both pathways. However, our data did not support a direct molecular
interplay of mediators of estrogen and epigenetic signaling at promoters of regulated
genes.
In PAPER V, we further explored the interactions between estrogen
signaling and DNA methylation, with focus on DNA methyltransferases (DNMT1,
DNMT3a and DNMT3b). E2, via ERα, up-regulated DNMT1 and down-regulated
DNMT3a and DNMT3b mRNA expression. Furthermore, DNMT3b interacted with
ERα. siRNA-mediated DNMT3b depletion increased the expression of two genes,
CDKN1A and FHL2. We proposed that the molecular mechanism underlying
regulation of FHL2 and CDKN1A gene expression involves interplay of DNMT3b and
ERα.
In conclusion, the studies presented in this thesis contribute to the knowledge of ERÎČ
function, and give additional insight into the cross-talk mechanisms underlying ERα
signaling with ERÎČ and with DNA methylation pathways
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