[Show abstract][Hide abstract] ABSTRACT: Background
Circulating interleukin-6 levels increase with advancing age and are a risk factor for various diseases and mortality. The characterization of gene expression profiles associated with interleukin-6 levels might suggest important molecular events underlying its regulation.
Methods and results
We studied the association of transcriptional profiles with interleukin-6 levels in 2422 participants from the Framingham Heart Study Offspring Cohort using Affymetrix Human Exon 1.0 ST Array. We identified 4139 genes that were significantly associated with interleukin-6 levels (FDR < 0.05) after adjusting for age, sex and blood cell components. We then replicated 807 genes in the InCHIANTI study with 694 participants. Many of the top genes are involved in inflammation-related pathways or erythrocyte function, including JAK/Stat signaling pathway and interleukin-10 signaling pathway.
We identified and replicated 807 genes that were associated with circulating interleukin-6 levels. Future characterization of interleukin-6 regulation networks may facilitate the identification of additional potential targets for treating inflammation-related diseases.
[Show abstract][Hide abstract] ABSTRACT: -The American Heart Association Cardiovascular Health score (CVH score) is inversely associated with cardiovascular disease (CVD) incidence but the mechanisms underlying this association warrant exploration.
[Show abstract][Hide abstract] ABSTRACT: Context: Cellular characteristics of fat quality have been associated with cardiometabolic risk and can be estimated by computed tomography (CT) attenuation. Objective: The aim was to determine the association between CT attenuation [measured in Hounsfield units (HU)] and clinical outcomes. Methods: Prospective community-based cohort study using data from the Framingham Heart Study (n=3324, 48% women, mean age 51) and Cox proportional hazard models. Main Outcomes: The primary outcomes of interest were incident CVD and all-cause mortality. The secondary outcomes of interest were incident cancer, non-CVD death and cancer death. Results: There were 111 incident CVD events, 137 incident cancers, 85 deaths including 69 non-CVD deaths, and 45 cancer deaths in up to 23,047 person-years of follow-up. One standard deviation (SD) increment in VAT HU was inversely associated with incident CVD in the age-sex adjusted model (hazard ratio [HR] 0.78, p=0.02) but not after multivariable adjustment (HR 0.83, p=0.11). VAT HU was directly associated with all-cause mortality (multivariable HR 1.40, p=0.003), which maintained significance after additional adjustment for BMI (HR 1.53, p<0.001) and VAT volume (HR 1.99, p<0.001). Non-CVD death remained significant in all three models, including after adjustment for VAT volume (HR 1.97, p<0.001). VAT HU was also associated with cancer mortality (HR 1.93, p=0.002). Similar results were obtained for SAT HU. Conclusions: Fat quality, as estimated by CT attenuation, is associated with all-cause mortality, non-CVD death, and cancer death. These associations highlight how indirect indices of fat quality can potentially add to a better understanding of obesity related complications.
The Journal of clinical endocrinology and metabolism. 09/2014;
[Show abstract][Hide abstract] ABSTRACT: The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 09/2014; · 4.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
[Show abstract][Hide abstract] ABSTRACT: Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11,000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of MKL2 (P=8.9 x 10(-9)), a menarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P=4.6 x 10(-5)) and short adult stature (P=1.1 x 10(-11)) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes.Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, BMI-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes, and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.
Human Molecular Genetics 04/2014; · 7.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: -Endogenous sex hormones have been related to cardiovascular outcomes and mortality. We hypothesized that sex hormones are related to atrial fibrillation (AF) in a community-based cohort of middle-aged to older men.
-We examined testosterone, estradiol, and dehydroepiandrosterone sulfate [DHEA-S]) in relation to incident AF in men participating in the Framingham Heart Study. We assessed the 10-year risk of AF in multivariable-adjusted hazard models. The cohort consisted of 1251 men (age 68.0±8.2), of whom 275 developed incident AF. We identified a significant interaction between age and testosterone, and therefore stratified men into age 55-69 (n=786), 70-79 (n=351), and ≥80 (n=114). In men 55-69 each 1-standard deviation (SD) decrease in testosterone was associated with hazard ratio (HR) 1.30 (95% confidence interval [CI], 1.07 to 1.59) for incident AF. The association between testosterone and 10-year incident AF in men 70-79 did not reach statistical significance. In men ≥80 years a 1-SD decrease in testosterone was associated with HR 3.53 (95% CI, 1.96 to 6.37) for AF risk. Estradiol was associated with incident AF (HR, 1.12; 95% CI, 1.01 to 1.26). DHEA-S had a borderline association with risk of AF that was not statistically significant (HR, 1.12; 95% CI, 0.99 to 1.28).
-Testosterone and estradiol are associated with incident AF in a cohort of older men. Testosterone deficiency in men ≥80 is strongly associated with AF risk. The clinical and electrophysiologic mechanisms underlying the associations between sex hormones and AF in older men merit continued investigation.
Circulation Arrhythmia and Electrophysiology 03/2014; · 5.95 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Whereas endogenous carbon monoxide (CO) is cytoprotective at physiologic levels, excess CO concentrations are associated with cardiometabolic risk and may represent an important marker of progression from subclinical to clinical cardiovascular disease (CVD).
In 1926 participants of the Framingham Offspring Study (aged 57 ± 10 years, 46% women), we investigated the relationship of exhaled CO, a surrogate of blood CO concentration, with both prevalent subclinical CVD and incident clinical CVD events. Presence of subclinical CVD was determined using a comprehensive panel of diagnostic tests used to assess cardiac and vascular structure and function. Individuals with the highest (>5 p.p.m.) compared with lowest (≤4 p.p.m.) CO exposure were more likely to have subclinical CVD [odds ratios (OR): 1.67, 95% CI: 1.32-2.12; P < 0.001]. During the follow-up period (mean 5 ± 3 years), 193 individuals developed overt CVD. Individuals with both high CO levels and any baseline subclinical CVD developed overt CVD at an almost four-fold higher rate compared with those with low CO levels and no subclinical disease (22.1 vs. 6.3%). Notably, elevated CO was associated with incident CVD in the presence [hazards ration (HR): 1.83, 95% CI: 1.08-3.11; P = 0.026] but not in the absence (HR: 0.80, 95% CI: 0.42-1.53; P = 0.51) of subclinical CVD (Pinteraction = 0.019). Similarly, subclinical CVD was associated with incident CVD in the presence of high but not low CO exposure.
Our findings in a community-based sample suggest that elevated CO is a marker of greater subclinical CVD burden and, furthermore, a potential key component in the progression from subclinical to clinical CVD.
European Heart Journal 02/2014; · 14.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Age at menopause marks the end of a woman¡¦s reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified twenty-seven loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from eleven studies across the United States. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (p-value <0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of fourteen loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in United States.
Human Molecular Genetics 02/2014; · 7.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
Circulating testosterone, oestradiol and oestrone concentrations vary considerably between men. Although a substantial proportion of this variation may be attributed to morbidity and behavioural factors, these cannot account for its entirety, suggesting genetic inheritance as a potential additional determinant. The analysis described here was intended to estimate the heritability of male circulating total testosterone (TT), calculated free testosterone (cFT), oestrone (E1), oestradiol (E2) and sex hormone binding globulin (SHBG), along with the genetic correlation between these factors. DesignCross-sectional, observational analysis of data from male members of the Offspring and Generation 3 cohorts of the Framingham Heart Study. Data were collected in the years 1998–2005. ParticipantsA total of 3367 community-dwelling men contributed to the analysis, including 1066 father/son and 1284 brother pairs among other family relationships. MeasurementsLevels of serum sex steroids (TT, E1 and E2) were measured by liquid chromatography–tandem mass spectrometry, SHBG by immunofluorometric assay and cFT by mass action equation. Heritability was obtained using variance components analysis with adjustment for covariates including age, diabetes mellitus, body mass index and smoking status. ResultsAge-adjusted heritability estimates were 0·19, 0·40, 0·40, 0·30 and 0·41 for cFT, TT, E1, E2 and SHBG, respectively. Adjustment for covariates did not substantially attenuate these estimates; SHBG-adjusted TT results were similar to those obtained for cFT. Genetic correlation coefficients (ρG) indicated substantial genetic association between TT and cFT (ρG = 0·68), between TT and SHBG (pG = 0·87), between E1 and E2 (ρG = 0·46) and between TT and E2 (ρG = 0·48). Conclusion
Circulating testosterone, oestradiol and oestrone concentrations exhibit substantial heritability in adult men. Significant genetic association between testosterone and oestrogen levels suggests shared genetic pathways.
[Show abstract][Hide abstract] ABSTRACT: To identify non-redundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.
AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.
We performed association testing conditioned on the most significant, independently associated genetic markers at nine established AF loci using two complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).
We observed at least four distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining eight AF loci. A multilocus score comprised of 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.
The chromosome 4q25 AF locus is architecturally complex and harbors at least four AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.
Journal of the American College of Cardiology 01/2014; · 14.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10(-9)), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.
Human Molecular Genetics 01/2014; · 7.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An increased inter-arm systolic blood pressure difference is an easily determined physical examination finding. The relationship between inter-arm systolic blood pressure difference and risk of future cardiovascular disease is uncertain. We described the prevalence and risk factor correlates of inter-arm systolic blood pressure difference in the Framingham Heart Study (FHS) original and offspring cohorts and examined the association between inter-arm systolic blood pressure difference and incident cardiovascular disease and all-cause mortality.
An increased inter-arm systolic blood pressure difference was defined as >10mmHg using the average of initial and repeat blood pressure measurements obtained in both arms. Participants were followed through 2010 for incident cardiovascular disease events. Multivariable Cox proportional hazards regression analyses were performed to investigate the effect of inter-arm systolic blood pressure difference on incident cardiovascular disease.
We examined 3,390 (56.3% female) participants aged 40 years and older, free of cardiovascular disease at baseline, mean age of 61.1 years, who attended a FHS examination between 1991 and 1994 (original cohort) and from 1995 to 1998 (offspring cohort). The mean absolute inter-arm systolic blood pressure difference was 4.6 mmHg (range 0 to 78). Increased inter-arm systolic blood pressure difference was present in 317 (9.4%) participants. The median follow-up time was 13.3 years, during which time 598 participants (17.6%) experienced a first cardiovascular event including 83 (26.2%) participants with inter-arm systolic blood pressure difference >10 mmHg. Compared to those with normal inter-arm systolic blood pressure difference, participants with an elevated inter-arm systolic blood pressure difference were older (63.0 years vs. 60.9 years), had a greater prevalence of diabetes mellitus (13.3% vs. 7.5%,), higher systolic blood pressure (136.3 mmHg vs. 129.3 mmHg), and a higher total cholesterol level (212.1 mg/dL vs. 206.5 mg/dL). Inter-arm systolic blood pressure difference was associated with a significantly increased hazard of incident cardiovascular events in the multivariable adjusted model (hazard ratio 1.38, 95% CI, 1.09 to 1.75). For each 1-standard deviation unit increase in absolute inter-arm systolic blood pressure difference, the hazard ratio for incident cardiovascular events was 1.07 (CI, 1.00 to 1.14) in the fully-adjusted model. There was no such association with mortality (hazard ratio 1.02, 95% CI 0.76 to 1.38).
In this community-based cohort, an inter-arm systolic blood pressure difference is common and associated with a significant increased risk for future cardiovascular events, even when the absolute difference in arm systolic blood pressure is modest. These findings support research to expand clinical use of this simple measurement.
The American journal of medicine 11/2013; · 5.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Many complex human diseases exhibit sex or age differences in gene expression. However, the presence and extent of genotype-specific variations in gene regulation are largely unknown. Here we report results of a comprehensive analysis of expression regulation of genetic variation related to 11,672 complex disease associated SNPs as a function of sex and age in whole blood derived RNA from 5,254 individuals. At FDR <0.05, we identified 14 sex- and 10 age-interacting expression quantitative trait loci (eQTLs). We show that these eQTLs are also associated with many sex- or age-associated traits. These findings provide important context regarding the regulation of phenotypes by genotype-environment interaction.
Human Molecular Genetics 11/2013; · 7.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: offspring of long-lived individuals have lower risk for dementia. We examined the relation between parental longevity and cognition and subclinical markers of brain ageing in community-dwelling adult offspring.
offspring participants with both parents in the Framingham Heart Study, aged ≥55 years and dementia-free underwent baseline and repeat neuropsychological (NP) testing and brain magnetic resonance imaging (MRI). Parental longevity was defined as having at least one parent survive to age ≥85 years. To test the association between parental longevity and measures of cognition and brain volumes, we used multivariable linear and logistic regression adjusting for age, sex, education and time to NP testing or brain MRI.
of 728 offspring (mean age 66 years, 54% women), 407 (56%) had ≥1 parent achieve longevity. In cross-sectional analysis, parental longevity was associated with better scores on attention (beta 0.21 ± 0.08, P = 0.006) and a lower odds of extensive white matter hyperintensity on brain MRI (odds ratio 0.59, 95% CI: 0.38, 0.92, P = 0.019). The association with white matter hyperintensity was no longer significant in models adjusted for cardiovascular risk factors and disease. In longitudinal analysis (6.7 ± 1.7 years later), offspring with parental longevity had slower decline in attention (0.18 ± 0.08, P = 0.038), executive function (beta 0.19 ± 0.09, P = 0.031) and visual memory (beta -0.18 ± 0.08, P = 0.023), and less increase in temporal horn volume (beta -0.25 ± 0.09, P = 0.005). The associations persisted in fully adjusted models.
parental longevity is associated with better brain ageing in middle-aged offspring.
[Show abstract][Hide abstract] ABSTRACT: As creatinine-based estimates of renal function are inaccurate in older adults, an alternative is an estimated glomerular filtration rate (eGFRcys) based on cystatin C. We examined the prospective association between chronic kidney disease (CKDcys) as determined by eGFRcys with the primary outcome of incident mobility disability and the secondary outcome of change in gait speed.
Framingham Offspring Study participants older than 60 years and free of mobility disability at baseline (1998-2001) were eligible. Baseline CKDcys was defined as eGFRcys less than 60 mL/min/1.73 m(2). At follow-up (2005-2008), the outcomes of mobility disability, defined as self-reported inability to walk 1/2 mile and/or climb a flight of stairs, and gait speed were measured. Logistic and linear regression models were adjusted for age, sex, body mass index, smoking, diabetes, C reactive protein, and physical activity.
Of 1,226 participants, 230 (19%) had CKDcys at baseline. After a mean follow-up of 6.6 years, 185 (15%) developed mobility disability. Of those with CKDcys, 60 (26%) developed mobility disability. Those with CKDcys had greater odds of mobility disability in the age- and sex-adjusted (odds ratio [OR] 1.91, 95% CI 1.32, 2.75) and fully adjusted (OR 1.55, 95% CI 1.05, 2.31) models compared with those without CKDcys. In fully adjusted models, participants with CKDcys had greater gait speed declines than those without CKDcys (β = 0.07 [SE 0.02], p = .0022).
CKDcys was associated with higher odds of incident mobility disability and greater decline in gait speed, highlighting the loss of physical independence in elders with CKD.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 08/2013; · 4.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine whether ectopic fat depots are prospectively associated with cardiovascular disease, cancer and all-cause mortality.
The morbidity associated with excess body weight varies among individuals of similar body mass index. Ectopic fat depots may underlie this risk differential. However, prospective studies of directly measured fat are limited.
Participants from the Framingham Heart Study (n=3086, 49% women, mean age 50.2 years) underwent assessment of fat depots (visceral adipose tissue, pericardial adipose tissue, and periaortic adipose tissue) using multidetector computed tomography, and were followed longitudinally for a median of 5.0 years. Cox proportional hazards regression models were used to examine the association of each fat depot (per 1 standard deviation increment) with the risk of incident cardiovascular disease, cancer, and all-cause mortality after adjustment for standard risk factors, including body mass index.
Overall, there were 90 cardiovascular events, 141 cancer events, and 71 deaths. After multivariable adjustment, visceral adipose tissue was associated with cardiovascular disease (HR 1.44, 95% CI 1.08-1.92, p=0.01) and cancer (HR 1.43, 95% CI 1.12-1.84, p=0.005). Addition of visceral adipose tissue to a multivariable model that included body mass index modestly improved cardiovascular risk prediction (net reclassification improvement of 16.3%). None of the fat depots were associated with all-cause mortality.
Visceral adiposity is associated with incident cardiovascular disease and cancer after adjustment for clinical risk factors and generalized adiposity. These findings support the growing appreciation of a pathogenic role of ectopic fat.
Journal of the American College of Cardiology 07/2013; · 14.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Atrial fibrillation (AF)-related symptoms and physical performance are relied upon to guide therapeutic management of patients with AF. We sought to understand whether AF predisposes to or is a result of physical disability and poor subjective health in the community.
We studied relations between physical disability (Rosow-Breslau Functional Health Scale), subjective health (self-report) and incident AF, and the converse, in the Framingham Heart Study.
In 3,609 participants (age 73 ± 8 years, 59% women), a subset of 861 participants (24%) had prevalent physical disability at baseline. During 5.8 ± 1.8 years of follow-up, 555 participants (10-year age- and sex-adjusted incidence rate 13%) developed incident AF. Prevalent physical disability was related to incident AF (multivariable-adjusted hazard ratio 1.25, 95% CI 1.02-1.54, P = .03). In 3,525 participants, prevalent poor subjective health (n = 333) also was related to incident AF (n = 552, multivariable-adjusted hazard ratio 1.31, 95% CI 1.00-1.70, P = .048). Conversely, in 2,080 participants (age 69 ± 6 years, 55% women), interim AF (n = 106) was associated with newly reported physical disability (n = 573) at a follow-up examination (multivariable-adjusted odds ratio 1.58, 95% CI 1.08-2.31, P = .01). In 1,954 participants, interim AF (n = 96) likewise was related to newly reported poor subjective health (n = 224, multivariable-adjusted odds ratio 1.83, 95% CI 1.10-3.02, P = .02).
Physical disability and poor subjective health were related to incident AF in a community-based cohort. Conversely, interim AF was related to newly reported physical disability and poor subjective health. Because AF guidelines incorporate symptoms, it is essential to clarify the temporality and mechanisms linking physical disability, subjective health, and AF.
American heart journal 07/2013; 166(1):171-178.e3. · 4.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES: The aim of this study was to evaluate whether computed tomography (CT) attenuation, as a measure of fat quality, is associated with cardiometabolic risk factors above and beyond fat quantity. BACKGROUND: Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) are pathogenic fat depots associated with cardiometabolic risk. Adipose tissue attenuation in CT images is variable, similar to adipose tissue volume. However, whether the quality of abdominal fat attenuation is associated with cardiometabolic risk independent of the quantity is uncertain. METHODS: Participants were drawn from the Framingham Heart Study CT substudy. The VAT and SAT volumes were acquired by semiquantitative assessment. Fat quality was measured by CT attenuation and recorded as mean Hounsfield unit (HU) within each fat depot. Sex-specific linear and logistic multivariable regression models were used to assess the association between standard deviation (SD) decrease in HU and each risk factor. RESULTS: Lower CT attenuation of VAT and SAT was correlated with higher body mass index levels in both sexes. Risk factors were generally more adverse with decreasing HU values. For example, in women, per 1 SD decrease in VAT HU, the odds ratio (OR) was increased for hypertension (OR 1.80), impaired fasting glucose (OR 2.10), metabolic syndrome (OR 3.65), and insulin resistance (OR 3.36; all p < 0.0001). In models that further adjusted for VAT volume, impaired fasting glucose, metabolic syndrome, and insulin resistance remained significant. Trends were similar but less pronounced for SAT and for men. There was evidence of an interaction between HU and fat volume among both women and men. CONCLUSIONS: Lower CT attenuation of VAT and SAT is associated with adverse cardiometabolic risk above and beyond total adipose tissue volume. Qualitative indices of abdominal fat depots may provide insight regarding cardiometabolic risk independent of fat quantity.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: Evidence suggests that chronic low-grade inflammation and oxidative stress are related to cardiovascular disease (CVD) and mortality. APPROACH AND RESULTS: We examined 11 established and novel biomarkers representing inflammation and oxidative stress (C-reactive protein, fibrinogen, interleukin-6, intercellular adhesion molecule-1, lipoprotein-associated phospholipase-A2 [mass and activity], monocyte chemoattractant protein-1, myeloperoxidase, CD40 ligand, P-selectin, and tumor necrosis factor receptor II [TNFRII]) in relation to incident major CVD and mortality in the community. We studied 3035 participants (mean age, 61±9 years; 53% women). During follow-up (median, 8.9 years), 253 participants experienced a CVD event and 343 died. C-reactive protein (hazard ratio [HR] reported per SD ln-transformed biomarker, 1.18; 95% confidence interval [CI], 1.02-1.35; nominal P=0.02) and TNFRII (HR, 1.15; 95% CI, 1.01-1.32; nominal P=0.04) were retained in multivariable-adjusted models for major CVD, but were not significant after adjustment for multiple testing. The biomarkers related to mortality were TNFRII (HR, 1.33; 95% CI, 1.19-1.49; P<0.0001), ICAM-1 (HR, 1.24; 95% CI, 1.12-1.37; P<0.0001), and interleukin-6 (HR, 1.25; 95% CI, 1.12-1.39; P<0.0001). The addition of these markers to the model, including traditional risk factors, increased discrimination and reclassification for risk of death (P<0.0001), but not for CVD. CONCLUSIONS: Of 11 biomarkers, TNFRII was associated nominally with incident major CVD, and significantly with all-cause mortality, which renders it an interesting target for future research. The combination of TNFRII with C-reactive protein in relation to CVD and with interleukin-6 to mortality increased the predictive ability in addition to CVD risk factors for total mortality but not for incident CVD.
Arteriosclerosis Thrombosis and Vascular Biology 05/2013; · 6.34 Impact Factor