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Background - The obesity-lung cancer association remains controversial. Concerns over confounding by smoking and reverse causation persist. The influence of obesity type and effect modifications by race/ethnicity and tumor histology are largely unexplored.
Methods - We examined associations of body mass index (BMI), waist circumference (WC), and waist-hip ratio (WHR) with lung cancer risk among 1.6 million Americans, Europeans, and Asians. Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for potential confounders. Analyses for WC/WHR were further adjusted for BMI. The joint effect of BMI and WC/WHR was also evaluated.
Results - During an average 12-year follow-up, 23 732 incident lung cancer cases were identified. While BMI was generally associated with a decreased risk, WC and WHR were associated with increased risk after controlling for BMI. These associations were seen 10 years before diagnosis in smokers and never smokers, were strongest among blacks, and varied by histological type. After excluding the first five years of follow-up, hazard ratios per 5 kg/m2 increase in BMI were 0.95 (95% CI = 0.90 to 1.00), 0.92 (95% CI = 0.89 to 0.95), and 0.89 (95% CI = 0.86 to 0.91) in never, former, and current smokers, and 0.86 (95% CI = 0.84 to 0.89), 0.94 (95% CI = 0.90 to 0.99), and 1.09 (95% CI = 1.03 to 1.15) for adenocarcinoma, squamous cell, and small cell carcinoma, respectively. Hazard ratios per 10 cm increase in WC were 1.09 (95% CI = 1.00 to 1.18), 1.12 (95% CI = 1.07 to 1.17), and 1.11 (95% CI = 1.07 to 1.16) in never, former, and current smokers, and 1.06 (95% CI = 1.01 to 1.12), 1.20 (95% CI = 1.12 to 1.29), and 1.13 (95% CI = 1.04 to 1.23) for adenocarcinoma, squamous cell, and small cell carcinoma, respectively. Participants with BMIs of less than 25 kg/m2 but high WC had a 40% higher risk (HR = 1.40, 95% CI = 1.26 to 1.56) than those with BMIs of 25 kg/m2 or greater but normal/moderate WC.
Conclusions - The inverse BMI-lung cancer association is not entirely due to smoking and reverse causation. Central obesity, particularly concurrent with low BMI, may help identify high-risk populations for lung cancer.
Background - Adiposity depots may differentially affect cognition. African Americans (AA) have higher rates of obesity and dementia but lower visceral adipose tissue (VAT) than whites, yet are underrepresented in studies of adiposity and cognition. Our study compared relations of cognitive function to clinical adiposity measures and computed tomography (CT)-imaged abdominal adiposity in AA.
Methods - CT-imaged subcutaneous adipose tissue (SAT) and VAT measurements were obtained in the AA cohort of the Genetic Epidemiology Network of Arteriopathy Study (N = 652, mean age 68 ± 8.4 years, 74% females, 59% obese, 82% hypertensive). Clinical adiposity measures included waist circumference (WC) and body mass index (BMI). Global cognition was operationalized as a global cognitive z-score generated from the average of four cognitive domain z-scores. Generalized estimating equations were used to examine cross-sectional associations between individual standardized adiposity measures and cognition, accounting for age, sex, education, smoking status, and familial clustering. A collective model was constructed including multiple supported adiposity measures and age-by-adiposity interactions.
Results - In the collective model, higher WC was associated with worse global cognition, β = -0.12 (95%CI: -0.21, -0.03); higher SAT was associated with better cognition, β = 0.09 (0.01, 0.18); higher BMI was associated with worse cognition at younger ages with attenuation at older ages (BMI-by-age-interaction p = .004). VAT was not significantly associated with global cognition, β = -0.03 (-0.07, 0.02).
Conclusions - WC may be the simplest and most efficient measure of adiposity to assess with respect to cognition in clinical settings, although studies to determine mechanistic effects of subcutaneous and other adiposity depots on cognition are warranted.
BACKGROUND - One potential use for the PR interval is as a biomarker of disease risk. We hypothesized that quantifying the shared genetic architectures of the PR interval and a set of clinical phenotypes would identify genetic mechanisms contributing to PR variability and identify diseases associated with a genetic predictor of PR variability.
METHODS AND RESULTS - We used ECG measurements from the ARIC study (Atherosclerosis Risk in Communities; n=6731 subjects) and 63 genetically modulated diseases from the eMERGE network (Electronic Medical Records and Genomics; n=12 978). We measured pairwise genetic correlations (rG) between PR phenotypes (PR interval, PR segment, P-wave duration) and each of the 63 phenotypes. The PR segment was genetically correlated with atrial fibrillation (rG=-0.88; =0.0009). An analysis of metabolic phenotypes in ARIC also showed that the P wave was genetically correlated with waist circumference (rG=0.47; =0.02). A genetically predicted PR interval phenotype based on 645 714 single-nucleotide polymorphisms was associated with atrial fibrillation (odds ratio=0.89 per SD change; 95% confidence interval, 0.83-0.95; =0.0006). The differing pattern of associations among the PR phenotypes is consistent with analyses that show that the genetic correlation between the P wave and PR segment was not significantly different from 0 (rG=-0.03 [0.16]).
CONCLUSIONS - The genetic architecture of the PR interval comprises modulators of atrial fibrillation risk and obesity.
© 2017 American Heart Association, Inc.
OBJECTIVES - Young women with hyperandrogenism have high risk of metabolic co-morbidities, including increased risk of nonalcoholic fatty liver disease (NAFLD). Whether testosterone (the predominant androgen) is associated with NAFLD independent of metabolic co-factors is unclear. Additionally, whether testosterone confers increased risk of NAFLD in women without hyperandrogenism is unknown.
METHODS - Among women in the prospective population-based multicenter Coronary Artery Risk Development in Young Adults (CARDIA) study, we assessed whether free testosterone levels measured at Year 2 (1987-1988) were associated with prevalent NAFLD at Year 25 (2010-2011) (n=1052). NAFLD was defined using noncontrast abdominal CT scan with liver attenuation≤40 Hounsfield units after excluding other causes of hepatic fat. The association of free testosterone with prevalent NAFLD was assessed by logistic regression.
RESULTS - Increasing quintiles of free testosterone were associated with prevalent NAFLD at Year 25 (adjusted odds ratio (AOR) 1.25, 95% confidence interval (CI) 1.04-1.50, P=0.015), independent of insulin resistance, body mass index, waist circumference, and serum lipids. Importantly, the association persisted among n=955 women without androgen excess (AOR 1.27, 95% CI 1.05-1.53, P=0.016). Visceral adipose tissue (VAT) volume partially mediated the association of free testosterone with NAFLD (mediating effect 41.0%, 95% CI 22-119%).
CONCLUSIONS - Increasing free testosterone is associated with prevalent NAFLD in middle age, even in women without androgen excess. Visceral adiposity appears to play an important role in the relationship between testosterone and NAFLD in women. Testosterone may provide a potential novel target for NAFLD therapeutics, and future studies in pre-menopausal women should consider the importance of testosterone as a risk factor for NAFLD.
BACKGROUND - Despite evidence suggesting that early metabolic dysfunction impacts cardiovascular disease risk, current guidelines focus on risk assessments later in life, missing early transitions in metabolic risk that may represent opportunities for averting the development of cardiovascular disease.
METHODS AND RESULTS - In 4420 young adults in the Coronary Artery Risk Development in Young Adults (CARDIA) study, we defined a "metabolic" risk score based on components of the Third Report of the Adult Treatment Panel's definition of metabolic syndrome. Using latent class trajectory analysis adjusted for sex, race, and time-dependent body mass index, we identified 6 distinct metabolic trajectories over time, specified by initial and final risk: low-stable, low-worsening, high-stable, intermediate-worsening, intermediate-stable, and high-worsening. Overall, individuals gained weight over time in CARDIA with statistically but not clinically different body mass index trend over time. Dysglycemia and dyslipidemia over time were highest in initially high or worsening trajectory groups. Divergence in metabolic trajectories occurred in early adulthood (before age 40), with 2 of 3 individuals experiencing an increase in metabolic risk over time. Membership in a higher-risk trajectory (defined as initially high or worsening over time) was associated with greater prevalence and extent of coronary artery calcification, left ventricular mass, and decreased left ventricular strain at year 25. Importantly, despite similar rise in body mass index across trajectories over 25 years, coronary artery calcification and left ventricular structure and function more closely tracked risk factor trajectories.
CONCLUSIONS - Transitions in metabolic risk occur early in life. Obesity-related metabolic dysfunction is related to subclinical cardiovascular phenotypes independent of evolution in body mass index, including coronary artery calcification and myocardial hypertrophy and dysfunction.
© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
AIMS - To assess associations between body mass index (BMI), waist circumference (WC), and computed tomography-determined volumes of pericardial, visceral, and subcutaneous adipose tissue with magnetic resonance imaging-(MRI) based cerebral structure and cognitive performance in individuals with type 2 diabetes (T2D).
METHODS - This study was performed in 348 African Americans (AAs) and 256 European Americans (EAs) with T2D. Associations between adiposity measures with cerebral volumes of white matter (WMV), gray matter (GMV), white matter lesions, hippocampal GMV, and hippocampal WMV, cognitive performance and depression were examined using marginal models incorporating generalized estimating equations. All models were adjusted for age, sex, education, smoking, HbA1c, hypertension, statins, cardiovascular disease, MRI scanner (MRI outcomes only), and time between scans; some neuroimaging measures were additionally adjusted for intracranial volume.
RESULTS - Participants were 59.9% female with mean (SD) age 57.7(9.3)years, diabetes duration 9.6(6.8)years, and HbA1c 7.8(1.9)%. In AAs, inverse associations were detected between hippocampal GMV and both BMI (β [95% CI]-0.18 [-0.30, -0.07], P=0.0018) and WC (-0.23 [-0.35, -0.12], P=0.0001). In the full bi-ethnic sample, inverse associations were detected between hippocampal WMV and WC (P≤0.0001). Positive relationships were observed between BMI (P=0.0007) and WC (P<0.0001) with depression in EAs.
CONCLUSIONS - In patients with T2D, adiposity is inversely associated with hippocampal gray and white matter volumes.
Copyright © 2016 Elsevier Inc. All rights reserved.
OBJECTIVE - Metabolic syndrome is associated with insulin resistance and increased future risk of type 2 diabetes. This study investigates the relationship between insulin secretion, insulin resistance and individual metabolic syndrome components in subjects without a prior diagnosis of diabetes.
RESEARCH DESIGN AND METHODS - We assessed insulin secretion during hyperglycemic clamps by infusing dextrose to maintain hyperglycemia (200mg/dL), followed by L-arginine administration. Studies in 98 individuals (mean age 45.3±1.2years, 56% female, 22% African-American, 49% with metabolic syndrome) were analyzed. We tested the association between the number of metabolic syndrome components and individual outcome variables using linear mixed-effects models to adjust for potential confounding effects of age, sex, and race.
RESULTS - Insulin sensitivity index was reduced in the presence of 1 or more metabolic syndrome components. Insulin sensitivity was independently associated with age, waist circumference, male gender and decreased HDL cholesterol. The acute insulin response was greater with two or more metabolic syndrome components, and late glucose-stimulated and L-arginine-stimulated insulin responses exhibited a similar trend. In contrast, the disposition index, a measure of beta cell compensation for insulin resistance, was linearly lower with the number of metabolic syndrome components, and was negatively associated with age, Caucasian race, waist circumference, fasting glucose, and decreased HDL cholesterol.
CONCLUSIONS - The insulin secretory response in metabolic syndrome is inadequate for the worsening insulin sensitivity, as demonstrated by a decline in disposition index. A dysfunctional insulin secretory response is evident in non-diabetic individuals and worsens with accumulation of metabolic syndrome components.
Copyright © 2016 Elsevier Inc. All rights reserved.
BACKGROUND AND AIMS - Pericardial adipose tissue (PAT) is located on both sides of the pericardium. We tested whether PAT was associated with prevalent diabetes at the year 25 exam of the Coronary Artery Risk Development in Young Adults (CARDIA) study.
METHODS AND RESULTS - The CARDIA Year 25 exam (2010-2011) included complete data for all covariates on 3107 participants. Prevalent diabetes (n = 436) was defined as high fasting (≥126 mg/dl) or 2-h postload glucose (≥200 mg/dl) or HbA1c (≥6.5%) or use of diabetes medications. Volume of PAT was measured from computed tomographic scans. Logistic regression was performed to examine the relationship between quartiles of PAT and diabetes. In regression models adjusted for field center, sex, race, age, systolic blood pressure, total cholesterol, log triglycerides, and treatment with blood pressure and cholesterol lowering medication, PAT volume in the 4th quartile was significantly associated with diabetes status after adjustment for BMI (OR 2.57, 95% CI 1.66, 3.98) or visceral adipose tissue (OR 2.08, 95% CI 1.32, 3.29). PAT volume in the 2nd and 3rd quartiles was not significantly associated with diabetes status relative to the first quartile.
CONCLUSIONS - Metabolically active pericardial adipose tissue is associated with prevalent diabetes only at higher volumes independent of overall obesity.
Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.
Sixty genetic loci associated with abdominal obesity, measured by waist circumference (WC) and waist-hip ratio (WHR), have been previously identified, primarily from studies conducted in European-ancestry populations. We conducted a meta-analysis of associations of abdominal obesity with approximately 2.5 million single nucleotide polymorphisms (SNPs) among 53,052 (for WC) and 48,312 (for WHR) individuals of Asian descent, and replicated 33 selected SNPs among 3,762 to 17,110 additional individuals. We identified four novel loci near the EFEMP1, ADAMTSL3 , CNPY2, and GNAS genes that were associated with WC after adjustment for body mass index (BMI); two loci near the NID2 and HLA-DRB5 genes associated with WHR after adjustment for BMI, and three loci near the CEP120, TSC22D2, and SLC22A2 genes associated with WC without adjustment for BMI. Functional enrichment analyses revealed enrichment of corticotropin-releasing hormone signaling, GNRH signaling, and/or CDK5 signaling pathways for those newly-identified loci. Our study provides additional insight on genetic contribution to abdominal obesity.
BACKGROUND - Associations between anthropometry and head and neck cancer (HNC) risk are inconsistent. We aimed to evaluate these associations while minimizing biases found in previous studies.
METHODS - We pooled data from 1,941,300 participants, including 3760 cases, in 20 cohort studies and used multivariable-adjusted Cox proportional hazard regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of anthropometric measures with HNC risk overall and stratified by smoking status.
RESULTS - Greater waist circumference (per 5 cm: HR = 1.04, 95% CI 1.03-1.05, P-value for trend = <0.0001) and waist-to-hip ratio (per 0.1 unit: HR = 1.07, 95% CI 1.05-1.09, P-value for trend = <0.0001), adjusted for body mass index (BMI), were associated with higher risk and did not vary by smoking status (P-value for heterogeneity = 0.85 and 0.44, respectively). Associations with BMI (P-value for interaction = <0.0001) varied by smoking status. Larger BMI was associated with higher HNC risk in never smokers (per 5 kg/m(2): HR = 1.15, 95% CI 1.06-1.24, P-value for trend = 0.0006), but not in former smokers (per 5 kg/m(2): HR = 0.99, 95% CI 0.93-1.06, P-value for trend = 0.79) or current smokers (per 5 kg/m(2): HR = 0.76, 95% CI 0.71-0.82, P-value for trend = <0.0001). Larger hip circumference was not associated with a higher HNC risk. Greater height (per 5 cm) was associated with higher risk of HNC in never and former smokers, but not in current smokers.
CONCLUSIONS - Waist circumference and waist-to-hip ratio were associated positively with HNC risk regardless of smoking status, whereas a positive association with BMI was only found in never smokers.
© The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.