This article reviews existing research at the intersection of genetics and economics, presents some new findings that illustrate the state of genoeconomics research, and surveys the prospects of this emerging field. Twin studies suggest that economic outcomes and preferences, once corrected for measurement error, appear to be about as heritable as many medical conditions and personality traits. Consistent with this pattern, we present new evidence on the heritability of permanent income and wealth. Turning to genetic association studies, we survey the main ways that the direct measurement of genetic variation across individuals is likely to contribute to economics, and we outline the challenges that have slowed progress in making these contributions. The most urgent problem facing researchers in this field is that most existing efforts to find associations between genetic variation and economic behavior are based on samples that are too small to ensure adequate statistical power. This has led to many false positives in the literature. We suggest a number of possible strategies to improve and remedy this problem: (a) pooling data sets, (b) using statistical techniques that exploit the greater information content of many genes considered jointly, and (c) focusing on economically relevant traits that are most proximate to known biological mechanisms.
genetics; heritability; GWAS
To determine whether consumption of whole-grain; rye bread, oatmeal, and whole-wheat bread, during different periods of life, is associated with risk of prostate cancer (PCa).
In 2002 to 2006, 2,268 men, aged 67-96 years, reported their dietary habits in the AGES-Reykjavik cohort study. Dietary habits were assessed for early-, mid- , and current life using a validated food frequency questionnaire (FFQ). Through linkage to cancer- and mortality registers, we retrieved information on PCa diagnosis and mortality through 2009. We used regression models to estimate odds ratios (ORs) and hazard ratios (HRs) for PCa according to whole grain consumption, adjusted for possible confounding factors including fish-, fish liver oil-, meat-, and milk intake.
Of the 2,268 men, 347 had or were diagnosed with PCa during follow-up, 63 with advanced disease (stage 3+ or died of PCa). Daily rye bread consumption in adolescence (vs. less than daily) was associated with a decreased risk of PCa diagnosis (OR = 0.76, 95% Confidence interval (CI): 0.59-0.98), and of advanced PCa (OR = 0.47, 95% CI: 0.27-0.84). High intake of oatmeal in adolescence (≥5 vs. ≤4 times/ week) was not significantly associated with risk of PCa diagnosis (OR = 0.99, 95% CI: 0.77-1.27) nor advanced PCa (OR = 0.67, 95% CI: 0.37-1.20). Mid-, and late life consumption of rye bread, oatmeal, or whole-wheat bread was not associated with PCa risk.
Our results suggest that rye bread consumption in adolescence may be associated with reduced risk of PCa, particularly advanced disease.
adolescent; diet; epidemiology; rye bread; prostatic neoplasms; whole-grain; AGES Reykjavik study
Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.
A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy.
No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, −1.3±0.23 (beta ± standard error), p = 6.6×10−9. Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r2 ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension.
This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.
The authors investigated whether early-life residency in certain areas of Iceland marked by distinct differences in milk intake was associated with risk of prostate cancer in a population-based cohort of 8,894 men born between 1907 and 1935. Through linkage to cancer and mortality registers, the men were followed for prostate cancer diagnosis and mortality from study entry (in waves from 1967 to 1987) through 2009. In 2002–2006, a subgroup of 2,268 participants reported their milk intake in early, mid-, and current life. During a mean follow-up period of 24.3 years, 1,123 men were diagnosed with prostate cancer, including 371 with advanced disease (stage 3 or higher or prostate cancer death). Compared with early-life residency in the capital area, rural residency in the first 20 years of life was marginally associated with increased risk of advanced prostate cancer (hazard ratio = 1.29, 95% confidence interval (CI): 0.97, 1.73), particularly among men born before 1920 (hazard ratio = 1.64, 95% CI: 1.06, 2.56). Daily milk consumption in adolescence (vs. less than daily), but not in midlife or currently, was associated with a 3.2-fold risk of advanced prostate cancer (95% CI: 1.25, 8.28). These data suggest that frequent milk intake in adolescence increases risk of advanced prostate cancer.
adolescent; diet; Iceland; milk; prostatic neoplasms; risk factors
To examine the relationships between knee osteoarthritis (OA) and muscle parameters in a biracial cohort of older adults.
858 participants in the Health, Aging and Body Composition Study were included in this cross-sectional analysis. Computed tomography (CT) was used to measure muscle area and quadriceps strength was measured isokinetically. Muscle quality (specific torque) was defined as strength per unit of muscle area for both total thigh and quadriceps. Knee OA was assessed based on radiographic features and knee pain. We compared muscle parameters between those with and without radiographic knee OA (+RKOA, −RKOA) and among four groups defined by +/− RKOA with and without pain.
The mean age was 73.5 (2.9) years and mean BMI was 27.9 (4.8) kg/m2. 58% of participants were women and 44% were Black. Compared to − RKOA, +RKOA participants had a higher BMI (30.2 vs. 26.8 kg/m2), larger thigh muscles (117.9 vs. 108.9 cm2), and a greater amount of intermuscular fat (12.5 vs. 9.9 cm2) (all p<0.0001). In adjusted models, +RKOA subjects had significantly lower specific torque (p<0.001), indicating poorer muscle quality, than −RKOA subjects, but there was no difference between groups in quadriceps specific torque. +RKOA/−pain (p<0.05) and +RKOA/+pain (p<0.001) subjects had lower specific torque compared to −RKOA/−pain group. There were no significant differences in quadriceps specific torque among RKOA/pain groups.
Muscle quality was significantly poorer in participants with RKOA regardless of pain status. Future studies should address how lifestyle interventions might affect muscle quality and progression of knee OA.
Aortic stiffness increases with age and vascular risk factor exposure and is associated with increased risk for structural and functional abnormalities in the brain. High ambient flow and low impedance are thought to sensitize the cerebral microcirculation to harmful effects of excessive pressure and flow pulsatility. However, haemodynamic mechanisms contributing to structural brain lesions and cognitive impairment in the presence of high aortic stiffness remain unclear. We hypothesized that disproportionate stiffening of the proximal aorta as compared with the carotid arteries reduces wave reflection at this important interface and thereby facilitates transmission of excessive pulsatile energy into the cerebral microcirculation, leading to microvascular damage and impaired function. To assess this hypothesis, we evaluated carotid pressure and flow, carotid–femoral pulse wave velocity, brain magnetic resonance images and cognitive scores in participants in the community-based Age, Gene/Environment Susceptibility – Reykjavik study who had no history of stroke, transient ischaemic attack or dementia (n = 668, 378 females, 69–93 years of age). Aortic characteristic impedance was assessed in a random subset (n = 422) and the reflection coefficient at the aorta–carotid interface was computed. Carotid flow pulsatility index was negatively related to the aorta–carotid reflection coefficient (R = −0.66, P<0.001). Carotid pulse pressure, pulsatility index and carotid–femoral pulse wave velocity were each associated with increased risk for silent subcortical infarcts (hazard ratios of 1.62–1.71 per standard deviation, P<0.002). Carotid–femoral pulse wave velocity was associated with higher white matter hyperintensity volume (0.108 ± 0.045 SD/SD, P = 0.018). Pulsatility index was associated with lower whole brain (−0.127 ± 0.037 SD/SD, P<0.001), grey matter (−0.079 ± 0.038 SD/SD, P = 0.038) and white matter (−0.128 ± 0.039 SD/SD, P<0.001) volumes. Carotid–femoral pulse wave velocity (−0.095 ± 0.043 SD/SD, P = 0.028) and carotid pulse pressure (−0.114 ± 0.045 SD/SD, P = 0.013) were associated with lower memory scores. Pulsatility index was associated with lower memory scores (−0.165 ± 0.039 SD/SD, P<0.001), slower processing speed (−0.118 ± 0.033 SD/SD, P<0.001) and worse performance on tests assessing executive function (−0.155 ± 0.041 SD/SD, P<0.001). When magnetic resonance imaging measures (grey and white matter volumes, white matter hyperintensity volumes and prevalent subcortical infarcts) were included in cognitive models, haemodynamic associations were attenuated or no longer significant, consistent with the hypothesis that increased aortic stiffness and excessive flow pulsatility damage the microcirculation, leading to quantifiable tissue damage and reduced cognitive performance. Marked stiffening of the aorta is associated with reduced wave reflection at the interface between carotid and aorta, transmission of excessive flow pulsatility into the brain, microvascular structural brain damage and lower scores in various cognitive domains.
haemodynamics; aortic stiffness; magnetic resonance imaging; brain structure; cognitive function
The mechanisms that underlie the association between abdominal obesity and depression risk in older persons are not well known, but the “leptin hypothesis” of depression suggests that leptin resistance may be involved in mood regulation. We tested whether high circulatory concentration of leptin, alone and in combination with visceral adiposity, is associated with onset of depression in a sample of older persons.
Participants were 1220 men and 1282 women aged 70–79 years, enrolled in the Health, Aging and Body Composition study. Plasma concentration of leptin and abdominal visceral fat ascertained by computed tomography were assessed at baseline (April 1997 – June 1998). Onset of depression was defined as a Center for Epidemiological Studies-Depression Scale 10-item score ≥ 10 and/or new antidepressant medication use at any annual visit over a 5-year follow-up.
Higher leptin was associated with the risk of depression onset in men with high visceral fat (HR=1.25,95%CI=1.06–1.46, p=0.01) but not in those with normal visceral fat (HR=0.98,95%CI=0.80–1.19, p=0.80) (leptin*visceral fat p=0.04). No interaction between leptin and visceral fat was detected in the analysis focusing on women (p=0.90).
In older men, high leptin was associated with an increased onset of depressive symptoms especially in the presence of abdominal obesity, suggesting that underlying leptin resistance may play a role in this link. Differences in visceral fat levels and metabolic consequences may explain the absence of this association in women. These findings suggest a potential biological link between depression, obesity and their joint association with negative health outcomes.
leptin; depression; obesity; aging
Epigenetic studies are commonly conducted on DNA from tissue samples. However, tissues are ensembles of cells that may each have their own epigenetic profile, and therefore inter-individual cellular heterogeneity may compromise these studies. Here, we explore the potential for such confounding on DNA methylation measurement outcomes when using DNA from whole blood. DNA methylation was measured using pyrosequencing-based methodology in whole blood (n = 50–179) and in two white blood cell fractions (n = 20), isolated using density gradient centrifugation, in four CGIs (CpG Islands) located in genes HHEX (10 CpG sites assayed), KCNJ11 (8 CpGs), KCNQ1 (4 CpGs) and PM20D1 (7 CpGs). Cellular heterogeneity (variation in proportional white blood cell counts of neutrophils, lymphocytes, monocytes, eosinophils and basophils, counted by an automated cell counter) explained up to 40% (p<0.0001) of the inter-individual variation in whole blood DNA methylation levels in the HHEX CGI, but not a significant proportion of the variation in the other three CGIs tested. DNA methylation levels in the two cell fractions, polymorphonuclear and mononuclear cells, differed significantly in the HHEX CGI; specifically the average absolute difference ranged between 3.4–15.7 percentage points per CpG site. In the other three CGIs tested, methylation levels in the two fractions did not differ significantly, and/or the difference was more moderate. In the examined CGIs, methylation levels were highly correlated between cell fractions. In summary, our analysis detects region-specific differential DNA methylation between white blood cell subtypes, which can confound the outcome of whole blood DNA methylation measurements. Finally, by demonstrating the high correlation between methylation levels in cell fractions, our results suggest a possibility to use a proportional number of a single white blood cell type to correct for this confounding effect in analyses.
Objective methods to measure daily energy expenditure in studies of aging are needed. We sought to determine the accuracy of total energy expenditure (TEE) and activity energy expenditure (AEE) estimates from the SenseWear Pro armband (SWA) using software versions 6.1 (SWA 6.1) and 5.1 (SWA 5.1) relative to criterion methods in free-living older adults.
Participants (n = 19, mean age 82.0 years) wore a SWA for a mean ± SD 12.5 ± 1.1 days, including while sleeping. During this same period, criterion values for TEE were assessed with doubly labeled water and for resting metabolic rate (RMR) with indirect calorimetry. AEE was calculated as 0.9 TEE – RMR.
For TEE, there was no difference in mean ± SD values from doubly labeled water (2,040 ± 472 kcal/day) versus SWA 6.1 (2,012 ± 497 kcal/day, p = .593) or SWA 5.1 (2,066 ± 474 kcal/day, p = .606); individual values were highly correlated between methods (SWA 6.1 r = .893, p < .001; SWA 5.1 r = .901, p < .001) and demonstrated strong agreement (SWA 6.1 intraclass correlation coefficient = .896; SWA 5.1 intraclass correlation coefficient = .904). For AEE, mean values from SWA 6.1 (427 ± 304 kcal/day) were lower by 26.8% than criterion values (583 ± 242 kcal/day, p = .003), and mean values from SWA 5.1 (475 ± 299 kcal/day) were lower by 18.5% than criterion values (p = .021); however, individual values were highly correlated between methods (SWA 6.1 r = .760, p < .001; SWA 5.1 r = .786, p < .001) and demonstrated moderate agreement (SWA 6.1 intraclass correlation coefficient = .645; SWA 5.1 intraclass correlation coefficient = .720). Bland–Altman plots identified no systematic bias for TEE or AEE.
Acceptable levels of agreement were observed between SWA and criterion measurements of TEE and AEE in older adults.
Accelerometer; Activity monitor; Physical activity; Aged; DLW
Previous cross-sectional studies demonstrate positive associations of fat-free mass and negative associations of centrally distributed fat deposits with respiratory function in older adults. Few studies have evaluated whether greater losses of muscle and increases in fat are associated with more rapid decline in respiratory function in aging.
Nine hundred and fifty-seven men and 1,024 women aged, respectively, 73.6 ± 2.8 years and 73.2 ± 2.8 years at baseline were followed for 5 years. Body weight, waist circumference, bone mineral density, fat-free mass, fat mass and fat mass percentage as measured by DXA, abdominal subcutaneous and visceral adipose tissue, thigh muscle area, thigh intermuscular fat by CT and forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were evaluated at baseline and after 5-years follow-up.
Cross-sectional analyses showed that height and thigh muscle area were positively and visceral adipose tissue negatively related to FEV1 and FVC. Increase in fat mass over five years was associated with concurrent FEV1 and FVC decline. In analyses stratified by weight-change categories, men and women who gained weight (vs stable/lost weight) had more rapid declines in FEV1 and FVC.
In this well-functioning cohort, less muscle and greater abdominal fat were each associated with poorer lung spirometry cross-sectionally, whereas increase in fat mass over 5 years was associated with concurrent FEV1 and FVC decline. Weight gain and accompanying fat deposition may accelerate age-related declines in respiratory function.
Aging; Lung function; Body composition
Several studies have linked dietary patterns to insulin sensitivity and systemic inflammation, which affect risk of multiple chronic diseases. The purpose of this study was to investigate the dietary patterns of a cohort of older adults, and examine relationships of dietary patterns with markers of insulin sensitivity and systemic inflammation.
The Health, Aging and Body Composition (Health ABC) Study is a prospective cohort study of 3075 older adults. In Health ABC, multiple indicators of glucose metabolism and systemic inflammation were assessed. Food intake was estimated with a modified Block food frequency questionnaire (FFQ). In this study, dietary patterns of 1751 participants with complete data were derived by cluster analysis.
Six clusters were identified, including a ‘Healthy foods’ cluster, characterized by higher intake of lowfat dairy products, fruit, whole grains, poultry, fish and vegetables. In the main analysis, the ‘Healthy foods’ cluster had significantly lower fasting insulin and HOMA-IR than the ‘Breakfast cereal’ and ‘High-fat dairy products’ clusters, and lower fasting glucose than the ‘High-fat dairy products’ cluster (P ≤ 0.05). No differences were found in 2-hour glucose. With respect to inflammation, the ‘Healthy foods’ cluster had lower IL-6 than the ‘Sweets and desserts’ and ‘High-fat dairy products’ clusters, and no differences were seen in CRP or TNF-α.
A dietary pattern high in lowfat dairy products, fruit, whole grains, poultry, fish and vegetables may be associated with greater insulin sensitivity and lower systemic inflammation in older adults.
diet; dietary patterns; insulin sensitivity; inflammation; older adults
Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed genome-wide association to search for genetic susceptibility loci for serum urate and gout, and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD).
Methods and Results
Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the CHARGE consortium for serum urate and gout in 28,283 white individuals. The effect of the most significant SNP at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women’s Genome Health Study (WGHS; n=22,054). SNPs at 8 genetic loci achieved genome-wide significance with serum urate levels (p-values 4×10−8 to 2×10−242; SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, SLC17A1). Only two loci [SLC2A9, ABCG2] showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio 12.4 per 100 umol/L; p-value=3×10−39), but not with blood pressure, glucose, eGFR, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes was also observed in WGHS.
The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.
urate; gout; cardiovascular disease risk factors; genome-wide association study; Mendelian randomization
Lens transparency, or the magnitude of cataract severity, is a potential in vivo marker of aging distinguishable from diagnosed cataract. To explore lens transparency as a marker of aging, we determined its association with leukocyte telomere length (LTL) measured with quantitative polymerase chain reaction. Cataract severity was directly measured in 259 participants, and prevalent cataract and incident cataract surgery were ascertained in 2,750 participants of the Health, Aging, and Body Composition Study. LTL was unassociated with clinical cataract outcomes. Six of 259 had successfully aged lenses and a mean LTL of 5,700 bp, whereas 253/259 with poorly aged lenses had a mean LTL of 4,770 bp. Participants with a 1,000 bp greater mean LTL had nearly half the odds of any cataract (odds ratio = 0.47, 95% confidence interval 0.22–1.02) after adjustment. Lens transparency might be associated with longer LTL in community-dwelling older adults and should be investigated further as a possible biomarker of aging.
Lens transparency; Cataract; Leukocyte telomere length; Aging; Biomarker
To describe the prevalence and signs of early and late age-related macular degeneration (AMD) in an old cohort.
Population based cohort study
We included 5,272 persons 66 years and older, randomly sampled from the Reykjavik area.
Fundus images were taken through dilated pupils using a 45°digital camera and were graded for drusen size, type, area, increased retinal pigment, retinal pigment epithelial depigmentation, neovascular lesions and geographic atrophy using the modified Wisconsin Age-Related Maculopathy Grading System.
Main outcome measure
Age-related macular degenerationin an old cohort.
Mean age of participants was 76 years. The prevalence of early AMD was 12.4% (95% confidence interval [CI] 11.0–13.9) for those 66–74 year old and 36% (95% CI 30.9–41.1) for those 85 years and older. The prevalence of exudative AMD was 3.3% (95% CI 2.8–3.8) and for pure geographic atrophy 2.4% (95% CI 2.0–2.8). The highest prevalence for late AMD was among those 85 years and older 11.4% (95% CI 8.2–14.5) for exudative AMD and 7.6% (95% CI 4.8–10.4) for pure geographic atrophy.
Persons 85 years and older have 10-fold higher prevalence of late AMD than those 70–74 years old. The high prevalence of late AMD in the oldest age-group and expected increase of old people in the western world in coming years call for improved preventive measures and novel treatments.
Age-related macular degeneration; exudative AMD; geographic atrophy
The impact of abnormal spirometric findings on risk for incident heart failure among older adults without clinically apparent lung disease is not well elucidated.
We evaluated the association of baseline lung function with incident heart failure, defined as first hospitalization for heart failure, in 2125 participants of the community-based Health, Aging, and Body Composition Study (age, 73.6±2.9 years; 50.5% men; 62.3% white; 37.7% black) without prevalent lung disease or heart failure. Abnormal lung function was defined either as forced vital capacity (FVC) or forced expiratory volume in 1st second (FEV1) to FVC ratio below lower limit of normal. Percent predicted FVC and FEV1 were also assessed as continuous variables.
During follow-up (median, 9.4years), heart failure developed in 68 of 350 (19.4%) participants with abnormal baseline lung function, as compared to 172 of 1775 (9.7%) participants with normal lung function (hazard ratio [HR], 2.31; 95% confidence interval [CI], 1.74-3.07; P<.001). This increased risk persisted after adjusting for previously identified heart failure risk factors in the Health ABC Study, body mass index, incident coronary heart disease, and inflammatory markers (HR, 1.83; 95% CI, 1.33-2.50; P<.001). Percent predicted (%) FVC and FEV1 had a linear association with heart failure risk (HR, 1.21; 95%CI, 1.11-1.32 and 1.18; 95%CI, 1.10-1.26, per 10% lower %FVC and %FEV1, respectively; both P<.001 in fully adjusted models). Findings were consistent in sex and race subgroups, and for heart failure with preserved or reduced ejection fraction.
Abnormal spirometric findings in older adults without clinical lung disease are associated with increased heart failure risk.
Elderly; Epidemiology; Heart Failure; Pulmonary Function Test
Genetic discoveries are validated through the meta-analysis of genome-wide association scans in large international consortia. Because environmental variables may interact with genetic factors, investigation of differing genetic effects for distinct levels of an environmental exposure in these large consortia may yield additional susceptibility loci undetected by main effects analysis. We describe a method of joint meta-analysis of SNP and SNP by Environment (SNP×E) regression coefficients for use in gene-environment interaction studies.
In testing SNP×E interactions, one approach uses a two degree of freedom test to identify genetic variants that influence the trait of interest. This approach detects both main and interaction effects between the trait and the SNP. We propose a method to jointly meta-analyze the SNP and SNP×E coefficients using multivariate generalized least squares. This approach provides confidence intervals of the two estimates, a joint significance test for SNP and SNP×E terms, and a test of homogeneity across samples.
We present a simulation study comparing this method to four other methods of meta-analysis and demonstrate that the joint meta-analysis performs better than the others when both main and interaction effects are present. Additionally, we implemented our methods in a meta-analysis of the association between SNPs from the type 2 diabetes-associated gene PPARG and log-transformed fasting insulin levels and interaction by body mass index in a combined sample of 19,466 individuals from 5 cohorts.
2 degree of freedom meta-analysis; joint meta-analysis; PPARG; Gene-environment interaction meta-analysis
Although diabetes mellitus is implicated in susceptibility to infection, the association of diabetes with the subsequent course and outcome is unclear.
Design and setting
Retrospective analysis of two multicenter cohorts. We determined the association of pre-existing diabetes on the host immune response, acute organ function, and mortality in patients hospitalized with community-acquired pneumonia (CAP) in the GenIMS study (n=1895) and on mortality following either CAP or non-infectious hospitalizations in the population-based cohort study, Health ABC (n=1639).
Mortality rate within first year, risk of organ dysfunction, and immune responses, including circulating inflammatory (tumor necrosis factor, interleukin-6, interleukin-10), coagulation (Factor IX, thrombin-antithrombin complexes, antithrombin), fibrinolysis (plasminogen-activator inhibitor-1, and D-dimer), and cell-surface markers (CD120a, CD120b, HLA-DR, TLR-2 and TLR-4).
In GenIMS, diabetes increased mortality rate within first year after CAP (unadjusted hazard ratio [HR]=1.41, 95% confidence interval [CI]=1.12–1.76, p=0.002), even after adjusting for pre-existing cardiovascular and renal disease (adjusted HR=1.3, CI=1.03–1.65, p=0.02). In Health ABC, diabetes increased mortality rate within first year following CAP hospitalization, but not after hospitalization for non-infectious illnesses (significant interaction for diabetes and reason for hospitalization [p=0.04]; HR for diabetes on mortality over first year after CAP 1.87, CI=0.76–4.6, p=0.16 and after non-infectious hospitalization=1.16, CI=0.8–1.6, p=0.37). In GenIMS, immediate immune response was similar, as evidenced by similar circulating immune marker levels in the emergency department and during the first week. Those with diabetes had higher risk of acute kidney injury during hospitalization (39.3% vs. 31.7%, p=0.005) and they were more likely to die due to cardiovascular and kidney disease (34.4% vs. 26.8% and 10.4% vs. 4.5%, p=0.03).
Pre-existing diabetes was associated with a higher risk of death following CAP. The mechanism is not due to an altered immune response, at least as measured by a broad panel of circulating and cell surface markers, but may be due to worsening of pre-existing cardiovascular and kidney disease.
Background and Purpose
Several cardiovascular risk factors are associated with cognitive disorders in older persons. Little is known about the association of the burden of coronary atherosclerosis with brain structure and function.
Cross-sectional analysis of data from the AGES Reykjavik Study cohort of men and women born 1907-35. Coronary artery calcification (CAC), a marker of atherosclerotic burden was measured with computed tomography. Memory, speed of processing, and executive function composites were calculated from a cognitive test battery. Dementia was assessed in a multi-step procedure and diagnosed according to international guidelines. Quantitative data on total intracranial and tissue volumes [total, Gray (GMV), White (WMV), and White Matter Lesions (WMLV)], cerebral infarcts and cerebral microbleeds (CMB) were obtained with brain MRI. The association of CAC with dementia (n=165 cases) and cognitive function in non-demented subjects (n=4085), and separately with MRI outcomes, was examined in multivariate models adjusting for demographic and vascular risk factors. Analyses tested whether brain structure mediated the associations of CAC to cognitive function.
Subjects with higher CAC were more likely to have dementia and lower cognitive scores, more likely to have lower WMV, GMV and total brain tissue, and more cerebral infarcts, CMB and WMLV. The relations of cognitive performance and dementia to CAC were significantly attenuated when the models were adjusted for brain lesions and volumes.
In a population-based sample increasing atherosclerotic load, assessed by CAC, is associated with poorer cognitive performance and dementia, and these relations are mediated by evidence of brain pathology.
Atherosclerosis; Coronary Artery Disease; Calcinosis/radiography; Dementia; Cognitive function
To determine the extent to which disease-related symptoms and impairments, which constitute measures of disease severity or targets of therapy, account for the associations between chronic diseases and universal health outcomes.
Cardiovascular Health Study (CHS) and Health ABC.
5,654 CHS, and 2,706 Health ABC, members.
Diseases included heart failure (HF), chronic obstructive pulmonary disease (COPD), osteoarthritis, and cognitive impairment. The universal health outcomes included self-rated health, basic and instrumental activities of daily living (BADLs-IADLs), and death. Disease-related symptoms/impairments included HF symptoms and ejection fraction (EF) for HF; Dyspnea Scale and FEV1 for COPD; joint pain for osteoarthritis, and executive function for cognitive impairment.
The diseases were associated with the universal health outcomes (p<0.001) except osteoarthritis with death (both cohorts) and cognitive impairment with self-rated health (Health ABC). Symptoms/impairments accounted for ≥30% of each disease’s effect on the universal health outcomes. In CHS, for example, HF, compared with no HF, was associated with one fewer (0.918) BADLs-IADL performed without difficulty; 27% of this effect was accounted for by HF symptoms, only 5% by EF. The hazard ratio for death with HF was 6.5 (95% CI, 4.7, 8.9) with 40% accounted for by EF and only 14% by HF symptoms.
Disease-related symptoms/impairments accounted for much of the significant associations between the 4 chronic diseases and the universal health outcomes. Results support considering universal health outcomes as common metrics across diseases in clinical decision-making, perhaps by targeting the disease-related symptoms/impairments that contribute most strongly to the effect of the disease on the universal health outcomes.
chronic diseases; universal health outcomes; patient-reported outcomes; clinical decision-making
Type 2 diabetes is associated with higher bone density (BMD) and, paradoxically, with increased fracture risk. It is not known if low BMD, central to fracture prediction in older adults, identifies fracture risk in diabetic patients.
Determine if femoral neck (FN) BMD T-score and FRAX score are associated with fracture in older diabetic adults.
Three observational studies: Study of Osteoporotic Fractures, Osteoporotic Fractures in Men, and Health, Aging and Body Composition study.
Older community-dwelling adults in U.S.
9,449 women; 7,436 men.
Main outcome measure(s)
Self-reported incident fractures, verified by radiology reports.
Of 770 diabetic women, 84 experienced a hip and 262 a non-spine fracture during mean (SD) follow-up of 12.6 (5.3) years. Of 1,199 diabetic men, 32 experienced a hip and 133 a non-spine fracture during mean follow-up of 7.9 (2.5) years. Age-adjusted hazard ratios (HR) for one unit decrease in FN BMD T-score in diabetic women were 1.88 (95% confidence interval [CI], 1.43–2.48) for hip and 1.52 (95% CI, 1.31–1.75) for non-spine fracture. HRs in diabetic men were 5.71 (95% CI, 3.42–9.53) for hip and 2.17 (95% CI, 1.75–2.69) for non-spine fracture. FRAX score was also associated with fracture risk in diabetic participants. However, for a given T-score and age or FRAX score, diabetic participants had a higher fracture risk than those without diabetes. For a similar hip fracture risk, diabetic participants had a higher T-score than non-diabetic participants. The difference in T-score was 0.59 (95% CI, 0.31–0.87) for women and 0.38 (95% CI, 0.09–0.66) for men.
Among older adults with type 2 diabetes, FN BMD T-score and FRAX score were associated with hip and non-spine fracture risk. However, in these patients, compared with participants without diabetes, fracture risk was higher for a given T-score and age or a given FRAX score.
The recently developed and internally validated Health ABC HF model uses nine routinely available clinical variables to determine incident heart failure risk. In this study, we sought to externally validate the Health ABC HF model.
Methods and Results
Observed 5-year incidence of heart failure, defined as first hospitalization for new onset heart failure, was compared with 5-year risk estimates derived from the Health ABC HF model among participants without heart failure at baseline in the Cardiovascular Health Study. During follow-up, 400 of 5335 (7.5%) participants developed heart failure over 5 years vs. 364 (6.8%) predicted by the Health ABC HF model (predicted to observed ratio, 0.90). Observed vs. predicted 5-year heart failure probabilities were 3.2% vs. 2.8%, 9.0% vs. 7.0%, 15.9% vs. 13.7%, and 24.6% vs. 30.8% for the <5%, 5–10%, 10–20%, and >20% 5-year risk categories, respectively. The Hosmer-Lemeshow χ2 was 14.72 (d.f.=10; P=0.14) and the C index was 0.74 (95% CI, 0.72–0.76). Calibration and discrimination demonstrated adequate performance across sex and race overall; however risk was underestimated in white men, especially in the 5–10% risk category. Model performance was optimal when participants with normal left ventricular function at baseline were assessed separately. Performance was consistent across age groups. Analyses with death as a competing risk yielded similar results.
The Health ABC HF model adequately predicted 5-year heart failure risk in a large community-based study, providing support for the external validity of the model. This tool may be used to identify individuals to target heart failure prevention efforts.
Heart failure; epidemiology; elderly
Depression has been hypothesized to result in abdominal obesity through the accumulation of visceral fat. No large study has tested this hypothesis longitudinally.
To examine whether depressive symptoms predict an increase in abdominal obesity in a large population-based sample of well-functioning older persons.
The Health, Aging, and Body Composition Study, an ongoing prospective cohort study, with 5 years of follow-up.
Community-dwelling older persons residing in the areas surrounding Pittsburgh, Pennsylvania, and Memphis, Tennessee.
2088 well-functioning white and black persons aged 70–79 years.
Main Outcome Measures
Baseline depression was defined as a Center for Epidemiological Studies Depression (CES-D) score of ≥ 16. At baseline and after 5 years, overall obesity measures included body mass index and percent body fat (measured by dual energy x-ray absorptiometry). Abdominal obesity measures included waist circumference, sagittal diameter, and visceral fat (measured by computed tomography).
After adjustment for sociodemographics, lifestyle, diseases and overall obesity, baseline depression was associated with a 5-year increase in sagittal diameter (β=.054, p=.01) and visceral fat (β=.080, p=.001).
This study shows that depressive symptoms result in an increase in abdominal obesity, independent of overall obesity, suggesting that there may be specific pathophysiological mechanisms which link depression with visceral fat accumulation. These results might also help explain why depression increases risk of diabetes and cardiovascular disease.
Background and aims
Cross-sectional studies suggest that Obstructive Lung Disease (OLD) and smoking affect lean mass and mobility. We aimed to investigate whether OLD and smoking accelerate aging-related decline in lean mass and physical functioning.
260 persons with OLD (FEV1 63±18 %predicted), 157 smoking controls (FEV1 95±16 %predicted), 866 formerly smoking controls (FEV1 100±16 %predicted) and 891 never-smoking controls (FEV1 104±17 %predicted) participating in the Health, Aging and Body Composition (ABC) Study were studied. At baseline, the mean age was 74±3 y and participants reported no functional limitations. Baseline and seven-year longitudinal data were investigated of body composition (by Dual-energy X-ray absorptiometry), muscle strength (by hand and leg dynamometry) and Short Physical Performance Battery (SPPB).
Compared to never-smoking controls, OLD persons and smoking controls had a significantly lower weight, fat mass, lean mass and bone mineral content (BMC) at baseline (p<0.05). While the loss of weight, fat mass, lean mass and strength was comparable between OLD persons and never-smoking controls, the SPPB declined 0.12 points/yr faster in OLD men (p=0.01) and BMC 4 g/yr faster in OLD women (p=0.02). In smoking controls, only lean mass declined 0.1 kg/yr faster in women (p=0.03) and BMC 8 g/yr faster in men (p=0.02) compared to never-smoking controls.
Initially well-functioning older adults with mild-to-moderate OLD and smokers without OLD have a comparable compromised baseline profile of body composition and physical functioning, while seven-year longitudinal trajectories are to a large extent comparable to those observed in never-smokers without OLD. This suggests a common insult earlier in life related to smoking. 3
Obstructive Lung Disease; Body Composition; Aging
Excessive non-subcutaneous fat deposition may impair the functions of surrounding tissues and organs through the release of inflammatory cytokines and free fatty acids.
We examined the cross-sectional association between non-subcutaneous adiposity and calcified coronary plaque, a non-invasive measure of coronary artery disease burden.
Participants in the Multi-Ethnic Study of Atherosclerosis underwent CT assessment of calcified coronary plaque. We measured multiple fat depots in 398 white and black participants (47% men and 43% black), ages 47–86 years, from Forsyth County, NC during 2002–2005, using cardiac and abdominal CT scans. In addition to examining each depot separately, we also created a non-subcutaneous fat index using the standard scores of non-subcutaneous fat depots.
A total of 219 participants (55%) were found to have calcified coronary plaque. After adjusting for demographics, lifestyle factors and height, calcified coronary plaque was associated with a one standard deviation increment in the non-subcutaneous fat index (OR = 1.41; 95% CI: 1.08, 1.84), pericardial fat (OR = 1.38; 95% CI: 1.04, 1.84), abdominal visceral fat (OR = 1.35; 95% CI: 1.03, 1.76), but not with fat content in the liver, intermuscular fat, or abdominal subcutaneous fat. The relation between non-subcutaneous fat index and calcified coronary plaque remained after further adjustment for abdominal subcutaneous fat (OR = 1.40; 95% CI: 1.00, 1.94). The relation did not differ by gender and ethnicity.
The overall burden of non-subcutaneous fat deposition, but not abdominal subcutaneous fat, may be a correlate of coronary atherosclerosis.
Chronic disease is a risk factor for frailty. Previous studies typically consider individual diagnosed diseases, but disease builds over time, possibly in several organs simultaneously.
We hypothesize that disease burden is associated with frailty independent of diagnosed chronic disease and that physiologic measurements provide greater understanding of the etiology of frailty.
Cardiovascular Health Study, 1992–93 examination (N=2437, mean (SD) age 74.8 (4.8) years, 43.4% male, 95.8% white).
Disease burden and frailty were tabulated using 10-point scales (0=healthy, 10=unhealthy). Disease burden was the sum of measurements characterizing the vasculature, brain, kidneys, lungs, and glucose metabolism. Frailty was assessed with the frailty index reported by Fried. Multivariate linear models were used to determine the association of disease burden (predictor) to frailty (outcome).
Unadjusted, 1 point higher disease burden was associated with a 0.28 point higher frailty score (p<0.0001). White matter grade, forced vital capacity, and cystatin-C were particularly strongly and significantly associated with frailty. Disease burden attenuated the association of frailty with age by 29%, and disease burden and age had similar associations with frailty. Disease burden attenuated the association of frailty with fibrinogen, Factor VIII, and CRP by 32%, 56%, and 83%. Frailty was associated with diagnosed depression, stroke, cognitive impairment, arthritis, and pulmonary disease but not coronary heart disease, diabetes, or kidney disease in the presence of a summary of disease burden. In the adjusted model disease burden remained significantly associated with frailty (β=0.11, p<0.0001).
Disease burden was independently and significantly associated with frailty. These results emphasize that typically unrecognized physiologic changes may importantly contribute to frailty.
Frailty; etiology; disease burden