Person:

Hoffmann, Udo

Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (~26%–27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ~2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10−8) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT–assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.

Background: Excess accumulation of abdominal subcutaneous (SAT) and visceral adipose tissue (VAT) is associated with adverse levels of adipokines and cardiovascular disease risk. Whether fat quality is associated with adipokines has not been firmly established. This study examined the association between abdominal SAT and VAT density, an indirect measure of fat quality, with a panel of metabolic regulatory biomarkers secreted by adipose tissue or the liver independently of absolute fat volumes. Methods and Results: We evaluated 1829 Framingham Heart Study participants (44.9% women). Abdominal SAT and VAT density was estimated indirectly by adipose tissue attenuation using computed tomography. Adipokines included adiponectin, leptin receptor, leptin, fatty acid‐binding protein 4 (FABP‐4), retinol‐binding protein 4 (RBP‐4), and fetuin‐A. Fat density was associated with all the biomarkers evaluated, except fetuin‐A. Lower fat density (ie, more‐negative fat attenuation) was associated with lower adiponectin and leptin receptor, but higher leptin and FABP‐4 levels (all P<0.0001). SAT density was inversely associated with RPB‐4 in both sexes, whereas the association between VAT density and RPB‐4 was only observed in men (P<0.0001). In women, after additional adjustment for respective fat volume, SAT density retained the significant associations with adiponectin, leptin, FABP‐4, and RBP‐4; and VAT density with adiponectin only (all P<0.0001). In men, significant associations were maintained upon additional adjustment for respective fat volume (P<0.005). Conclusions: Lower abdominal fat density was associated with a profile of biomarkers suggestive of greater cardiometabolic risk. These observations support that fat density may be a valid biomarker of cardiometabolic risk.

Background & Aims Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular related death, particularly in those with hepatic fibrosis. We determined the prevalence of predicted fibrosis based on non-invasive fibrosis markers and the association of hepatic fibrosis with cardiovascular risk factors. Methods: Cross-sectional study of 575 Framingham Heart Study participants with NAFLD based on computed tomography. We determined the prevalence of predicted fibrosis based on the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, AST to platelet ratio index (APRI), the Fibrosis-4 score (FIB4), and the NAFLD Fibrosis Score (NFS). Using multivariable logistic regression models, we examined the association between low, indeterminate, or high risk for fibrosis according to the NFS and various cardiometabolic risk factors. Results: The predicted risk of fibrosis was 12%, 4%, 5%, and 32% for the NFS, FIB4, APRI, and AST/ALT ratio, respectively. In multivariable models, participants with a high risk for advanced fibrosis by the NFS had a wider pulse pressure (adjusted mean difference = 6.87 mm Hg; p = 0.0002) and an increased odds of hypertension (OR 2.92; p = 0.007) compared to those with low risk of fibrosis. There were no statistically significant differences between other cardiovascular risk factors for those with a high versus low risk of fibrosis. Conclusions: The AST/ALT ratio, APRI, and NFS give widely disparate predictions of liver fibrosis. Participants with a high risk for fibrosis based on NFS had wider pulse pressure and increased odds of hypertension. Whether modifying these risk factors impacts cardiovascular endpoints in NAFLD patients remains unknown.

Background: Obesity is associated with altered atrial electrophysiology and a prominent risk factor for atrial fibrillation. Body mass index, the most widely used adiposity measure, has been related to atrial electrical remodeling. We tested the hypothesis that pericardial fat is independently associated with electrocardiographic measures of atrial conduction. Methods and Results: We performed a cross‐sectional analysis of 1946 Framingham Heart Study participants (45% women) to determine the relation between pericardial fat and atrial conduction as measured by P wave indices (PWI): PR interval, P wave duration (P‐duration), P wave amplitude (P‐amplitude), P wave area (P‐area), and P wave terminal force (P‐terminal). We performed sex‐stratified linear regression analyses adjusted for relevant clinical variables and ectopic fat depots. Each 1‐SD increase in pericardial fat was significantly associated with PR interval (β=1.7 ms, P=0.049), P‐duration (β=2.3 ms, P<0.001), and P‐terminal (β=297 μV·ms, P<0.001) among women; and P‐duration (β=1.2 ms, P=0.002), P‐amplitude (β=−2.5 μV, P<0. 001), and P‐terminal (β=160 μV·ms, P=0.002) among men. Among both sexes, pericardial fat was significantly associated with P‐duration in analyses additionally adjusting for visceral fat or intrathoracic fat; a similar but non‐significant trend existed with P‐terminal. Among women, pericardial fat was significantly associated with P wave area after adjustment for visceral and intrathoracic fat. Conclusions: Pericardial fat is associated with atrial conduction as quantified by PWI, even with adjustment for extracardiac fat depots. Further studies are warranted to identify the mechanisms through which pericardial fat may modify atrial electrophysiology and promote subsequent risk for arrhythmogenesis.

OBJECTIVE— The purpose of this study was to assess the relationship between lifestyle factors and abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in a community-based setting. RESEARCH DESIGN AND METHODS— Cross-sectional associations between lifestyle factors (dietary quality, physical activity, smoking, and alcohol consumption) and SAT and VAT volumes were examined in 2,926 Framingham Heart Study participants (48.6% women, aged 50 ± 10 years). RESULTS— Diets consistent with the 2005 Dietary Guidelines Adherence Index and greater physical activity were inversely associated with SAT and VAT (P < 0.0001–0.002). In men, former smoking was associated with higher SAT (2,743 ± 56 cm(^3)) compared with current smokers (2,629 ± 88 cm(^3)) or those who never smoked (2,538 ± 44 cm(^3); P = 0.02). Both former and current smoking was associated with higher VAT (P = 0.03 [women]; P = 0.005 [men]). Women with high amounts of alcohol intake (>7 drinks/week) had lower SAT (2,869 ± 106 cm(^3)) than those who consumed less alcohol (3,184 ± 44 cm(^3), P = 0.006); significant differences in VAT were not observed (P = 0.18). In men, high amounts of alcohol intake (>14 drinks/week) were associated with higher VAT (2,272 ± 59 cm(^3)) compared with intake of ≤14 drinks/week (2,139 ± 25 cm(^3), P = 0.04), whereas SAT did not differ (P = 0.91). An increasing number of healthy lifestyle factors were associated with lower SAT and VAT volumes (all P < 0.003). CONCLUSIONS— Adherence to recommended dietary guidelines and physical activity are associated with lower SAT and VAT volumes. However, both smoking and high alcohol intake are differentially associated with VAT volumes. Further research to uncover the putative mechanisms is warranted.

To examine the relation between measures of adiposity and depressive symptoms in a large well characterized community-based sample, we examined the relations of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) to depressive symptoms in 1581 women (mean age 52.2 years) and 1718 men (mean age 49.8 years) in the Framingham Heart Study. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression (CES-D) scale. Regression models were created to examine the association between each fat depot (exposure) and depressive symptoms (outcome). Sex specific models were adjusted for age, body mass index, smoking, alcohol consumption, diabetes, hypertension, total and HDL cholesterol, lipid lowering treatment, CVD, menopause, C-reactive protein, and physical activity. Mean CES-D scores were 6.8 and 5.6 in women and men. High levels of depressive symptoms were present in 22.5% of women and 12.3% of men. In women, one standard deviation increase in VAT was associated with a 1.3 point higher CES-D score after adjusting for age and BMI (p<0.01) and remained significant in the fully adjusted model (p=0.03). The odds ratio of depressive symptoms per 1 standard deviation increase in VAT in women was 1.33 (p=0.015); results were attenuated in fully adjusted models (OR 1.29, p=0.055). In men, the association between VAT and CES-D score and depressive symptoms was not significant. SAT was not associated with CES-D score or depressive symptoms. This study supports an association between VAT and depressive symptoms in women. Further work is needed to uncover the complex biologic mechanisms mediating the association.

Background: Thoracic periaortic adipose tissue (TAT) is associated with atherosclerosis and cardiovascular disease (CVD) risk factors and may play a role in obesity‐mediated vascular disease. We sought to determine the prevalence, distribution, and risk factor correlates of high TAT. Methods and Results: Participants from the Framingham Heart Study (n=3246, 48% women, mean age 51.1 years) underwent multidetector computed tomography; high TAT and visceral adipose tissue (VAT) were defined on the basis of sex‐specific 90th percentiles in a healthy referent sample. The prevalence of high TAT was 38.1% in women and 35.7% in men. Among individuals without high VAT, 10.1% had high TAT. After adjustment for age and VAT, both women and men with high TAT in the absence of high VAT were older and had a higher prevalence of CVD (P<0.0001) compared with those without high TAT. In addition, men in this group were more likely to be smokers (P=0.02), whereas women were more likely to have low high‐density lipoprotein cholesterol (P=0.005). Conclusions: Individuals in our community‐based sample with high TAT in the absence of high VAT were characterized by an adverse cardiometabolic profile. This adipose tissue phenotype may identify a subset of individuals with distinct metabolic characteristics.

OBJECTIVE: Obesity is associated with increased metabolic and cardiovascular risk. The ectopic fat hypothesis suggests that subcutaneous fat may be protective, but this theory has yet to be fully explored. RESEARCH DESIGN AND METHODS: Participants from the Framingham Heart Study (n = 3,001, 48.5% women) were stratified by visceral adipose tissue (VAT) into sex-specific tertiles. Within these tertiles, age-adjusted abdominal subcutaneous adipose tissue (SAT) tertiles were examined in relation to cardiometabolic risk factors. RESULTS: In the lowest VAT tertile, risk factor prevalence was low, although systolic blood pressure in women and rates of high triglycerides, impaired fasting glucose, hypertension, and the metabolic syndrome in men increased with increasing SAT tertile (all P < 0.04). In contrast, in the top VAT tertile, lower triglycerides were observed in men with increasing SAT (64.4% high triglycerides in SAT tertile 1 vs. 52.7% in SAT tertile 3, P = 0.03). Similar observations were made for women, although results were not statistically significant (50.6% high triglycerides in SAT tertile 1 vs. 41.0% in tertile 3, P = 0.10). Results in the highest VAT tertile were notable for a lack of increase in the prevalence of low HDL in men and women and in rates of impaired fasting glucose in men with increasing subcutaneous fat, despite sizable differences in BMI across SAT tertiles (27.1 to 36.3 kg/m(^2) [women]; 28.1 to 35.7 kg/m(^2) [men]). CONCLUSIONS: Although adiposity increases the absolute risk of metabolic and cardiovascular disease, abdominal subcutaneous fat is not associated with a linear increase in the prevalence of all risk factors among the obese, most notably, high triglycerides.

OBJECTIVE—The prevalence of abdominal obesity exceeds that of general obesity. We sought to determine the prevalence of abdominal subcutaneous and visceral obesity and to characterize the different patterns of fat distribution in a community-based sample. RESEARCH DESIGN AND METHODS—Participants from the Framingham Heart Study (n = 3,348, 48% women, mean age 52 years) underwent multidetector computed tomography; subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes were assessed. Sex-specific high SAT and VAT definitions were based on 90th percentile cut points from a healthy referent sample. Metabolic risk factors were examined in subgroups with elevated SAT and VAT. RESULTS—The prevalence of high SAT was 30% (women) and 31% (men) and that for high VAT was 44% (women) and 42% (men). Overall, 27.8% of the sample was discordant for high SAT and high VAT: 19.9% had SAT less than but VAT equal to or greater than the 90th percentile, and 7.9% had SAT greater than but VAT less than the 90th percentile. The prevalence of metabolic syndrome was higher among women and men with SAT less than the 90th percentile and high VAT than in those with high SAT but VAT less than the 90th percentile, despite lower BMI and waist circumference. Findings were similar for hypertension, elevated triglycerides, and low HDL cholesterol. CONCLUSIONS—Nearly one-third of our sample has abdominal subcutaneous obesity, and <40% have visceral obesity. Clinical measures of BMI and waist circumference may misclassify individuals in terms of VAT and metabolic risk.

Background: Ectopic fat density is associated with cardiovascular disease (CVD) risk factors above and beyond fat volume. Volumetric measures of ectopic fat have been associated with CVD risk factors and subclinical atherosclerosis. The aim of this study was to investigate the association between fat density and subclinical atherosclerosis. Methods and Results: Participants were drawn from the Multi‐Detector Computed Tomography (MDCT) substudy of the Framingham Heart Study (n=3079; mean age, 50.1 years; 49.2% women). Fat density was indirectly estimated by computed tomography attenuation (Hounsfield Units [HU]) on abdominal scan slices. Visceral fat (VAT), subcutaneous fat (SAT), and pericardial fat HU and volumes were quantified using standard protocols; coronary and abdominal aortic calcium (CAC and AAC, respectively) were measured radiographically. Multivariable‐adjusted logistic regression models were used to evaluate the association between adipose tissue HU and the presence of CAC and AAC. Overall, 17.1% of the participants had elevated CAC (Agatston score [AS]>100), and 23.3% had elevated AAC (AS>age‐/sex‐specific cutoffs). Per 5‐unit decrement in VAT HU, the odds ratio (OR) for elevated CAC was 0.76 (95% confidence interval [CI], 0.65 to 0.89; P=0.0005), even after adjustment for body mass index or VAT volume. Results were similar for SAT HU. With decreasing VAT HU, we also observed an OR of 0.79 (95% CI, 0.67 to 0.92; P=0.004) for elevated AAC after multivariable adjustment. We found no significant associations between SAT HU and AAC. There was no significant association between pericardial fat HU and either CAC or AAC. Conclusions: Lower VAT and SAT HU, indirect estimates of fat quality, are associated with a lower risk of subclinical atherosclerosis.