David S Siscovick

Group Health Cooperative, Seattle, Washington, United States

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Publications (707)6627.82 Total impact

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    ABSTRACT: Purpose: Studies suggest that long-chain ω-3 polyunsaturated fatty acid (LCω3PUFA) intake and its primary food source-fish-may have beneficial effects on the individual components of metabolic syndrome (MetS). We examined the longitudinal association between fish or LCω3PUFA intake and MetS incidence. Methods: We prospectively followed 4356 American young adults, free from MetS and diabetes at baseline, for incident MetS and its components in relation to fish and LCω3PUFA intake. MetS was defined by the National Cholesterol Education Program/Adult Treatment Panel III criteria. Cox proportional hazards model was used for analyses, controlling for socio-demographic, behavioral, and dietary factors. Results: During the 25-year follow-up, a total of 1069 incident cases of MetS were identified. LCω3PUFA intake was inversely associated with the incidence of MetS in a dose-response manner. The multivariable adjusted hazards ratio (HR) [95 % confidence interval (CI)] of incident MetS was 0.54 (95 % CI 0.44, 0.67; P for linear trend < 0.01) as compared the highest to the lowest quintile of LCω3PUFA intake. A threshold inverse association was found between non-fried fish consumption and the incidence of MetS. The multivariable adjusted HRs (95 % CIs) from the lowest to the highest quintile were 1.00, 0.70 (0.51, 0.95), 0.68 (0.52, 0.91), 0.67 (0.53, 0.86), and 0.71 (0.56, 0.89) (P for linear trend = 0.49). The observed inverse associations were independent of the status of baseline individual components of MetS. Conclusions: Our findings suggest that intakes of LCω3PUFAs and non-fried fish in young adulthood are inversely associated with the incidence of MetS later in life.
    No preview · Article · Jan 2016 · European Journal of Nutrition
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    Cristian Pattaro · Alexander Teumer · Mathias Gorski · Audrey Y. Chu · Man Li · Vladan Mijatovic · Maija Garnaas · Adrienne Tin · Rossella Sorice · Yong Li · [...] · Katalin Susztak · Pavel Hamet · Johanne Tremblay · Ian H. de Boer · Carsten A. Böger · Wolfram Goessling · Daniel I. Chasman · Anna Köttgen · W. H. Linda Kao · Caroline S. Fox ·

    Full-text · Article · Jan 2016 · Nature Communications
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    ABSTRACT: Background: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression. Objective: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation. Design: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium. Results: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (β = -0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (β = 3.87 mg/dL, P = 5.62 × 10(21)). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (β = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (β = 8.84%, P = 3.51 × 10(18)) and lower circulating EPA (β = -1.46%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 (β = -2.83%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = -0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = -0.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05). Conclusion: We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation.
    Full-text · Article · Jan 2016 · American Journal of Clinical Nutrition
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    ABSTRACT: Waist-to-hip ratio (WHR), a relative comparison of waist and hip circumferences, is an easily accessible measurement of body fat distribution, in particular central abdominal fat. A high WHR indicates more intra-abdominal fat deposition and is an established risk factor for cardiovascular disease and type 2 diabetes. Recent genome-wide association studies have identified numerous common genetic loci influencing WHR, but the contributions of rare variants have not been previously reported. We investigated rare variant associations with WHR in 1510 European-American and 1186 African-American women from the National Heart, Lung, and Blood Institute-Exome Sequencing Project. Association analysis was performed on the gene level using several rare variant association methods. The strongest association was observed for rare variants in IKBKB (P=4.0 × 10(-8)) in European-Americans, where rare variants in this gene are predicted to decrease WHRs. The activation of the IKBKB gene is involved in inflammatory processes and insulin resistance, which may affect normal food intake and body weight and shape. Meanwhile, aggregation of rare variants in COBLL1, previously found to harbor common variants associated with WHR and fasting insulin, were nominally associated (P=2.23 × 10(-4)) with higher WHR in European-Americans. However, these significant results are not shared between African-Americans and European-Americans that may be due to differences in the allelic architecture of the two populations and the small sample sizes. Our study indicates that the combined effect of rare variants contribute to the inter-individual variation in fat distribution through the regulation of insulin response.European Journal of Human Genetics advance online publication, 13 January 2016; doi:10.1038/ejhg.2015.272.
    Full-text · Article · Jan 2016 · European journal of human genetics: EJHG
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    ABSTRACT: Thiazide diuretic (TZ) use is associated with higher bone mineral density, whereas loop diuretic (LD) use is associated with lower bone density and incident fracture. Dihydropyridine sensitive calcium channels are expressed on parathyroid cells and may play a role in PTH regulation. The potential for diuretics and calcium-channel blockers (CCBs) to modulate PTH and calcium homeostasis may represent a mechanism by which they influence skeletal outcomes. We hypothesized that the use of LD and dihydropyridine CCBs is associated with higher PTH, and TZ use is associated with lower PTH. We conducted cross-sectional analyses of participants treated for hypertension in the Multi-Ethnic Study of Atherosclerosis who did not have primary hyperparathyroidism or chronic kidney disease (n = 1888). We used adjusted regression models to evaluate the independent association between TZ, LD, and CCB medication classes and PTH. TZ use was associated with lower PTH when compared to non-TZ use (44.4 vs. 46.9 pg/mL, p = 0.02), whereas the use of LD and CCBs was associated with higher PTH when compared to non-users of each medication class (LD: 60.7 vs. 45.5 pg/mL, p < 0.0001; CCB: 49.5 vs. 44.4 pg/mL, p < 0.0001). Adjusted regression models confirmed independent associations between TZ use and lower PTH (β = -3.2 pg/mL, p = 0.0007), and LD or CCB use and higher PTH (LD: β = +12.0 pg/mL, p < 0.0001; CCB: +3.7 pg/mL, p < 0.0001). Among CCB users, the use of dihydropyridines was independently associated with higher PTH (β= +5.0 pg/mL, p < 0.0001) whereas non-dihydropyridine use was not (β= +0.58 pg/mL, p = 0.68). We conclude that in a large community-based cohort with normal kidney function, TZ use is associated with lower PTH, whereas LD and dihydropyridine CCB use is associated with higher PTH. These associations may provide a mechanistic explanation linking use of these medications to the development of skeletal outcomes. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
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    ABSTRACT: Epidemiological studies suggest that levels of n-3 and n-6 long-chain polyunsaturated fatty acids are associated with risk of cardio-metabolic outcomes across different ethnic groups. Recent genome-wide association studies in populations of European ancestry have identified several loci associated with plasma and/or erythrocyte polyunsaturated fatty acids. To identify additional novel loci, we carried out a genome-wide association study in two population-based cohorts consisting of 3521 Chinese participants, followed by a trans-ethnic meta-analysis with meta-analysis results from 8962 participants of European ancestry. Four novel loci (MYB, AGPAT4, DGAT2 and PPT2) reached genome-wide significance in the trans-ethnic meta-analysis (log10(Bayes Factor)≥6). Of them, associations of MYB and AGPAT4 with docosatetraenoic acid (log10(Bayes Factor)=11.5 and 8.69, respectively) also reached genome-wide significance in the Chinese-specific genome-wide association analyses (P=4.15×10(-14) and 4.30×10(-12), respectively), while associations of DGAT2 with gamma-linolenic acid (log10(Bayes Factor)=6.16) and of PPT2 with docosapentaenoic acid (log10(Bayes Factor)=6.24) were nominally significant in both Chinese- and European-specific genome-wide association analyses (P≤0.003). We also confirmed previously reported loci including FADS1, NTAN1, NRBF2, ELOVL2 and GCKR Different effect sizes in FADS1 and independent association signals in ELOVL2 were observed. These results provide novel insight into the genetic background of polyunsaturated fatty acids and their differences between Chinese and European populations.
    No preview · Article · Jan 2016 · Human Molecular Genetics
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    ABSTRACT: Background: Not much is known about the relations of circulating saturated fatty acids (SFAs), which are influenced by both metabolic and dietary determinants, with total and cause-specific mortality. Objective: We examined the associations of plasma phospholipid SFAs with total and cause-specific mortality among 3941 older adults from the Cardiovascular Health Study, a population-based prospective study of adults aged ≥65 y who were followed from 1992 through 2011. Methods: The relations of total and cause-specific mortality with plasma phospholipid palmitic acid (16:0), stearic acid (18:0), arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) were assessed using Cox proportional hazards models. Results: During 45,450 person-years of follow-up, 3134 deaths occurred. Higher concentrations of the plasma phospholipid SFAs 18:0, 22:0, and 24:0 were associated with a lower risk of total mortality [multivariable-adjusted HRs (95% CIs)] for the top compared with the bottom quintile: 0.85 (0.75, 0.95) for 18:0; 0.85 (0.75, 0.95) for 22:0; and 0.80 (0.71, 0.90) for 24:0. In contrast, plasma 16:0 concentrations in the highest quintile were associated with a higher risk of total mortality compared with concentrations in the lowest quintile [1.25 (1.11, 1.41)]. We also found no association of plasma phospholipid 20:0 with total mortality. Conclusions: These findings suggest that the associations of plasma phospholipid SFAs with the risk of death differ according to SFA chain length and support future studies to better characterize the determinants of circulating SFAs and to explore the mechanisms underlying these relations.
    Preview · Article · Dec 2015 · Journal of Nutrition
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    ABSTRACT: Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and associate with increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes mellitus and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (p=2.4*10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. SNPs at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in average UACR per minor allele was 21% for HS6ST1 and 13% for RAB38/CTSC (p=6.3*10(-7) and 5.8*10(-7), respectively). Experiments using streptozotocin-treated diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout vs. control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared to controls. The loci identified here confirm known and highlight novel pathways influencing albuminuria.
    Full-text · Article · Dec 2015 · Diabetes
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    ABSTRACT: Objective: To investigate associations of maternal periconceptional shellfish, lean fish and fatty fish intake with risk of pregnancy complications. Design: In this prospective cohort study, we collected information on intake of seafood subtypes using FFQ. We categorized seafood intake into frequencies of 1 servings/week. We ascertained gestational hypertension, pre-eclampsia, gestational diabetes and preterm birth diagnoses from medical records. Using generalized linear models with a log link, the Poisson family and robust standard errors, we estimated risk ratios and 95 % confidence intervals across seafood intake categories. Setting: The Omega study, a study of risk factors for pregnancy complications among women recruited from prenatal clinics in Washington State, USA, 1996-2008. Subjects: The current study included 3279 participants from the Omega study. Results: Median (interquartile range) shellfish, lean fish and fatty fish intake was 0·3 (0-0·9), 0·5 (0-1·0) and 0·5 (0·1-1·0) servings/week, respectively. Lean fish intake of >1 servings/week (v. <0·2 servings/month) was associated with a 1·55-fold higher risk of preterm birth (95 % CI 1·04, 2·30) and was not associated with the other pregnancy complications. Higher intake of seafood (total or other subtypes) was not associated with pregnancy complications (separately or combined). Conclusions: Higher intake of lean fish, but not fatty fish or shellfish, was associated with a higher risk of preterm birth; these findings may have significance for preterm birth prevention. Studies of mechanisms and potential contributing factors (including seafood preparation and nutrient/contaminant content) are warranted.
    No preview · Article · Dec 2015 · Public Health Nutrition
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    ABSTRACT: Dietary quality affects cardiometabolic risk, yet its pathways of influence on regional adipose tissue depots involved in metabolic and diabetes risk are not well established. We aimed to investigate the relationship between dietary quality and regional adiposity.
    No preview · Article · Dec 2015

  • No preview · Article · Nov 2015 · Clinical nephrology
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    ABSTRACT: Background: -While guidelines suggest that older adults engage in regular physical activity (PA) to reduce cardiovascular disease (CVD), surprisingly few studies have evaluated this relationship, especially in those older than 75 years. Additionally, with advancing age the ability to perform some types of PA might decrease, making light-moderate exercise such as walking especially important to meet recommendations. Methods and results: -Prospective cohort analysis among 4207 US men and women of mean age 73 years (SD=6) who were free of CVD at baseline in the Cardiovascular Health Study and followed from 1989 to 1999. PA was assessed and cumulatively updated over time to minimize misclassification and assess long-term effects of habitual activity. Walking (pace, blocks, combined walking score) was updated annually from baseline through 1999. Leisure-time activity and exercise intensity were updated at baseline, 1992, and 1996. Incident CVD (fatal or nonfatal myocardial infarction, coronary death, or stroke) was adjudicated using medical records. During 41 995 person-years of follow-up, 1182 CVD events occurred. After multivariable adjustment, greater PA was inversely associated with coronary heart disease (CHD), stroke (especially ischemic stroke), and total CVD, even in those 75 years and older. Walking pace, distance, and overall walking score, leisure-time activity, and exercise intensity were each associated with lower risk. For example, compared with a walking pace under 2 mph, those that habitually walked at a pace above 3 mph had lower risk of CHD (0.50; CI:0.38-0.67), stroke (0.47; CI:033-0.66) and CVD (0.50; CI:0.40-0.62). Conclusions: -These data provide empiric suggestion supporting PA recommendations, in particular walking, to reduce incidence of CVD among older adults.
    No preview · Article · Nov 2015 · Circulation
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    ABSTRACT: Loci identified in genome-wide association studies (GWAS) of cardio-metabolic traits account for a small proportion of the traits' heritability. To date, most association studies have not considered parent-of-origin effects (POEs). Here we report investigation of POEs on adiposity and glycemic traits in young adults. The Jerusalem Perinatal Family Follow-Up Study (JPS), comprising 1250 young adults and their mothers was used for discovery. Focusing on 18 genes identified by previous GWAS as associated with cardio-metabolic traits, we used linear regression to examine the associations of maternally- and paternally-derived offspring minor alleles with body mass index (BMI), waist circumference (WC), fasting glucose and insulin. We replicated and meta-analyzed JPS findings in individuals of European ancestry aged ≤50 belonging to pedigrees from the Framingham Heart Study, Family Heart Study and Erasmus Rucphen Family study (total N≅4800). We considered p<2.7x10-4 statistically significant to account for multiple testing. We identified a common coding variant in the 4th exon of APOB (rs1367117) with a significant maternally-derived effect on BMI (β = 0.8; 95%CI:0.4,1.1; p = 3.1x10-5) and WC (β = 2.7; 95%CI:1.7,3.7; p = 2.1x10-7). The corresponding paternally-derived effects were non-significant (p>0.6). Suggestive maternally-derived associations of rs1367117 were observed with fasting glucose (β = 0.9; 95%CI:0.3,1.5; p = 4.0x10-3) and insulin (ln-transformed, β = 0.06; 95%CI:0.03,0.1; p = 7.4x10-4). Bioinformatic annotation for rs1367117 revealed a variety of regulatory functions in this region in liver and adipose tissues and a 50% methylation pattern in liver only, consistent with allelic-specific methylation, which may indicate tissue-specific POE. Our findings demonstrate a maternal-specific association between a common APOB variant and adiposity, an association that was not previously detected in GWAS. These results provide evidence for the role of regulatory mechanisms, POEs specifically, in adiposity. In addition this study highlights the benefit of utilizing family studies for deciphering the genetic architecture of complex traits.
    Full-text · Article · Oct 2015 · PLoS Genetics
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    ABSTRACT: Obesity is linked to type 2 diabetes (T2D) and cardiovascular diseases; however, the underlying molecular mechanisms remain unclear. We aimed to identify obesity-associated molecular features that may contribute to obesity-related diseases. Using circulating monocytes from 1,264 Multi-Ethnic Study of Atherosclerosis participants, we quantified the transcriptome and epigenome. We discovered that alterations in a network of co-expressed cholesterol metabolism genes are a signature feature of obesity and inflammatory stress. This network included 11 body mass index (BMI)-associated genes related to sterol uptake (↑LDLR, ↓MYLIP), synthesis (↑SCD, FADS1, HMGCS1, FDFT1, SQLE, CYP51A1, SC4MOL) and efflux (↓ABCA1, ABCG1) - producing a molecular profile expected to increase intracellular cholesterol. Importantly, these alterations were associated with T2D and coronary artery calcium (CAC), independent from cardiometabolic factors including serum lipid profiles. This network mediated the associations between obesity and T2D/CAC. Several genes in the network harbored CpG dinucleotides (e.g. ABCG1/cg06500161) which overlapped ENCODE-annotated regulatory regions, and had methylation profiles that mediated the associations between BMI/inflammation and expression of their cognate genes. Taken together with several lines of previous experimental evidence, these data suggest that alterations of the cholesterol metabolism gene network represent a molecular link between obesity/inflammation and T2D/CAC. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Full-text · Article · Oct 2015 · Diabetes
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    ABSTRACT: OBJECTIVE We examined the associations of symptoms of sleep-disordered breathing (SDB), which was defined as loud snoring, stopping breathing for a while during sleep, and daytime sleepiness, and insomnia, with glucose metabolism and incident type 2 diabetes in older adults. RESEARCH DESIGN AND METHODS Between 1989 and 1993, the Cardiovascular Health Study recruited 5,888 participants ≥65 years of age from four U.S. communities. Participants reported SDB and insomnia symptoms yearly through 1989–1994. In 1989–1990, participants underwent an oral glucose tolerance test, from which insulin secretion and insulin sensitivity were estimated. Fasting glucose levels were measured in 1989–1990 and again in 1992–1993, 1994–1995, 1996–1997, and 1998–1999, and medication use was ascertained yearly. We determined the cross-sectional associations of sleep symptoms with fasting glucose levels, 2-h glucose levels, insulin sensitivity, and insulin secretion using generalized estimated equations and linear regression models. We determined the associations of updated and averaged sleep symptoms with incident diabetes in Cox proportional hazard models. We adjusted for sociodemographics, lifestyle factors, and medical history. RESULTS Observed apnea, snoring, and daytime sleepiness were associated with higher fasting glucose levels, higher 2-h glucose levels, lower insulin sensitivity, and higher insulin secretion. The risk of the development of type 2 diabetes was positively associated with observed apnea (hazard ratio [HR] 1.84 [95% CI 1.19–2.86]), snoring (HR 1.27 [95% CI 0.95–1.71]), and daytime sleepiness (HR 1.54 [95% CI 1.13–2.12]). In contrast, we did not find consistent associations between insomnia symptoms and glucose metabolism or incident type 2 diabetes. CONCLUSIONS Easily collected symptoms of SDB are strongly associated with insulin resistance and the incidence of type 2 diabetes in older adults. Monitoring glucose metabolism in such patients may prove useful in identifying candidates for lifestyle or pharmacological therapy. Further studies are needed to determine whether insomnia symptoms affect the risk of diabetes in younger adults.
    No preview · Article · Sep 2015 · Diabetes Care
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    ABSTRACT: Background: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown. Objective: We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus. Design: Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined 1) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations. Results: Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049-ln-pmol/L (95% CI: 0.035, 0.063-ln-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic loci known to influence fasting glucose or insulin resistance. Conclusion: The association of higher fasting glucose and insulin concentrations with meat consumption was not modified by an index of glucose- and insulin-related single-nucleotide polymorphisms. Six of the participating studies are registered at clinicaltrials.gov as NCT0000513 (Atherosclerosis Risk in Communities), NCT00149435 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetics of Lipid Lowering Drugs and Diet Network), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
    Full-text · Article · Sep 2015 · American Journal of Clinical Nutrition
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    ABSTRACT: Background N-terminal-pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin T (TnT) predict cardiovascular disease (CVD) risk in a variety of populations. Whether their predictive value varies by ethnicity is unknown. We sought to determine whether NT-proBNP and TnT improve prediction of incident coronary heart disease (CHD) and CVD, independent of CVD risk factors, in a multiethnic population; whether NT-proBNP improves prediction compared with the Framingham Risk Score or the Pooled Cohort Risk Equation; and whether a second NT-proBNP further improves prediction. Methods Both NT-proBNP and TnT were measured in 5,592 MESA white, black, Hispanic, and Chinese participants (60% nonwhite; mean age 62.3 ± 10.3 years) in 2000 to 2002 and 2004 to 2005. We evaluated adjusted risk of incident CHD and CVD based on baseline and change in biomarker concentration. Results Participants were followed up through 2011 and incurred 370 CVD events (232 CHD). Concentrations of NT-proBNP and TnT varied by ethnicity. Both NT-proBNP and TnT were associated with an increased risk of events (adjusted hazard ratio [HR] for CHD [95% CI] for fifth quintile vs other 4 quintiles of NT-proBNP, 2.03 [1.50-2.76]; HR for CHD for detectable vs undetectable TnT, 3.95 [2.29-6.81]). N-terminal-pro-B-type natriuretic peptide improved risk prediction and classification compared with the Framingham Risk Score and the Pooled Cohort Risk Equation. Change in NT-proBNP was independently associated with events (HR for CHD per unit increase in ΔlogNT-proBNP, 1.95 [1.16-3.26]). None of the observed associations varied by ethnicity. Conclusions Both NT-proBNP and TnT are predictors of incident CHD, independent of established risk factors and ethnicity, in a multiethnic population without known CVD. Change in NT-proBNP may add additional prognostic information.
    No preview · Article · Sep 2015
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    ABSTRACT: Older adults have a high prevalence of postload hyperglycemia. Postload glucose has shown more robust associations with cardiovascular disease (CVD) and death than fasting glucose, but data in the oldest old are sparse. Fasting and 2-hour postload glucose were measured in community-dwelling older adults, mean age 78, at the 1996-1997 follow-up visit of the Cardiovascular Health Study. We evaluated their associations with atherosclerotic CVD (ASCVD) and mortality using standard Cox regression and competing-risks analyses and assessed improvement in prediction-model discrimination with the c-statistic. Among 2,394 participants without treated diabetes and available data on glycemic measures, there were 579 ASCVD events and 1,698 deaths during median follow-up of 11.2 years. In fully adjusted models, both fasting and 2-hour glucose were associated with ASCVD (HR per SD, 1.13 [1.03-1.25] and 1.17 [1.07-1.28], respectively) and all-cause mortality (HR 1.12 [1.07-1.18] and 1.14 [1.08-1.20]). After mutual adjustment, however, the associations for fasting glucose with both outcomes were abolished, but those for postload glucose were largely unchanged. Consistent findings were observed for ASCVD in competing-risks models. In adults surviving to advanced old age, postload glucose was associated with ASCVD and mortality independently of fasting glucose, but fasting glucose was not associated with these outcomes independently of postload glucose. These findings affirm the robust association of postload glucose with ASCVD and death late in life. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    No preview · Article · Aug 2015 · The Journals of Gerontology Series A Biological Sciences and Medical Sciences
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    ABSTRACT: BACKGROUND: Tobacco smoke contains numerous agonists of the aryl-hydrocarbon receptor (AhR) pathway, and activation of the AhR pathway was shown to promote atherosclerosis in mice. Intriguingly, cigarette smoking is most strongly and robustly associated with DNA modifications to an AhR pathway gene, the aryl-hydrocarbon receptor repressor (AHRR). We hypothesized that altered AHRR methylation in monocytes, a cell type sensitive to cigarette smoking and involved in atherogenesis, may be a part of the biological link between cigarette smoking and atherosclerosis. METHODS AND RESULTS: DNA methylation profiles of AHRR in monocytes (542 CpG sites ± 150kb of AHRR, using Illumina 450K array) were integrated with smoking habits and ultrasound-measured carotid plaque scores from 1,256 participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Methylation of cg05575921 significantly associated (p = 6.1×10-134) with smoking status (current vs. never). Novel associations between cg05575921 methylation and carotid plaque scores (p = 3.1×10-10) were identified, which remained significant in current and former smokers even after adjusting for self-reported smoking habits, urinary cotinine, and well-known CVD risk factors. This association replicated in an independent cohort using hepatic DNA (n = 141). Functionally, cg05575921 was located in a predicted gene expression regulatory element (enhancer), and had methylation correlated with AHRR mRNA profiles (p = 1.4×10-17) obtained from RNA sequencing conducted on a subset (n = 373) of the samples. CONCLUSIONS: These findings suggest AHRR methylation may be functionally related to AHRR expression in monocytes, and represents a potential biomarker of subclinical atherosclerosis in smokers. http://circgenetics.ahajournals.org/content/early/2015/08/25/CIRCGENETICS.115.001097.abstract
    No preview · Article · Aug 2015 · Circulation Cardiovascular Genetics

  • No preview · Article · Aug 2015 · American journal of epidemiology

Publication Stats

44k Citations
6,627.82 Total Impact Points


  • 2015
    • Group Health Cooperative
      Seattle, Washington, United States
  • 2014-2015
    • New York Academy of Medicine
      New York, New York, United States
    • The New York Academy of Sciences
      New York, New York, United States
  • 1983-2015
    • University of Washington Seattle
      • • Department of Medicine
      • • Department of Epidemiology
      • • Cardiovascular Health Research Unit (CHRU)
      • • Department of Biostatistics
      • • Department of Health Services
      Seattle, Washington, United States
  • 2002-2014
    • Trinity Washington University
      Washington, Washington, D.C., United States
  • 2013
    • Geisel School of Medicine at Dartmouth
      • Institute for Health Policy and Clinical Practice
      Hanover, New Hampshire, United States
    • American University Washington D.C.
      Washington, Washington, D.C., United States
  • 2002-2013
    • Harvard University
      • Department of Nutrition
      Cambridge, Massachusetts, United States
  • 2012
    • McGill University
      • Department of Epidemiology, Biostatistics and Occupational Health
      Montréal, Quebec, Canada
    • Brigham and Women's Hospital
      • Division of Preventive Medicine
      Boston, MA, United States
  • 2011
    • The Ohio State University
      Columbus, Ohio, United States
  • 2007-2011
    • Columbia University
      • • Department of Medicine
      • • Institute for Social and Economic Research and Policy
      New York, New York, United States
  • 2002-2011
    • University of Alabama at Birmingham
      • Division of Preventive Medicine
      Birmingham, Alabama, United States
  • 1996-2011
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2009
    • Massachusetts General Hospital
      • Center for Human Genetic Research
      Boston, Massachusetts, United States
  • 2003-2009
    • University of Vermont
      • • College of Medicine
      • • Department of Pathology
      Burlington, Vermont, United States
    • Beth Israel Deaconess Medical Center
      • Division of General Medicine and Primary Care
      Boston, MA, United States
  • 2000-2007
    • University of Pittsburgh
      • Department of Epidemiology
      Pittsburgh, Pennsylvania, United States
  • 1992-2006
    • Johns Hopkins University
      • Department of Epidemiology
      Baltimore, Maryland, United States
    • Zoo Atlanta
      Atlanta, Georgia, United States
  • 2005
    • San Francisco VA Medical Center
      San Francisco, California, United States
    • Stanford University
      Stanford, California, United States
  • 1984-2005
    • University of North Carolina at Chapel Hill
      • • Department of Epidemiology
      • • Department of Nutrition
      • • Department of Medicine
      Chapel Hill, NC, United States
  • 1990-2001
    • Swedish Medical Center Seattle
      Seattle, Washington, United States
  • 1998
    • Kaiser Permanente
      Oakland, California, United States
  • 1997
    • Leiden University
      Leyden, South Holland, Netherlands
  • 1985
    • Centers for Disease Control and Prevention
      Атланта, Michigan, United States