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Background: Plasma ceramides and sphingomyelins have been independently linked to diabetes risk, glucose and insulin levels, and the risk of several cardiovascular (CVD) outcomes. However, whether individual ceramide and sphingomyelin species contribute to CVD risk among people with type 2 diabetes is uncertain. Our goal was to evaluate associations of 4 ceramide and 4 sphingomyelin species with incident CVD in a longitudinal population-based study among American Indians with diabetes. Methods: This analysis included participants with prevalent type 2 diabetes from two cohorts: a prospective cohort of 597 participants in the Strong Heart Family Study (116 incident CVD cases; mean age: 49 years; average length of follow-up: 14 years), and a nested case–control sample of 267 participants in the Strong Heart Study (78 cases of CVD and 189 controls; mean age: 61 years; average time until incident CVD in cases: 3.8 years). The average onset of diabetes was 7 years prior to sphingolipid measurement. Sphingolipid species were measured using liquid chromatography and mass spectrometry. Cox regression and logistic regression were used to assess associations of sphingolipid species with incident CVD; results were combined across cohorts using inverse-variance weighted meta-analysis. Results: There were 194 cases of incident CVD in the two cohorts. In meta-analysis of the 2 cohort results, higher plasma levels of Cer-16 (ceramide with acylated palmitic acid) were associated with higher CVD risk (HR per two-fold higher Cer-16: 1.85; 95% CI 1.05–3.25), and higher plasma levels of sphingomyelin species with a very long chain saturated fatty acid were associated with lower CVD risk (HR per two-fold higher SM-22: 0.48; 95% CI 0.26–0.87), although none of the associations met our pre-specified threshold for statistical significance of p = 0.006. Conclusions: While replication of the findings from the SHS in other populations is warranted, our findings add to a growing body of research suggesting that ceramides, in particular Cer-16, not only are associated with higher diabetes risk, but may also be associated with higher CVD risk after diabetes onset. We also find support for the hypothesis that sphingomyelins with a very long chain saturated fatty acid are associated with lower CVD risk among adults with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D). Methods and findings: Seventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970–1973 to 2006–2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3–75.5 years; % women = 20.4%–62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41–1.66; p < 0.001) for 16:0, 1.40 (1.33–1.48; p < 0.001) for 16:1n-7, 1.14 (1.05–1.22; p = 0.001) for 18:0, and 1.16 (1.07–1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%–73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94–1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors. Conclusions: Concentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D. Fumiaki Imamura and colleagues investigate the association between concentrations of fatty acid involved in de-novo lipogensis and incidence of Type 2 diabetes. Author summary: Why was this study done?: De novo lipogenesis (DNL) is a metabolic pathway involved in the endogenous synthesis of specific fatty acids, such as 16:0, 16:1n7, 18:0, and 18:1n9, and it is linked to the pathophysiology of cardiometabolic diseases, including type 2 diabetes (T2D). Circulating or tissue concentrations of these fatty acids have been investigated for the associations with T2D incidence in epidemiological research. However, published studies reported inconsistent associations inconsistently and were subject to publication bias. Summary evidence is not available to date for the associations between these fatty acids and T2D incidence. An integration of available cohort studies would increase statistical power and allow assessment of generalizability, standardization of analytical strategies, and evidence synthesis with the potential publication bias minimized. What did the researchers do and find?: As a part of the Fatty Acids and Outcomes Research Consortium (FORCE), we conducted new individual-participant data analyses of 17 cohort studies of a total of 65,225 adults free of T2D at baseline, among whom 15,383 developed incident T2D over up to 20 years of follow-up. The cohort studies analyzed the associations between fatty acids (16:0, 16:1n7, 18:0, and 18:1n9) and the risk of developing T2D with standardized analytic strategy. In pooled analyses, each of the fatty acids was positively associated with a higher risk of developing T2D. The associations were independent of major risk factors for T2D, such as age, sex, race/ethnicity, socioeconomic characteristics, smoking status, physical activity, and obesity. What do these findings mean?: The findings provide the first summary evidence to date for the positive relationships of concentrations of the DNL-related fatty acids with a risk of T2D, indicating the strong relevance of DNL and its determinants to the development of T2D. These fatty acids potentially reflect the status of DNL activity, which may be stimulated or suppressed by a combination of carbohydrate intake, alcohol intake, polyunsaturated fatty acid intake, and other lifestyle and clinical factors. Therefore, the current findings indicate the need for investigation into determinants and consequences of elevated concentrations of these fatty acids. Despite several advantages of our individual-level data analysis in this pooling project, the results cannot establish whether elevated concentrations of these fatty acids caused the development of T2D or whether underlying peripheral or hepatic insulin resistance, for example, may elevate both the fatty acid concentrations and the risk of T2D independently. [ABSTRACT FROM AUTHOR]

Background: Few studies have assessed the associations of ceramides and sphingomyelins (SMs) with diabetes in humans.Objective: We assessed associations of 15 circulating ceramides and SM species with incident diabetes in 2 studies.Methods: The analysis included 435 American-Indian participants from the Strong Heart Study (nested case-control design for analyses; mean age: 57 y; 34% male; median time until diabetes 4.3 y for cases) and 1902 participants from the Strong Heart Family Study (prospective design for analyses; mean age: 37 y; 39% male; median 12.5 y of follow-up). Sphingolipid species were measured using stored plasma samples by sequential LC and MS. Using logistic regression and parametric survival models within studies, and an inverse-variance-weighted meta-analysis across studies, we examined associations of 15 ceramides and SM species with incident diabetes.Results: There were 446 cases of incident diabetes across the studies. Higher circulating concentrations of ceramides containing stearic acid (Cer-18), arachidic acid (Cer-20), and behenic acid (Cer-22) were each associated with a higher risk of diabetes. The RRs for incident diabetes per 1 SD of each log ceramide species (μM) were 1.22 (95% CI: 1.09, 1.37) for Cer-18, 1.18 (95% CI: 1.06, 1.31) for Cer-20, and 1.20 (95% CI: 1.08, 1.32) for Cer-22. Although the magnitude of the risk estimates for the association of ceramides containing lignoceric acid (Cer-24) with diabetes was similar to those for Cer-18, Cer-20, and Cer-22 (RR = 1.13; 95% CI: 1.01, 1.26), the association was not statistically significant after correction for multiple testing (P = 0.007). Ceramides carrying palmitic acid (Cer-16), SMs, glucosyl-ceramides, or a lactosyl-ceramide were not associated with diabetes risk.Conclusions: Higher concentrations of circulating Cer-18, Cer-20, and Cer-22 were associated with a higher risk of developing diabetes in 2 studies of American-Indian adults. This trial was registered at clinicaltrials.gov as NCT00005134. [ABSTRACT FROM AUTHOR]

Background: Telomeres are repetitive nucleotide sequences (TTAGGG) and their associated proteins at the end of eukaryote chromosomes. Telomere length shortens throughout the lifespan with each cell division, and leukocyte telomere length (LTL) is often used as a biomarker of cellular aging. LTL is related to many chronic diseases, including cardiovascular disease and diabetes. However, to our knowledge, the relation between LTL and risk factors for cardiovascular disease and diabetes, such as dietary intake of processed meat and unprocessed red meat, is largely unknown.Objective: We examined the associations of processed meat intake and unprocessed red meat intake with LTL.Methods: This cross-sectional study comprised 2846 American Indians from the Strong Heart Family Study who participated in the 2001-2003 examination. Dietary factors, including past-year consumption of processed meat and unprocessed red meat, were assessed with the use of a 119-item Block Food-Frequency Questionnaire. LTL was measured with the use of quantitative polymerase chain reaction. Generalized estimating equations were used to examine the associations of intake of processed meat and unprocessed red meat with LTL.Results: Consumption of processed meat was negatively associated with LTL after adjustment for age, sex, site, education, smoking, alcohol use, physical activity, and other dietary factors. For every additional daily serving of processed meat, LTL was 0.021 units (telomeric product-to-single-copy gene ratio) shorter (β ± SE = -0.021 ± 0.008, P = 0.009). No association was observed between the intake of unprocessed red meat and LTL (β ± SE = 0.008 ± 0.011, P = 0.46).Conclusions: In the Strong Heart Family Study, consumption of processed meat, but not unprocessed red meat, was associated with shorter LTL, a potential mediator for several age-related diseases. Further studies are needed to better understand the biological mechanism by which processed meat intake influences cellular aging. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: The American Heart Association's recommendations for optimal health, summarized in Life's Simple 7, have been associated with reduced risk of cardiovascular disease (CVD)-related end points, but no studies have examined the association of these goals with incident type 2 diabetes, which is associated with high risk for CVD. The purpose of this analysis was to examine the associations of Life's Simple 7 goals with incident diabetes among American Indians, a population at high risk of cardiometabolic diseases. Research Design and Methods: Strong Heart Family Study participants without diabetes (n = 1,639) at baseline and who participated in a follow-up examination were included in the analysis. Risk scores ranging from 0 to 7 were created using physical activity, diet, BMI, smoking, blood pressure, fasting glucose, and cholesterol metrics in accordance with Life's Simple 7 goals. Diabetes was defined using 2003 American Diabetes Association criteria, including use of insulin or oral antidiabetes medication or a follow-up fasting plasma glucose level ≥126 mg/dL. Generalized estimating equations were used to examine the association of risk scores with incident diabetes. Results: During a mean 5-year follow-up (range 4-8 years), we identified 210 cases of incident type 2 diabetes. Compared with participants who achieved 0-1 goals, those who achieved 2-3 or 4+ goals had lower odds of diabetes, with odds ratios = 0.40 (95% CI 0.29-0.56) and 0.11 (95% CI 0.05-0.21), respectively. Conclusions: The adoption of as few as two or three Life's Simple 7 goals is associated with a lower risk of diabetes. [ABSTRACT FROM AUTHOR]

The authors examined the association between total physical activity (leisure-time plus occupational) and incident diabetes among 1,651 American Indians who participated in the Strong Heart Study, a longitudinal study of cardiovascular disease and its risk factors among 13 American Indian communities in 4 states (North Dakota, South Dakota, Oklahoma, and Arizona). Discrete Cox models were used to examine the association between physical activity level (in tertiles), compared with no physical activity, and incident diabetes, after adjustment for potential confounders. During 10 years of follow-up (f1989–1999), 454 incident cases of diabetes were identified. Compared with participants who reported no physical activity, those who reported any physical activity had a lower risk of diabetes: Odds ratios were 0.67 (95% confidence interval (CI): 0.46, 0.99), 0.67 (95% CI: 0.45, 0.99), and 0.67 (95% CI: 0.45, 0.99) for increasing tertile of physical activity, after adjustment for age, sex, study site, education, smoking, alcohol use, and family history of diabetes. Further adjustment for body mass index and other potential mediators attenuated the risk estimates. These data suggest that physical activity is associated with a lower risk of incident diabetes in American Indians. This study identifies physical activity as an important determinant of diabetes among American Indians and suggests the need for physical activity outreach programs that target inactive American Indians. [ABSTRACT FROM PUBLISHER]

Coronary heart disease (CHD) is one of the leading causes of mortality and morbidity in the United States. Accurate time-to-event CHD prediction models with high-dimensional DNA methylation and clinical features may assist with early prediction and intervention strategies. We developed a state-of-the-art deep learning autoencoder survival analysis model (AESurv) to effectively analyze high-dimensional blood DNA methylation features and traditional clinical risk factors by learning low-dimensional representation of participants for time-to-event CHD prediction. We demonstrated the utility of our model in two cohort studies: the Strong Heart Study cohort (SHS) , a prospective cohort studying cardiovascular disease and its risk factors among American Indians adults; the Women's Health Initiative (WHI) , a prospective cohort study including randomized clinical trials and observational study to improve postmenopausal women's health with one of the main focuses on cardiovascular disease. Our AESurv model effectively learned participant representations in low-dimensional latent space and achieved better model performance (concordance index-C index of 0.864 ± 0.009 and time-to-event mean area under the receiver operating characteristic curve-AUROC of 0.905 ± 0.009) than other survival analysis models (Cox proportional hazard, Cox proportional hazard deep neural network survival analysis, random survival forest, and gradient boosting survival analysis models) in the SHS. We further validated the AESurv model in WHI and also achieved the best model performance. The AESurv model can be used for accurate CHD prediction and assist health care professionals and patients to perform early intervention strategies. We suggest using AESurv model for future time-to-event CHD prediction based on DNA methylation features. [ABSTRACT FROM AUTHOR]

OBJECTIVE--To examine the association of objectively measured participation in low levels of physical activity with incident type 2 diabetes. RESEARCH DESIGN AND METHODS--The study population included participants free of diabetes and cardiovascular disease at baseline (n = 1,826) who participated in a follow-up examination. Generalized estimating equations were used to examine the association of steps per day with incident diabetes. RESULTS--During 5 years of follow-up, 243 incident cases of diabetes were identified. When compared with participants in the lowest quartile of steps per day (<3,500 steps), participants in the upper three quartiles of steps per day had lower odds for diabetes, consistent with a threshold effect. Contrasting the three upper quartiles with the lowest quartile, the odds ratio of diabetes was 0.71 (95% CI 0.51-0.98). CONCLUSIONS--Modest levels of physical activity are associated with a lower risk of incident diabetes, compared with lower levels of activity. [ABSTRACT FROM AUTHOR]

Background: De novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D).Methods and Findings: Seventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970-1973 to 2006-2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3-75.5 years; % women = 20.4%-62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41-1.66; p < 0.001) for 16:0, 1.40 (1.33-1.48; p < 0.001) for 16:1n-7, 1.14 (1.05-1.22; p = 0.001) for 18:0, and 1.16 (1.07-1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%-73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94-1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors.Conclusions: Concentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D. [ABSTRACT FROM AUTHOR]

OBJECTIVE We examined the association of arsenic in federally regulated community water systems (CWS) and unregulated private wells with type 2 diabetes (T2D) incidence in the Strong Heart Family Study (SHFS), a prospective study of American Indian communities, and the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective study of racially and ethnically diverse urban U.S. communities. RESEARCH DESIGN AND METHODS We evaluated 1,791 participants from SHFS and 5,777 participants from MESA who had water arsenic estimates available and were free of T2D at baseline (2001-2003 and 2000-2002, respectively). Participants were followed for incident T2D until 2010 (SHFS cohort) or 2019 (MESA cohort). We used Cox proportional hazards mixed-effects models to account for clustering by family and residential zip code, with adjustment for sex, baseline age, BMI, smoking status, and education. RESULTS T2D incidence was 24.4 cases per 1,000 person-years (mean follow-up, 5.6 years) in SHFS and 11.2 per 1,000 person-years (mean follow-up, 14.0 years) in MESA. In a meta-analysis across the SHFS and MESA cohorts, the hazard ratio (95% CI) per doubling in CWS arsenic was 1.10 (1.02, 1.18). The corresponding hazard ratio was 1.09 (0.95, 1.26) in the SHFS group and 1.10 (1.01, 1.20) in the MESA group. The corresponding hazard ratio (95% CI) for arsenic in private wells and incident T2D in SHFS was 1.05 (0.95, 1.16). We observed statistical interaction and larger magnitude hazard ratios for participants with BMI <25 kg/m² and female participants. CONCLUSIONS Low to moderate water arsenic levels (<10 µg/L) were associated with T2D incidence in the SHFS and MESA cohorts. [ABSTRACT FROM AUTHOR]

Background: Prior studies suggest that circulating fatty acids may influence the risk of atrial fibrillation (AF), but little is known about the associations of circulating saturated fatty acids (SFA) with risk of AF. SFAs of different length differ in dietary and metabolic origin, incorporation into membrane lipid species, membrane properties, and biological activities that may influence the pathophysiology of AF. Moreover, both diet and metabolic pathways are determinants of circulating SFAs. Methods: The study population included 2,899 participants from the Cardiovascular Health Study, a community-based longitudinal cohort of adults aged 65 years or older, free of prevalent coronary heart disease and AF. Cox regression was used to assess the association of all the long-chain saturated fatty acids, palmitic acid (16:0), stearic acid (18:0), arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0), with incident AF. Results: During 29,864 person-years of follow-up, 707 cases of incident AF occurred. After adjustment for other AF risk factors, higher levels of circulating 16:0 were associated with a higher risk of AF (hazard ratio comparing highest to lowest quartiles: 1.48. 95% CI: 1.18, 1.86). On the other hand, higher levels of circulating 18:0, 20:0, 22:0 and 24:0 were each associated with a lower risk of AF. The hazard ratios (95% CI) for AF in the top versus bottom quartile were 0.76 (0.61, 0.95) for 18:0; 0.78 (0.63, 0.97) for 20:0; 0.62 (0.50, 0.78) for 22:0; and 0.68 (0.55, 0.85) for 24:0. Conclusions: Results from this prospective cohort study of older adults demonstrate divergent associations of circulating 16:0 versus longer-chain saturated fatty acids with incident AF, highlighting the need to investigate both determinants of these levels and potential pathways of the observed differential risk. [ABSTRACT FROM AUTHOR]

Coronary heart disease has several risk factors that require a multifactorial community intervention approach in prevention efforts. Prevalence of coronary heart disease and its risk factors have been disproportionately high among American Indians. The objective of this study is to evaluate the impact of ambulatory activity levels on the development of coronary heart disease in this population. Using pedometer data and other lifestyle and clinical factors from 2492 participants in the Strong Heart Family Study, we examined the associations of average daily step counts with incident coronary heart disease during an 18 to 20 year follow-up. After adjusting for potential confounders, participants with daily step counts in the 4th quartile (>7282 steps per day) had significantly lower odds of developing coronary heart disease compared to those in the 1st quartile (<3010 steps per day) (p = 0.035). Higher daily step count (over 7282 steps per day) is significantly associated with lower incidence of coronary heart disease among American Indian participants of the Strong Heart Family Study in a 20-year follow-up period. • High daily step counts lower risk of coronary heart disease among American Indians. • Ambulatory activity levels reflect trend in coronary heart disease prevention. • Results show public health implications in population with prevalent risk factors. [ABSTRACT FROM AUTHOR]

Objectives: To examine the associations of dietary Mg intake with inflammatory biomarkers (C-reactive protein (CRP) and interleukin 6 (IL-6)), and the interaction of dietary Mg intake with single nucleotide polymorphism (SNP) rs3740393, a SNP related to Mg metabolism and transport, on CRP and IL-6 among American Indians (AIs). Methods: This cross-sectional study included AI participants (n = 1,924) from the Strong Heart Family Study (SHFS). Mg intake from foods and dietary supplements was ascertained using a 119-item Block food frequency questionnaire, CRP and IL-6 were measured from blood, and SNP rs3740393 was genotyped using MetaboChip. Generalized estimating equations were used to examine associations of Mg intake, and the interaction between rs3740393 and dietary Mg, with CRP and IL-6. Results: Reported Mg intake was not associated with CRP or IL-6, irrespective of genotype. A significant interaction (p-interaction = 0.018) was observed between Mg intake and rs3740393 on IL-6. Among participants with the C/C genotype, for every 1 SD higher in log-Mg, log-IL-6 was 0.04 (95% CI: -0.10 to 0.17) pg/mL higher. Among participants with the C/G genotype, for every 1 SD higher in log-Mg, log-IL-6 was 0.08 (95% CI: -0.21 to 0.05) pg/mL lower, and among participants with the G/G genotype, for every 1 SD higher in log-Mg, log-IL-6 was 0.19 (95% CI: -0.38 to -0.01) pg/mL lower. Conclusions: Mg intake may be associated with lower IL-6 with increasing dosage of the G allele at rs3740393. Future research is necessary to replicate this finding and examine other Mg-related genes that influence associations of Mg intake with inflammation. [ABSTRACT FROM AUTHOR]

Multiple randomized controlled trials (RCTs) have assessed the effects of supplementation with eicosapentaenoic acid plus docosahexaenoic acid (omega-3 polyunsaturated fatty acids, commonly called fish oils) on the occurrence of clinical cardiovascular diseases. Although the effects of supplementation for the primary prevention of clinical cardiovascular events in the general population have not been examined, RCTs have assessed the role of supplementation in secondary prevention among patients with diabetes mellitus and prediabetes, patients at high risk of cardiovascular disease, and those with prevalent coronary heart disease. In this scientific advisory, we take a clinical approach and focus on common indications for omega-3 polyunsaturated fatty acid supplements related to the prevention of clinical cardiovascular events. We limited the scope of our review to large RCTs of supplementation with major clinical cardiovascular disease end points; meta-analyses were considered secondarily. We discuss the features of available RCTs and provide the rationale for our recommendations. We then use existing American Heart Association criteria to assess the strength of the recommendation and the level of evidence. On the basis of our review of the cumulative evidence from RCTs designed to assess the effect of omega-3 polyunsaturated fatty acid supplementation on clinical cardiovascular events, we update prior recommendations for patients with prevalent coronary heart disease, and we offer recommendations, when data are available, for patients with other clinical indications, including patients with diabetes mellitus and prediabetes and those with high risk of cardiovascular disease, stroke, heart failure, and atrial fibrillation. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is the leading cause of death in women, yet differences exist among certain racial and ethnic groups. Aside from traditional risk factors, behavioral and environmental factors and social determinants of health affect cardiovascular health and risk in women. Language barriers, discrimination, acculturation, and health care access disproportionately affect women of underrepresented races and ethnicities. These factors result in a higher prevalence of cardiovascular disease and significant challenges in the diagnosis and treatment of cardiovascular conditions. Culturally sensitive, peer-led community and health care professional education is a necessary step in the prevention of cardiovascular disease. Equitable access to evidence-based cardiovascular preventive health care should be available for all women regardless of race and ethnicity; however, these guidelines are not equally incorporated into clinical practice. This scientific statement reviews the current evidence on racial and ethnic differences in cardiovascular risk factors and current cardiovascular preventive therapies for women in the United States. [ABSTRACT FROM AUTHOR]

Background: The prevalence of type 2 diabetes has dramatically increased in the past years. Increasing evidence supports that blood DNA methylation, the best studied epigenetic mark, is related to diabetes risk. Few prospective studies, however, are available. We studied the association of blood DNA methylation with diabetes in the Strong Heart Study. We used limma, Iterative Sure Independence Screening and Cox regression to study the association of blood DNA methylation with fasting glucose, HOMA-IR and incident type 2 diabetes among 1312 American Indians from the Strong Heart Study. DNA methylation was measured using Illumina's MethylationEPIC beadchip. We also assessed the biological relevance of our findings using bioinformatics analyses. Results: Among the 358 differentially methylated positions (DMPs) that were cross-sectionally associated either with fasting glucose or HOMA-IR, 49 were prospectively associated with incident type 2 diabetes, although no DMPs remained significant after multiple comparisons correction. Multiple of the top DMPs were annotated to genes with relevant functions for diabetes including SREBF1, associated with obesity, type 2 diabetes and insulin sensitivity; ABCG1, involved in cholesterol and phospholipids transport; and HDAC1, of the HDAC family. (HDAC inhibitors have been proposed as an emerging treatment for diabetes and its complications.) Conclusions: Our results suggest that differences in peripheral blood DNA methylation are related to cross-sectional markers of glucose metabolism and insulin activity. While some of these DMPs were modestly associated with prospective incident type 2 diabetes, they did not survive multiple testing. Common DMPs with diabetes epigenome-wide association studies from other populations suggest a partially common epigenomic signature of glucose and insulin activity. [ABSTRACT FROM AUTHOR]

Diet quality has been shown to be inversely associated with depression, but this has not been studied in American Indians (AIs). We examined the prospective association of diet quality and probable depression in a family-based cohort of rural AIs. Using data from the Strong Heart Family Study, we included 1,100 AIs ≥14 years old who were free of probable depression at baseline. We defined probable depression as the presence of moderate or severe depressive symptoms on the Center for Epidemiologic Studies Depression Scale or current use of antidepressant medications. We calculated baseline diet quality from food frequency questionnaires using the Alternative Healthy Eating Index-2010 (AHEI). We used GEE-based multivariate logistic regression to estimate the odds ratio of probable depression at follow up associated with a 10-point higher AHEI score at baseline, adjusted for demographic, psychosocial, and health factors. At follow up, 19% (n = 207) of the sample reported probable depression. Diet quality was not associated with report of probable depression at follow up (OR = 1.16, 95% CI [0.96, 1.39]). Research is needed to examine other temporal dimensions of this relationship and unique aspects of rural AI diets and psychosocial factors that may influence depression. [ABSTRACT FROM AUTHOR]

[Display omitted] • Urinary selenium levels were associated with changes in DNA methylation. • Elastic net models selected 425 differentially methylated positions (DMPs) • The top associated site cg00163554 was annotated to the DIP2C. • The biological implications of these DMPs relative to disease must be further studied. Selenium (Se) is an essential nutrient linked to adverse health endpoints at low and high levels. The mechanisms behind these relationships remain unclear and there is a need to further understand the epigenetic impacts of Se and their relationship to disease. We investigated the association between urinary Se levels and DNA methylation (DNAm) in the Strong Heart Study (SHS), a prospective study of cardiovascular disease (CVD) among American Indians adults. Selenium concentrations were measured in urine (collected in 1989–1991) using inductively coupled plasma mass spectrometry among 1,357 participants free of CVD and diabetes. DNAm in whole blood was measured cross-sectionally using the Illumina MethylationEPIC BeadChip (850 K) Array. We used epigenome-wide robust linear regressions and elastic net to identify differentially methylated cytosine-guanine dinucleotide (CpG) sites associated with urinary Se levels. The mean (standard deviation) urinary Se concentration was 51.8 (25.1) μg/g creatinine. Across 788,368 CpG sites, five differentially methylated positions (DMP) (hypermethylated: cg00163554, cg18212762, cg11270656, and hypomethylated: cg25194720, cg00886293) were significantly associated with Se in linear regressions after accounting for multiple comparisons (false discovery rate p-value: 0.10). The top hypermethylated DMP (cg00163554) was annotated to the Disco Interacting Protein 2 Homolog C (DIP2C) gene, which relates to transcription factor binding. Elastic net models selected 425 hypo- and hyper-methylated DMPs associated with urinary Se, including three sites (cg00163554 [DIP2C], cg18212762 [ MAP4K2 ], cg11270656 [ GPIHBP1 ]) identified in linear regressions. Urinary Se was associated with minimal changes in DNAm in adults from American Indian communities across the Southwest and the Great Plains in the United States, suggesting that other mechanisms may be driving health impacts. Future analyses should explore other mechanistic biomarkers in human populations, determine these relationships prospectively, and investigate the potential role of differentially methylated sites with disease endpoints. [ABSTRACT FROM AUTHOR]

To evaluate the association of nonesterified fatty acids (NEFA) with dysglycemia in older adults, NEFA levels were measured among participants in the Cardiovascular Health Study (United States; enrolled 1989–1993). Associations with insulin sensitivity and pancreatic β-cell function, and with incident type 2 diabetes mellitus (DM), were examined. The sample comprised 2,144 participants (aged 77.9 (standard deviation, 4.5) years). Participant data from the Cardiovascular Health Study visit in 1996–1997 was used with prospective follow-up through 2010. Fasting and postload NEFA showed significant associations with lower insulin sensitivity and pancreatic β-cell function, individually and on concurrent adjustment. Over median follow-up of 9.7 years, 236 cases of DM occurred. Postload NEFA were associated with risk of DM (per standard deviation, hazard ratio = 1.18, 95% confidence interval: 1.08, 1.29), but fasting NEFA were not (hazard ratio = 1.12, 95% confidence interval: 0.97, 1.29). The association for postload NEFA persisted after adjustment for putative intermediates, and after adjustment for fasting NEFA. Sex and body mass index modified these associations, which were stronger for fasting NEFA with DM in men but were accentuated for postload NEFA in women and among leaner individuals. Fasting and postload NEFA were related to lower insulin sensitivity and pancreatic β-cell function, but only postload NEFA were associated with increased DM. Additional study into NEFA metabolism could uncover novel potential targets for diabetes prevention in elders. [ABSTRACT FROM AUTHOR]

Objective: Comprehensive assessment of alterations in lipid species preceding type 2 diabetes (T2D) is largely unknown. We aimed to identify plasma molecular lipids associated with risk of T2D in American Indians.Research Design and Methods: Using untargeted liquid chromatography-mass spectrometry, we repeatedly measured 3,907 fasting plasma samples from 1,958 participants who attended two examinations (∼5.5 years apart) and were followed up to 16 years in the Strong Heart Family Study. Mixed-effects logistic regression was used to identify lipids associated with risk of T2D, adjusting for traditional risk factors. Repeated measurement analysis was performed to examine the association between change in lipidome and change in continuous measures of T2D, adjusting for baseline lipids. Multiple testing was controlled by false discovery rate at 0.05.Results: Higher baseline level of 33 lipid species, including triacylglycerols, diacylglycerols, phosphoethanolamines, and phosphocholines, was significantly associated with increased risk of T2D (odds ratio [OR] per SD increase in log2-transformed baseline lipids 1.50-2.85) at 5-year follow-up. Of these, 21 lipids were also associated with risk of T2D at 16-year follow-up. Aberrant lipid profiles were also observed in prediabetes (OR per SD increase in log2-transformed baseline lipids 1.30-2.19 for risk lipids and 0.70-0.78 for protective lipids). Longitudinal changes in 568 lipids were significantly associated with changes in continuous measures of T2D. Multivariate analysis identified distinct lipidomic signatures differentiating high- from low-risk groups.Conclusions: Lipid dysregulation occurs many years preceding T2D, and novel molecular lipids (both baseline level and longitudinal change over time) are significantly associated with risk of T2D beyond traditional risk factors. Our findings shed light on the mechanisms linking dyslipidemia to T2D and may yield novel therapeutic targets for early intervention tailored to American Indians. [ABSTRACT FROM AUTHOR]

Long chain polyunsaturated fatty acids (LC-PUFAs) have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS gene cluster accounts for a large portion of interindividual differences in circulating and tissue levels of LC-PUFAs, with the genotypes most strongly predictive of low LC-PUFA levels at strikingly higher frequencies in Amerind ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation in 1102 Hispanic American participants from the Multi-Ethnic Study of Atherosclerosis. We demonstrate strong negative associations between Amerind genetic ancestry and LC-PUFA levels. The FADS rs174537 single nucleotide polymorphism (SNP) accounted for much of the AI ancestry effect on LC-PUFAs, especially for low levels of n-3 LC-PUFAs. Rs174537 was also strongly associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides (TGs) and E-selectin in MESA Hispanics. Our study demonstrates that Amerind ancestry provides a useful and readily available tool to identify individuals most likely to have FADS-related n-3 LC-PUFA deficiencies and associated cardiovascular risk. Yang et al. examine whether genetic ancestry is associated with genetic variation in fatty acid desaturases and plasma phospholipid levels of long chain polyunsaturated fatty acids (LC-PUFAs) in Hispanic Americans. They find strong associations between Amerind genetic ancestry and LC-PUFA levels; and report that the well-known FADS rs174537 variant was associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides. [ABSTRACT FROM AUTHOR]

Arsenic has been associated with hypertension, though it is unclear whether associations persist at the exposure concentrations (e.g. <100 μg/L) in drinking water occurring in parts of the Western United States. We assessed associations between arsenic biomarkers and systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension in the Strong Heart Family Study, a family-based cohort of American Indians from the Northern plains, Southern plains, and Southwest. We included 1910 participants from three study centers with complete baseline visit data (2001–2003) in the cross-sectional analysis of all three outcomes, and 1453 participants in the prospective analysis of incident hypertension (follow-up 2006–2009). We used generalized estimating equations with exchangeable correlation structure conditional on family membership to estimate the association of arsenic exposure biomarker levels with SBP or DBP (linear regressions) or hypertension prevalence and incidence (Poisson regressions), adjusting for urine creatinine, urine arsenobetaine, and measured confounders. We observed cross-sectional associations for a two-fold increase in inorganic and methylated urine arsenic species of 0.64 (95% CI: 0.07, 1.35) mm Hg for SBP, 0.49 (95% CI: 0.03, 1.02) mm Hg for DBP, and a prevalence ratio of 1.10 (95% CI: 1.01, 1.21) for hypertension in fully adjusted models. During follow-up, 14% of subjects developed hypertension. We observed non-monotonic relationships between quartiles of arsenic and incident hypertension. Effect estimates were null for incident hypertension with continuous exposure metrics. Stratification by study site revealed elevated associations in Arizona, the site with the highest arsenic levels, while results for Oklahoma and North and South Dakota were largely null. Blood pressure changes with increasing arsenic concentrations were larger for those with diabetes at baseline. Our results suggest a modest cross-sectional association of arsenic exposure biomarkers with blood pressure, and possible non-linear effects on incident hypertension. • Arsenic was positively associated with prevalent hypertension and blood pressure. • Associations were strongest in the study site with the highest exposure levels. • Blood pressure associations were stronger for participants with baseline diabetes. • Arsenic and incident hypertension had a non-monotonic relationship. [ABSTRACT FROM AUTHOR]

Background: The prevalence of poor diet quality and type 2 diabetes are exceedingly high in many rural American Indian (AI) communities. Because of limited resources and infrastructure in some communities, implementation of interventions to promote a healthy diet is challenging-which may exacerbate health disparities by region (urban/rural) and ethnicity (AIs/other populations). It is critical to adapt existing evidence-based healthy food budgeting, purchasing, and cooking programs to be relevant to underserved populations with a high burden of diabetes and related complications. The Cooking for Health Study will work in partnership with an AI community in South Dakota to develop a culturally-adapted 12-month distance-learning-based healthy food budgeting, purchasing, and cooking intervention to improve diet among AI adults with type 2 diabetes.Methods: The study will enroll 165 AIs with physician-diagnosed type 2 diabetes who reside on the reservation. Participants will be randomized to an intervention or control arm. The intervention arm will receive a 12-month distance-learning curriculum adapted from Cooking Matters® that focuses on healthy food budgeting, purchasing, and cooking skills. In-person assessments at baseline, month 6 and month 12 will include completion of the Nutrition Assessment Shared Resources Food Frequency Questionnaire and a survey to assess frequency of healthy and unhealthy food purchases. Primary outcomes of interest are: (1) change in self-reported intake of sugar-sweetened beverages (SSBs); and (2) change in the frequency of healthy and unhealthy food purchases. Secondary outcomes include: (1) change in self-reported food budgeting skills; (2) change in self-reported cooking skills; and (3) a mixed-methods process evaluation to assess intervention reach, fidelity, satisfaction, and dose delivered/received.Discussion: Targeted and sustainable interventions are needed to promote optimal health in rural AI communities. If effective, this intervention will reduce intake of SSBs and the purchase of unhealthy foods; increase the purchase of healthy foods; and improve healthy food budgeting and cooking skills among AIs with type 2 diabetes - a population at high risk of poor health outcomes. This work will help inform future health promotion efforts in resource-limited settings.Trial Registration: This study was registered on ClinicalTrials.gov on October 9, 2018 with Identifier NCT03699709 . [ABSTRACT FROM AUTHOR]

Objective: Perceptions of social-contextual food environments and associated factors that influence food purchases are understudied in American Indian (AI) communities. The purpose of the present study was to: (i) understand the perceived local food environment; (ii) investigate social-contextual factors that influence family food-purchasing choices; and (iii) identify diet intervention strategies.Design: This qualitative study consisted of focus groups with primary household shoppers and key-informant interviews with food retailers, local government food assistance programme directors and a dietitian. An inductive, constant comparison approach was used to identify major themes.Setting: A large AI reservation community in the north-central USA.Participants: Four focus groups (n 31) and seven key-informant interviews were conducted in February and May 2016.Results: Perceptions of both the higher cost of healthy foods and limited access to these foods influenced the types of foods participants purchased. Dependence on government assistance programmes and the timing of benefits also contributed to the types of foods purchased. Participants described purchasing foods based on the dietary needs and preferences of their children. Suggestions for improving the purchase and consumption of healthy foods included: culturally relevant and family-centred cooking classes and workshops focused on monthly food budgeting. Participants also emphasized the importance of involving the entire community in healthy eating initiatives.Conclusions: Cost and access were the major perceived barriers to healthy eating in this large rural AI community. Recommended interventions included: (i) family-friendly and culturally relevant cooking classes; (ii) healthy food-budgeting skills training; and (iii) approaches that engage the entire community. [ABSTRACT FROM AUTHOR]

Background: Diet plays a key role in development of diabetes, and there has been recent interest in better understanding the association of dairy food intake with diabetes.Objective: This study examined the associations of full-fat and low-fat dairy food intake with incident diabetes among American Indians-a population with a high burden of diabetes.Methods: The study included participants from the Strong Heart Family Study (SHFS), a family-based study of cardiovascular disease in American Indians, free of diabetes at baseline (2001-2003) (n = 1623). Participants were 14-86-y-old at baseline and 60.8% were female. Dairy food intake was assessed using a Block food frequency questionnaire. Incident diabetes was defined using American Diabetes Association criteria. Parametric survival models with a Weibull distribution were used to evaluate the associations of full-fat and low-fat dairy food intake with incident diabetes. Serving sizes were defined as 250 mL for milk and 42.5 g for cheese.Results: We identified 277 cases of diabetes during a mean follow-up of 11 y. Reported intake of dairy foods was low [median full-fat dairy food intake: 0.11 serving/1000 kcal; median low-fat dairy food intake: 0.03 serving/1000 kcal]. Participants who reported the highest full-fat dairy food intake had a lower risk of diabetes compared to those who reported the lowest full-fat food dairy intake [HR (95% CI): 0.79 (0.59, 1.06); P-trend = 0.03, comparing extreme tertiles, after adjustment for age, sex, site, physical activity, education, smoking, diet quality, and low-fat dairy food intake]. Low-fat dairy food intake was not associated with diabetes.Conclusions: American Indians who participated in the SHFS reported low dairy food intake. Participants who reported higher full-fat dairy food intake had a lower risk of diabetes than participants who reported lower intake. These findings may be of interest to populations with low dairy food intake. [ABSTRACT FROM AUTHOR]

Experimental studies suggest ceramides may play a role in insulin resistance. However, the relationships of circulating ceramides and related sphingolipids with plasma insulin have been underexplored in humans. We measured 15 ceramide and sphingomyelin species in fasting baseline samples from the Strong Heart Family Study (SHFS), a prospective cohort of American Indians. We examined sphingolipid associations with both baseline and follow-up measures of plasma insulin, HOMA of insulin resistance (HOMA-IR), and HOMA of β-cell function (HOMA-B) after adjustment for risk factors. Among the 2,086 participants without diabetes, higher levels of plasma ceramides carrying the fatty acids 16:0 (16 carbons, 0 double bond), 18:0, 20:0, or 22:0 were associated with higher plasma insulin and higher HOMA-IR at baseline and at follow-up an average of 5.4 years later. For example, a twofold higher baseline concentration of ceramide 16:0 was associated with 14% higher baseline insulin (P < 0.0001). Associations between sphingomyelin species carrying 18:0, 20:0, 22:0, or 24:0 and insulin were modified by BMI (P < 0.003): higher levels were associated with lower fasting insulin, HOMA-IR, and HOMA-B among those with normal BMI. Our study suggests lowering circulating ceramides might be a target in prediabetes and targeting circulating sphingomyelins should take into account BMI. [ABSTRACT FROM AUTHOR]

Reports on the associations between multiple clinical and behavioral health indicators and major health outcomes among older adults are scarce. We prospectively examined concordance with guidelines from the American Cancer Society and American Heart Association for disease prevention in relation to cancer, cardiovascular disease (CVD), and mortality among Cardiovascular Health Study enrollees aged 65-98 years who, at baseline assessment in 1989-1996 (n = 3,491), were free of CVD and cancer. Total and cause-specific mortality, as well as incidence of cancer and CVD, were lower with higher guideline concordance. Independent of body mass index, blood pressure, total cholesterol, and fasting plasma glucose, better health behaviors (diet, physical activity, and alcohol consumption) were associated with lower mortality (2-sided P < 0.0001). Among individuals with ideal levels for 3-4 of these 4 cardiometabolic biomarkers, those with poor concordance with health behavior recommendations had higher mortality compared with those who had the highest concordance with these behavioral recommendations (adjusted mortality hazard ratio = 1.82,95% confidence interval: 1.25,2.67). Older adults who are concordant with recommendations for cancer and CVD prevention have reduced rates of chronic disease and mortality. Interventions to achieve and maintain healthy lifestyle behaviors may offer benefits both in the presence and absence of adverse traditional clinical risk factors. [ABSTRACT FROM AUTHOR]

Objective: To examine the association of objectively measured participation in low levels of physical activity with incident type 2 diabetes.Research Design and Methods: The study population included participants free of diabetes and cardiovascular disease at baseline (n = 1,826) who participated in a follow-up examination. Generalized estimating equations were used to examine the association of steps per day with incident diabetes.Results: During 5 years of follow-up, 243 incident cases of diabetes were identified. When compared with participants in the lowest quartile of steps per day (<3,500 steps), participants in the upper three quartiles of steps per day had lower odds for diabetes, consistent with a threshold effect. Contrasting the three upper quartiles with the lowest quartile, the odds ratio of diabetes was 0.71 (95% CI 0.51-0.98).Conclusions: Modest levels of physical activity are associated with a lower risk of incident diabetes, compared with lower levels of activity. [ABSTRACT FROM AUTHOR]

Chronic exposure to inorganic arsenic (iAs) in the US occurs mainly through drinking water and diet. Although American Indian (AI) populations have elevated urinary arsenic concentrations compared to the general US population, dietary sources of arsenic exposure in AI populations are not well characterized. We evaluated food frequency questionnaires to determine the major dietary sources of urinary arsenic concentrations (measured as the sum of arsenite, arsenate, monomethylarsonate, and dimethylarsinate, ΣAs) for 1727 AI participants in the Strong Heart Family Study (SHFS). We compared geometric mean ratios (GMRs) of urinary ΣAs for an interquartile range (IQR) increase in reported food group consumption. Exploratory analyses were stratified by gender and study center. In fully adjusted generalized estimating equation models, the percent increase (95% confidence interval) of urinary ΣAs per increase in reported food consumption corresponding to the IQR was 13% (5%, 21%) for organ meat, 8% (4%, 13%) for rice, 7% (2%, 13%) for processed meat, and 4% (1%, 7%) for non-alcoholic drinks. In analyses stratified by study center, the association with organ meat was only observed in North/South Dakota. Consumption of red meat [percent increase −7% (−11%, −3%)] and fries and chips [-6% (−10%, −2%)] was inversely associated with urinary ΣAs. Organ meat, processed meat, rice, and non-alcoholic drinks contribute to ΣAs exposure in the SHFS population. Organ meat is a unique source of ΣAs exposure for North and South Dakota participants and may reflect local food consumption. Further studies should comprehensively evaluate drinking water arsenic in SHFS communities and determine the relative contribution of diet and drinking water to total arsenic exposure. • We evaluated self-reported food intake and urinary arsenic concentrations in a cohort of American Indian participants. • Self-reported consumption of organ meat, processed meat, rice, and non-alcoholic drinks were associated with urinary arsenic exposure. • Organ meat is a unique source of arsenic exposure for North and South Dakota participants. [ABSTRACT FROM AUTHOR]

Epoxyeicosatrienoic Acids (EETs) are cytochrome P450 derivatives of arachidonic acid that have multiple biological activities, including anti-inflammatory, vasodilatory and platelet anti-aggregation. Additionally, manipulation of EET levels in animal studies suggests a protective role in diabetes. Whether EET levels are related to risk of diabetes and cardiovascular complications of diabetes in humans is largely unknown. We measured 4 species of EET in fasting plasma samples from the Cardiovascular Health Study, a cohort of older adults. Using Cox regression models, we examined the associations of baseline EET levels with 1) risk of incident diabetes and 2) risk of incident myocardial infarction and stroke among participants with diabetes. Among 3222 participants without diabetes, increased levels of each plasma EET were associated with greater risk of diabetes (Table). Among participants with diabetes, increased EETs levels were associated with reduced risk of myocardial infarction but increased risk of stroke (Table). The study findings suggest that circulating EETs are not protective of diabetes in humans, and higher levels in the context of diabetes, may have mixed consequences on cardiovascular complications. Disclosure: R.N. Lemaitre: None. P.N. Jensen: None. M.B. Zeigler: None. A.M. Fretts: None. C. Sitlani: None. I.B. King: None. N. Sotoodehnia: None. B. McKnight: None. R.A. Totah: None. Funding: National Institutes of Health [ABSTRACT FROM AUTHOR]