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Omentin associates with serum metabolite profiles indicating lower diabetes risk: KORA F4 Study.
Ratter-Rieck, JM, Shi, M, Suhre, K, Prehn, C, Adamski, J, Rathmann, W, Thorand, B, Roden, M, Peters, A, Wang-Sattler, R, et al
BMJ open diabetes research & care. 2024;(2)
Abstract
INTRODUCTION Circulating omentin levels have been positively associated with insulin sensitivity. Although a role for adiponectin in this relationship has been suggested, underlying mechanisms remain elusive. In order to reveal the relationship between omentin and systemic metabolism, this study aimed to investigate associations of serum concentrations of omentin and metabolites. RESEARCH DESIGN AND METHODS This study is based on 1124 participants aged 61-82 years from the population-based KORA (Cooperative Health Research in the Region of Augsburg) F4 Study, for whom both serum omentin levels and metabolite concentration profiles were available. Associations were assessed with five multivariable regression models, which were stepwise adjusted for multiple potential confounders, including age, sex, body mass index, waist-to-hip ratio, lifestyle markers (physical activity, smoking behavior and alcohol consumption), serum adiponectin levels, high-density lipoprotein cholesterol, use of lipid-lowering or anti-inflammatory medication, history of myocardial infarction and stroke, homeostasis model assessment 2 of insulin resistance, diabetes status, and use of oral glucose-lowering medication and insulin. RESULTS Omentin levels significantly associated with multiple metabolites including amino acids, acylcarnitines, and lipids (eg, sphingomyelins and phosphatidylcholines (PCs)). Positive associations for several PCs, such as diacyl (PC aa C32:1) and alkyl-alkyl (PC ae C32:2), were significant in models 1-4, whereas those with hydroxytetradecenoylcarnitine (C14:1-OH) were significant in all five models. Omentin concentrations were negatively associated with several metabolite ratios, such as the valine-to-PC ae C32:2 and the serine-to-PC ae C32:2 ratios in most models. CONCLUSIONS Our results suggest that omentin may influence insulin sensitivity and diabetes risk by changing systemic lipid metabolism, but further mechanistic studies investigating effects of omentin on metabolism of insulin-sensitive tissues are needed.
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Epigenome-wide association study of dietary fatty acid intake.
Lange de Luna, J, Nounu, A, Neumeyer, S, Sinke, L, Wilson, R, Hellbach, F, Matías-García, PR, Delerue, T, Winkelmann, J, Peters, A, et al
Clinical epigenetics. 2024;(1):29
Abstract
BACKGROUND Dietary intake of n-3 polyunsaturated fatty acids (PUFA) may have a protective effect on the development of cardiovascular diseases, diabetes, depression and cancer, while a high intake of n-6 PUFA was often reported to be associated with inflammation-related traits. The effect of PUFAs on health outcomes might be mediated by DNA methylation (DNAm). The aim of our study is to identify the impact of PUFA intake on DNAm in the Cooperative Health Research in the Region of Augsburg (KORA) FF4 cohort and the Leiden Longevity Study (LLS). RESULTS DNA methylation levels were measured in whole blood from the population-based KORA FF4 study (N = 1354) and LLS (N = 448), using the Illumina MethylationEPIC BeadChip and Illumina HumanMethylation450 array, respectively. We assessed associations between DNAm and intake of eight and four PUFAs in KORA and LLS, respectively. Where possible, results were meta-analyzed. Below the Bonferroni correction threshold (p < 7.17 × 10-8), we identified two differentially methylated positions (DMPs) associated with PUFA intake in the KORA study. The DMP cg19937480, annotated to gene PRDX1, was positively associated with docosahexaenoic acid (DHA) in model 1 (beta: 2.00 × 10-5, 95%CI: 1.28 × 10-5-2.73 × 10-5, P value: 6.98 × 10-8), while cg05041783, annotated to gene MARK2, was positively associated with docosapentaenoic acid (DPA) in our fully adjusted model (beta: 9.80 × 10-5, 95%CI: 6.25 × 10-5-1.33 × 10-4, P value: 6.75 × 10-8). In the meta-analysis, we identified the CpG site (cg15951061), annotated to gene CDCA7L below Bonferroni correction (1.23 × 10-7) associated with eicosapentaenoic acid (EPA) intake in model 1 (beta: 2.00 × 10-5, 95% CI: 1.27 × 10-5-2.73 × 10-5, P value = 5.99 × 10-8) and we confirmed the association of cg19937480 with DHA in both models 1 and 2 (beta: 2.07 × 10-5, 95% CI: 1.31 × 10-5-2.83 × 10-5, P value = 1.00 × 10-7 and beta: 2.19 × 10-5, 95% CI: 1.41 × 10-5-2.97 × 10-5, P value = 5.91 × 10-8 respectively). CONCLUSIONS Our study identified three CpG sites associated with PUFA intake. The mechanisms of these sites remain largely unexplored, highlighting the novelty of our findings. Further research is essential to understand the links between CpG site methylation and PUFA outcomes.
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Global Effect of Modifiable Risk Factors on Cardiovascular Disease and Mortality.
, , Magnussen, C, Ojeda, FM, Leong, DP, Alegre-Diaz, J, Amouyel, P, Aviles-Santa, L, De Bacquer, D, Ballantyne, CM, Bernabé-Ortiz, A, et al
The New England journal of medicine. 2023;(14):1273-1285
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BACKGROUND Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking. METHODS We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality. RESULTS Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6). CONCLUSIONS Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.).
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Dietary and supplemental intake of vitamins C and E is associated with altered DNA methylation in an epigenome-wide association study meta-analysis.
Keshawarz, A, Joehanes, R, Ma, J, Lee, GY, Costeira, R, Tsai, PC, Masachs, OM, Bell, JT, Wilson, R, Thorand, B, et al
Epigenetics. 2023;(1):2211361
Abstract
BACKGROUND Dietary intake of antioxidants such as vitamins C and E protect against oxidative stress, and may also be associated with altered DNA methylation patterns. METHODS We meta-analysed epigenome-wide association study (EWAS) results from 11,866 participants across eight population-based cohorts to evaluate the association between self-reported dietary and supplemental intake of vitamins C and E with DNA methylation. EWAS were adjusted for age, sex, BMI, caloric intake, blood cell type proportion, smoking status, alcohol consumption, and technical covariates. Significant results of the meta-analysis were subsequently evaluated in gene set enrichment analysis (GSEA) and expression quantitative trait methylation (eQTM) analysis. RESULTS In meta-analysis, methylation at 4,656 CpG sites was significantly associated with vitamin C intake at FDR ≤ 0.05. The most significant CpG sites associated with vitamin C (at FDR ≤ 0.01) were enriched for pathways associated with systems development and cell signalling in GSEA, and were associated with downstream expression of genes enriched in the immune response in eQTM analysis. Furthermore, methylation at 160 CpG sites was significantly associated with vitamin E intake at FDR ≤ 0.05, but GSEA and eQTM analysis of the top most significant CpG sites associated with vitamin E did not identify significant enrichment of any biological pathways investigated. CONCLUSIONS We identified significant associations of many CpG sites with vitamin C and E intake, and our results suggest that vitamin C intake may be associated with systems development and the immune response.
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation.
Mahajan, A, Spracklen, CN, Zhang, W, Ng, MCY, Petty, LE, Kitajima, H, Yu, GZ, Rüeger, S, Speidel, L, Kim, YJ, et al
Nature genetics. 2022;(5):560-572
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We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10-9), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.
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Alcohol intake and total mortality in 142 960 individuals from the MORGAM Project: a population-based study.
Di Castelnuovo, A, Costanzo, S, Bonaccio, M, McElduff, P, Linneberg, A, Salomaa, V, Männistö, S, Moitry, M, Ferrières, J, Dallongeville, J, et al
Addiction (Abingdon, England). 2022;(2):312-325
Abstract
AIM: To test the association of alcohol consumption with total and cause-specific mortality risk. DESIGN Prospective observational multi-centre population-based study. SETTING Sixteen cohorts (15 from Europe) in the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) Project. PARTICIPANTS A total of 142 960 individuals (mean age 50 ± 13 years, 53.9% men). MEASUREMENTS Average alcohol intake by food frequency questionnaire, total and cause-specific mortality. FINDINGS In comparison with life-time abstainers, consumption of alcohol less than 10 g/day was associated with an average 11% [95% confidence interval (CI) = 7-14%] reduction in the risk of total mortality, while intake > 20 g/day was associated with a 13% (95% CI = 7-20%) increase in the risk of total mortality. Comparable findings were observed for cardiovascular (CV) deaths. With regard to cancer, drinking up to 10 g/day was not associated with either mortality risk reduction or increase, while alcohol intake > 20 g/day was associated with a 22% (95% CI = 10-35%) increased risk of mortality. The association of alcohol with fatal outcomes was similar in men and women, differed somewhat between countries and was more apparent in individuals preferring wine, suggesting that benefits may not be due to ethanol but other ingredients. Mediation analysis showed that high-density lipoprotein cholesterol explained 2.9 and 18.7% of the association between low alcohol intake and total as well as CV mortality, respectively. CONCLUSIONS In comparison with life-time abstainers, consuming less than one drink per day (nadir at 5 g/day) was associated with a reduced risk of total, cardiovascular and other causes mortality, except cancer. Intake of more than two drinks per day was associated with an increased risk of total, cardiovascular and especially cancer mortality.
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Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention.
Wang, Z, Emmerich, A, Pillon, NJ, Moore, T, Hemerich, D, Cornelis, MC, Mazzaferro, E, Broos, S, Ahluwalia, TS, Bartz, TM, et al
Nature genetics. 2022;(9):1332-1344
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Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.
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Association of Circulating Monocyte Chemoattractant Protein-1 Levels With Cardiovascular Mortality: A Meta-analysis of Population-Based Studies.
Georgakis, MK, de Lemos, JA, Ayers, C, Wang, B, Björkbacka, H, Pana, TA, Thorand, B, Sun, C, Fani, L, Malik, R, et al
JAMA cardiology. 2021;(5):587-592
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IMPORTANCE Human genetics and studies in experimental models support a key role of monocyte-chemoattractant protein-1 (MCP-1) in atherosclerosis. Yet, the associations of circulating MCP-1 levels with risk of coronary heart disease and cardiovascular death in the general population remain largely unexplored. OBJECTIVE To explore whether circulating levels of MCP-1 are associated with risk of incident coronary heart disease, myocardial infarction, and cardiovascular mortality in the general population. DATA SOURCES AND SELECTION Population-based cohort studies, identified through a systematic review, that have examined associations of circulating MCP-1 levels with cardiovascular end points. DATA EXTRACTION AND SYNTHESIS Using a prespecified harmonized analysis plan, study-specific summary data were obtained from Cox regression models after excluding individuals with overt cardiovascular disease at baseline. Derived hazard ratios (HRs) were synthesized using random-effects meta-analyses. MAIN OUTCOMES AND MEASURES Incident coronary heart disease (myocardial infarction, coronary revascularization, and unstable angina), nonfatal myocardial infarction, and cardiovascular death (from cardiac or cerebrovascular causes). RESULTS The meta-analysis included 7 cohort studies involving 21 401 individuals (mean [SD] age, 53.7 [10.2] years; 10 012 men [46.8%]). Mean (SD) follow-up was 15.3 (4.5) years (326 392 person-years at risk). In models adjusting for age, sex, and race/ethnicity, higher MCP-1 levels at baseline were associated with increased risk of coronary heart disease (HR per 1-SD increment in MCP-1 levels: 1.06 [95% CI, 1.01-1.11]; P = .01), nonfatal myocardial infarction (HR, 1.07 [95% CI, 1.01-1.13]; P = .02), and cardiovascular death (HR, 1.12 [95% CI, 1.05-1.20]; P < .001). In analyses comparing MCP-1 quartiles, these associations followed dose-response patterns. After additionally adjusting for vascular risk factors, the risk estimates were attenuated, but the associations of MCP-1 levels with cardiovascular death remained statistically significant, as did the association of MCP-1 levels in the upper quartile with coronary heart disease. There was no significant heterogeneity; the results did not change in sensitivity analyses excluding events occurring in the first 5 years after MCP-1 measurement, and the risk estimates were stable after additional adjustments for circulating levels of interleukin-6 and high-sensitivity C-reactive protein. CONCLUSIONS AND RELEVANCE Higher circulating MCP-1 levels are associated with higher long-term cardiovascular mortality in community-dwelling individuals free of overt cardiovascular disease. These findings provide further support for a key role of MCP-1-signaling in cardiovascular disease.
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Association between dietary patterns and prediabetes, undetected diabetes or clinically diagnosed diabetes: results from the KORA FF4 study.
Pestoni, G, Riedl, A, Breuninger, TA, Wawro, N, Krieger, JP, Meisinger, C, Rathmann, W, Thorand, B, Harris, C, Peters, A, et al
European journal of nutrition. 2021;(5):2331-2341
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PURPOSE Diet is one of the most important modifiable risk factors for the development of type 2 diabetes. Here, we aim to identify dietary patterns and to investigate their association with prediabetes, undetected diabetes and prevalent diabetes. METHODS The present study included 1305 participants of the cross-sectional population-based KORA FF4 study. Oral glucose tolerance test (OGTT) measurements together with a physician-confirmed diagnosis allowed for an accurate categorization of the participants according to their glucose tolerance status into normal glucose tolerance (n = 698), prediabetes (n = 459), undetected diabetes (n = 49), and prevalent diabetes (n = 99). Dietary patterns were identified through principal component analysis followed by hierarchical clustering. The association between dietary patterns and glucose tolerance status was investigated using multinomial logistic regression models. RESULTS A Prudent pattern, characterized by high consumption of vegetables, fruits, wholegrains and dairy products, and a Western pattern, characterized by high consumption of red and processed meat, alcoholic beverages, refined grains and sugar-sweetened beverages, were identified. Participants following the Western pattern had significantly higher chances of having prediabetes (odds ratio [OR] 1.92; 95% confidence interval [CI] 1.35, 2.73), undetected diabetes (OR 10.12; 95% CI 4.19, 24.43) or prevalent diabetes (OR 3.51; 95% CI 1.85, 6.67), compared to participants following the Prudent pattern. CONCLUSION To our knowledge, the present study is one of the few investigating the association between dietary patterns and prediabetes or undetected diabetes. The use of a reference group exclusively including participants with normal glucose tolerance might explain the strong associations observed in our study. These results suggest a very important role of dietary habits in the prevention of prediabetes and type 2 diabetes.
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Toward targeted prevention: risk factors for prediabetes defined by impaired fasting glucose, impaired glucose tolerance and increased HbA1c in the population-based KORA study from Germany.
Greiner, GG, Emmert-Fees, KMF, Becker, J, Rathmann, W, Thorand, B, Peters, A, Quante, AS, Schwettmann, L, Laxy, M
Acta diabetologica. 2020;(12):1481-1491
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AIMS: To identify socioeconomic, behavioral and clinical factors that are associated with prediabetes according to different prediabetes definition criteria. METHODS Analyses use pooled data of the population-based Cooperative Health Research in the Region of Augsburg (KORA) studies (n = 5312 observations aged ≥ 38 years without diabetes). Prediabetes was defined through either impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or elevated HbA1c according to thresholds of the American Diabetes Association. Explanatory variables were regressed on prediabetes using generalized estimating equations. RESULTS Mean age was 58.4 years; 50% had prediabetes (33% had IFG, 16% IGT, and 26% elevated HbA1c, 10% fulfilled all three criteria). Age, obesity, hypertension, low education, unemployment, statutory health insurance, urban residence and physical inactivity were associated with prediabetes. Male sex was a stronger risk factor for IFG (OR = 2.5; 95%-CI: 2.2-2.9) than for IGT or elevated HbA1c, and being unemployed was a stronger risk factor for IGT (OR = 3.2 95%-CI: 2.6-4.0) than for IFG or elevated HbA1c. CONCLUSIONS The overlap of people with IFG, IGT and elevated HbA1c is small, and some factors are associated with only one criterion. Knowledge on sociodemographic and socioeconomic risk factors can be used to effectively target interventions to people at high risk for type 2 diabetes.