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Pooled analysis of epigenome-wide association studies of food consumption in KORA, TwinsUK and LLS.
Hellbach, F, Sinke, L, Costeira, R, Baumeister, SE, Beekman, M, Louca, P, Leeming, ER, Mompeo, O, Berry, S, Wilson, R, et al
European journal of nutrition. 2023;(3):1357-1375
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Abstract
PURPOSE Examining epigenetic patterns is a crucial step in identifying molecular changes of disease pathophysiology, with DNA methylation as the most accessible epigenetic measure. Diet is suggested to affect metabolism and health via epigenetic modifications. Thus, our aim was to explore the association between food consumption and DNA methylation. METHODS Epigenome-wide association studies were conducted in three cohorts: KORA FF4, TwinsUK, and Leiden Longevity Study, and 37 dietary exposures were evaluated. Food group definition was harmonized across the three cohorts. DNA methylation was measured using Infinium MethylationEPIC BeadChip in KORA and Infinium HumanMethylation450 BeadChip in the Leiden study and the TwinsUK study. Overall, data from 2293 middle-aged men and women were included. A fixed-effects meta-analysis pooled study-specific estimates. The significance threshold was set at 0.05 for false-discovery rate-adjusted p values per food group. RESULTS We identified significant associations between the methylation level of CpG sites and the consumption of onions and garlic (2), nuts and seeds (18), milk (1), cream (11), plant oils (4), butter (13), and alcoholic beverages (27). The signals targeted genes of metabolic health relevance, for example, GLI1, RPTOR, and DIO1, among others. CONCLUSION This EWAS is unique with its focus on food groups that are part of a Western diet. Significant findings were mostly related to food groups with a high-fat content.
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Causal effects of time-varying body size on selected autoimmune disorders: a life course Mendelian randomisation study.
Freuer, D, Meisinger, C
RMD open. 2023;(4)
Abstract
BACKGROUND Based on Barker's hypothesis, some studies investigated the associations between birth weight and several disorders. Apart from issues with statistical power and well-known shortcomings of the observational study design, there are no studies accounting for changes in weight-related body size over the life course regarding rheumatoid arthritis, psoriasis, psoriatic arthritis and multiple sclerosis. METHODS Using genetic information of up to 806 834 participants, this study investigated the associations between time-varying weight-related body size from birth to adulthood and the mentioned autoimmune diseases. Performing Mendelian randomisation (MR), the radial inverse-variance weighted approach was used iteratively in primary analyses. Robustness of the results was confirmed in several sensitivity analyses. Potential time-dependent mediation mechanisms were identified through network-clustering and assessed using multivariable MR. RESULTS Genetically predicted birth weight (fetal effect) was positively associated with rheumatoid arthritis (OR 1.44; 95% CI 1.17 to 1.77; Padj =0.005) but not with psoriasis, psoriatic arthritis or multiple sclerosis. This association was found to be mediated by body mass index (BMI) in adulthood (OR 1.45; 95% CI 1.14 to 1.84; Padj =0.019) rather than childhood. The direct effect of birth weight attenuated (OR 1.19; 95% CI 0.88 to 1.62); Padj =1) after adjustment for time-varying BMI. CONCLUSION Increased birth weight appears to be a risk factor for later manifestation of rheumatoid arthritis due to both fetal genetic components and high BMI persisting into adulthood. Approaches to prevent and minimise the risk of rheumatoid arthritis could include preventing obesity in adults with high birth weight.
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Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies.
Gorski, M, Rasheed, H, Teumer, A, Thomas, LF, Graham, SE, Sveinbjornsson, G, Winkler, TW, Günther, F, Stark, KJ, Chai, JF, et al
Kidney international. 2022;(3):624-639
Abstract
Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genome-wide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR-baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant-by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with age-dependency of genetic cross-section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in-silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03-1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
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Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses.
Gaziano, L, Sun, L, Arnold, M, Bell, S, Cho, K, Kaptoge, SK, Song, RJ, Burgess, S, Posner, DC, Mosconi, K, et al
Circulation. 2022;(20):1507-1517
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Abstract
BACKGROUND End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. METHODS Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. RESULTS There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. CONCLUSIONS In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.
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Sedentary behavior and kidney function in adults: a narrative review.
Volaklis, K, Mamadjanov, T, Meisinger, C
Wiener klinische Wochenschrift. 2021;(3-4):144-152
Abstract
There is increasing evidence for an association between SB and CKD, an emerging public health problem particularly affecting old people. For this reason a systematic literature search was carried out in Embase and PubMed (Jan 2000-Dec 2018) looking for an association between SB and kidney function. A total of 10 studies met the inclusion criteria (7 cross-sectional and 3 longitudinal investigations). A sedentary lifestyle was positively and independently of several confounders related to an impaired kidney function (chronic kidney disease or decrease of glomerular filtration rate), particularly in cross-sectional studies; however, more studies are needed to further establish the current evidence and to explore the exact independent mechanisms of sedentary behavior in relation to kidney function. Due to the inconsistency of the few longitudinal studies, future investigations are required to explore if SB is prospectively associated with a higher risk of developing CKD.
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Low serum calcium is associated with higher long-term mortality in myocardial infarction patients from a population-based registry.
Schmitz, T, Thilo, C, Linseisen, J, Heier, M, Peters, A, Kuch, B, Meisinger, C
Scientific reports. 2021;(1):2476
Abstract
Calcium plays an essential role in physiology of the cardiovascular system. Aberrations from normal serum calcium levels are known to be associated with several cardiovascular diseases. Its possible role as a predictor for long-term mortality after acute myocardial infarction (AMI) is still uncertain. In this study, a total of 3732 patients (aged 25-74 years) with incident AMI surviving at least 28 days after AMI was included. The median follow-up time was 6.0 years. Admission total serum calcium levels were divided into quartiles. The Kaplan-Meier-Curve suggested a division of the follow up time in two different time periods. So, Cox regression models were calculated to assess association between admission serum calcium levels and all-cause long-term mortality with two observation periods: 28-2500 days and > 2500 days. The final model was adjusted for various comorbidities, clinical characteristics, in-hospital treatment and medication. The third quartile (normal-high Calcium levels) served as the reference group. The fully adjusted Cox-regression model shows significantly higher mortality risk for low serum calcium (quartile 1) within the timeframe 28-2500 days after the event (OR 1.53 [1.19-1.98]). The other groups did not differ significantly from each other. In the later observation period (from 2500 days until death or censoring) no more significant differences were seen between the four calcium quartiles. In summary, low serum calcium is an independent predictor of adverse outcome in the first 2500 days (about 7 years) after AMI. On later points in time this effect attenuates, so that no more significant differences can be observed.
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Significant Impact of Coffee Consumption on MR-Based Measures of Cardiac Function in a Population-Based Cohort Study without Manifest Cardiovascular Disease.
Beller, E, Lorbeer, R, Keeser, D, Galiè, F, Meinel, FG, Grosu, S, Bamberg, F, Storz, C, Schlett, CL, Peters, A, et al
Nutrients. 2021;(4)
Abstract
Subclinical effects of coffee consumption (CC) with regard to metabolic, cardiac, and neurological complications were evaluated using a whole-body magnetic resonance imaging (MRI) protocol. A blended approach was used to estimate habitual CC in a population-based study cohort without a history of cardiovascular disease. Associations of CC with MRI markers of gray matter volume, white matter hyperintensities, cerebral microhemorrhages, total and visceral adipose tissue (VAT), hepatic proton density fat fraction, early/late diastolic filling rate, end-diastolic/-systolic and stroke volume, ejection fraction, peak ejection rate, and myocardial mass were evaluated by linear regression. In our analysis with 132 women and 168 men, CC was positively associated with MR-based cardiac function parameters including late diastolic filling rate, stroke volume (p < 0.01 each), and ejection fraction (p < 0.05) when adjusting for age, sex, smoking, hypertension, diabetes, Low-density lipoprotein (LDL), triglycerides, cholesterol, and alcohol consumption. CC was inversely associated with VAT independent of demographic variables and cardiovascular risk factors (p < 0.05), but this association did not remain significant after additional adjustment for alcohol consumption. CC was not significantly associated with potential neurodegeneration. We found a significant positive and independent association between CC and MRI-based systolic and diastolic cardiac function. CC was also inversely associated with VAT but not independent of alcohol consumption.
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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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Abstract
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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Improving Identification of In-organello Protein-Protein Interactions Using an Affinity-enrichable, Isotopically Coded, and Mass Spectrometry-cleavable Chemical Crosslinker.
Makepeace, KAT, Mohammed, Y, Rudashevskaya, EL, Petrotchenko, EV, Vögtle, FN, Meisinger, C, Sickmann, A, Borchers, CH
Molecular & cellular proteomics : MCP. 2020;(4):624-639
Abstract
An experimental and computational approach for identification of protein-protein interactions by ex vivo chemical crosslinking and mass spectrometry (CLMS) has been developed that takes advantage of the specific characteristics of cyanurbiotindipropionylsuccinimide (CBDPS), an affinity-tagged isotopically coded mass spectrometry (MS)-cleavable crosslinking reagent. Utilizing this reagent in combination with a crosslinker-specific data-dependent acquisition strategy based on MS2 scans, and a software pipeline designed for integrating crosslinker-specific mass spectral information led to demonstrated improvements in the application of the CLMS technique, in terms of the detection, acquisition, and identification of crosslinker-modified peptides. This approach was evaluated on intact yeast mitochondria, and the results showed that hundreds of unique protein-protein interactions could be identified on an organelle proteome-wide scale. Both known and previously unknown protein-protein interactions were identified. These interactions were assessed based on their known sub-compartmental localizations. Additionally, the identified crosslinking distance constraints are in good agreement with existing structural models of protein complexes involved in the mitochondrial electron transport chain.
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Standardized Map of Iodine Status in Europe.
Ittermann, T, Albrecht, D, Arohonka, P, Bilek, R, de Castro, JJ, Dahl, L, Filipsson Nystrom, H, Gaberscek, S, Garcia-Fuentes, E, Gheorghiu, ML, et al
Thyroid : official journal of the American Thyroid Association. 2020;(9):1346-1354
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Abstract
Background: Knowledge about the population's iodine status is important, because it allows adjustment of iodine supply and prevention of iodine deficiency. The validity and comparability of iodine-related population studies can be improved by standardization, which was one of the goals of the EUthyroid project. The aim of this study was to establish the first standardized map of iodine status in Europe by using standardized urinary iodine concentration (UIC) data. Materials and Methods: We established a gold-standard laboratory in Helsinki measuring UIC by inductively coupled plasma mass spectrometry. A total of 40 studies from 23 European countries provided 75 urine samples covering the whole range of concentrations. Conversion formulas for UIC derived from the gold-standard values were established by linear regression models and were used to postharmonize the studies by standardizing the UIC data of the individual studies. Results: In comparison with the EUthyroid gold-standard, mean UIC measurements were higher in 11 laboratories and lower in 10 laboratories. The mean differences ranged from -36.6% to 49.5%. Of the 40 postharmonized studies providing data for the standardization, 16 were conducted in schoolchildren, 13 in adults, and 11 in pregnant women. Median standardized UIC was <100 μg/L in 1 out of 16 (6.3%) studies in schoolchildren, while in adults 7 out of 13 (53.8%) studies had a median standardized UIC <100 μg/L. Seven out of 11 (63.6%) studies in pregnant women revealed a median UIC <150 μg/L. Conclusions: We demonstrate that iodine deficiency is still present in Europe, using standardized data from a large number of studies. Adults and pregnant women, particularly, are at risk for iodine deficiency, which calls for action. For instance, a more uniform European legislation on iodine fortification is warranted to ensure that noniodized salt is replaced by iodized salt more often. In addition, further efforts should be put on harmonizing iodine-related studies and iodine measurements to improve the validity and comparability of results.