Immune cell function can be altered by lipids in circulation, a process potentially relevant to lipid-associated inflammatory diseases including atherosclerosis and rheumatoid arthritis. To gain... Show moreImmune cell function can be altered by lipids in circulation, a process potentially relevant to lipid-associated inflammatory diseases including atherosclerosis and rheumatoid arthritis. To gain further insight in the molecular changes involved, we here perform a transcriptome-wide association analysis of blood triglycerides, HDL cholesterol, and LDL cholesterol in 3229 individuals, followed by a systematic bidirectional Mendelian randomization analysis to assess the direction of effects and control for pleiotropy. Triglycerides are found to induce transcriptional changes in 55 genes and HDL cholesterol in 5 genes. The function and cell-specific expression pattern of these genes implies that triglycerides downregulate both cellular lipid metabolism and, unexpectedly, allergic response. Indeed, a Mendelian randomization approach based on GWAS summary statistics indicates that several of these genes, including interleukin-4 (IL4) and IgE receptors (FCER1A, MS4A2), affect the incidence of allergic diseases. Our findings highlight the interplay between triglycerides and immune cells in allergic disease. Show less
Hellbach, F.; Sinke, L.; Costeira, R.; Baumeister, S.E.; Beekman, M.; Louca, P.; ... ; Linseisen, J. 2022
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... Show morePurpose 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. Show less
Introduction: Immunosenescence and inflammaging have been implicated in the pathophysiology of frailty. Torquetenovirus (TTV), a single-stranded DNA anellovirus, the major component of the human... Show moreIntroduction: Immunosenescence and inflammaging have been implicated in the pathophysiology of frailty. Torquetenovirus (TTV), a single-stranded DNA anellovirus, the major component of the human blood virome, shows an increased replication rate with advancing age. An elevated TTV viremia has been associated with an impaired immune function and an increased risk of mortality in the older population. The objective of this study was to analyze the relation between TTV viremia, physical frailty and cognitive impairmentMethods: TTV viremia was measured in 1131 nonfrail, 45 physically frail, and 113 cognitively impaired older adults recruited in the MARK-AGE study (overall mean age 64.7 +/- 5.9 years), then the results were checked in two other independent cohorts from Spain and Portugal, including 126 frail, 252 prefrail and 141 nonfrail individuals (overall mean age: 77.5 +/- 8.3 years). Results: TTV viremia >= 4log was associated with physical frailty (OR: 4.69; 95% CI: 2.06-10.67, p<0.0001) and cognitive impairment (OR: 3.49, 95% CI : 2.14-5.69, p<0.0001) in the MARK-AGE population. The association between TTV DNA load and frailty status was confirmed in the Spanish cohort, while a slight association with cognitive impairment was observed (OR: 1.33; 95% CI: 1.000-1.773), only in the unadjusted model.No association between TTV load and frailty or cognitive impairment was found in the Portuguese sample, although a negative association between TTV viremia and MMSE score was observed in Spanish and Portuguese females. Conclusions: These findings demonstrate an association between TTV viremia and physical frailty, while the association with cognitive impairment was observed only in the younger population from the MARK-AGE study.Further research is necessary to clarify TTV's clinical relevance in the onset and progression of frailty and cognitive decline in older individuals. Show less
Bogaards, F.A.; Gehrmann, T.; Beekman, M.; Akker, E. ben van den; Rest, O. van de; Hangelbroek, R.W.J.; ... ; Slagboom, P.E. 2022
The response to lifestyle intervention studies is often heterogeneous, especially in older adults. Subtle responses that may represent a health gain for individuals are not always detected by... Show moreThe response to lifestyle intervention studies is often heterogeneous, especially in older adults. Subtle responses that may represent a health gain for individuals are not always detected by classical health variables, stressing the need for novel biomarkers that detect intermediate changes in metabolic, inflammatory, and immunity-related health. Here, our aim was to develop and validate a molecular multivariate biomarker maximally sensitive to the individual effect of a lifestyle intervention; the Personalized Lifestyle Intervention Status (PLIS). We used H-1-NMR fasting blood metabolite measurements from before and after the 13-week combined physical and nutritional Growing Old TOgether (GOTO) lifestyle intervention study in combination with a fivefold cross-validation and a bootstrapping method to train a separate PLIS score for men and women. The PLIS scores consisted of 14 and four metabolites for females and males, respectively. Performance of the PLIS score in tracking health gain was illustrated by association of the sex-specific PLIS scores with several classical metabolic health markers, such as BMI, trunk fat%, fasting HDL cholesterol, and fasting insulin, the primary outcome of the GOTO study. We also showed that the baseline PLIS score indicated which participants respond positively to the intervention. Finally, we explored PLIS in an independent physical activity lifestyle intervention study, showing similar, albeit remarkably weaker, associations of PLIS with classical metabolic health markers. To conclude, we found that the sex-specific PLIS score was able to track the individual short-term metabolic health gain of the GOTO lifestyle intervention study. The methodology used to train the PLIS score potentially provides a useful instrument to track personal responses and predict the participant's health benefit in lifestyle interventions similar to the GOTO study. Show less
Morwani Mangnani, J.; Giannos, P.; Belzer, C.; Beekman, M.; Slagboom, P.E.; Prokopidis, K. 2022
Major hallmarks of functional loss, loss of metabolic and musculoskeletal health and (multi)morbidity with aging are associated with sleep disturbances. With poor sleep shifts in gut microbial... Show moreMajor hallmarks of functional loss, loss of metabolic and musculoskeletal health and (multi)morbidity with aging are associated with sleep disturbances. With poor sleep shifts in gut microbial composition commonly manifest, which could mediate the pro-inflammatory state between sleep disturbances and sarcopenia. This systematic review presents the recent evidence on how sleep disturbances throughout the lifespan associate with and contribute to gut microbial composition changes, proposing a mechanism to understand the etiology of sarcopenia through sleep disturbances. The relationship between disturbed sleep and clinically relevant gut microbiota composition on health aspects of aging is discussed. A search was performed in PubMed, Cochrane Library, Scopus, Web of Science using keywords including (microbio* OR microflora) AND (sleep OR sleep disorder). Six cross-sectional population-based studies and five experimental clinical trials investigating healthy individuals with ages ranging from 4 to 71 were included. The cross-sectional studies reported similarities in associations with sleep disturbance and gut microbial diversity. In older adults, shorter sleep duration is associated with an increase in pro-inflammatory bacteria whereas increasing sleep quality is positively associated with an increase of beneficial Verrucomicrobia and Lentisphaerae phyla. In young adults, the effect of sleep disruption on gut microbiome composition, specifically the ratio of beneficial Firmicutes over Bacteroidetes phyla, remains contradictory and unclear. The findings of this review warrant further research in the modulation of the gut microbiome linking poor sleep with muscle-catabolic consequences throughout the lifespan. Show less
Wiersema, J.M.; Kamphuis, A.E.P.; Rohling, J.H.T.; Kervezee, L.; Akintola, A.A.; Jansen, S.W.; ... ; Spoel, E. van der 2022
Aging is associated with changes in heart rate (HR), heart rate variability (HRV), and 24-h rhythms in HR. Longevity has been linked to lower resting HR, while a higher resting HR and a decreased... Show moreAging is associated with changes in heart rate (HR), heart rate variability (HRV), and 24-h rhythms in HR. Longevity has been linked to lower resting HR, while a higher resting HR and a decreased HRV were linked to cardiovascular events and increased mortality risk. HR and HRV are often investigated during a short electrocardiogram (ECG) measurement at a hospital. In this study, we aim to investigate the relationship between HR parameters with familial longevity and chronological age derived from continuous ambulatory ECG measurements collected over a period of 24 to 90 hours. We included 73 middle-aged participants (mean (SD) age: 67.0 (6.16) years), comprising 37 offspring of long-lived families, 36 of their partners, and 35 young participants (22.8 (3.96) years). We found no association with familial longevity, but middle-aged participants had lower 24-h HR (average and maximum HR, not minimum HR), lower amplitudes, and earlier trough and peak times than young participants. Associations in HR with chronological age could be caused by the aging process or by differences in environmental factors. Interestingly, middle-aged participants had a less optimal HRV during long-term recordings in both the sleep and awake periods, which might indicate that their heart is less adaptable than that of young participants. This could be a first indication of deteriorated cardiovascular health in middle-aged individuals. Show less
Giacconi, R.; D'Aquila, P.; Malavolta, M.; Piacenza, F.; Burkle, A.; Villanueva, M.M.; ... ; Provinciali, M. 2022
Aging and age-related diseases have been linked to microbial dysbiosis with changes in blood bacterial DNA concentration. This condition may promote chronic low-grade inflammation, which can be... Show moreAging and age-related diseases have been linked to microbial dysbiosis with changes in blood bacterial DNA concentration. This condition may promote chronic low-grade inflammation, which can be further aggravated by antioxidant nutrient deficiency. Low plasma carotenoids are associated with an increased risk of inflammation and cellular damage and predict mortality. However, no evidence is yet available on the relationship between antioxidants and the blood bacterial DNA (BB-DNA). Therefore, this study aimed to compare BB-DNA from (a) GO (nonagenarian offspring), (b) age-matched controls (Randomly recruited Age-Stratified Individuals from the General population [RASIG]), and (c) spouses of GO (SGO) recruited in the MARK-AGE project, as well as to investigate the association between BB-DNA, behavior habits, Charlson Comorbidity Index (CCI), leucocyte subsets, and the circulating levels of some antioxidants and oxidative stress markers. BB-DNA was higher in RASIG than GO and SGO, whereas GO and SGO participants showed similar values. BB-DNA increased in smokers and males with CCI >= 2 compared with those with CCI <= 1 within RASIG. Moreover, BB-DNA was positively associated with lymphocyte, neutrophil, and monocyte counts, but not with self-reported dietary habits. Higher quartiles of BB-DNA were associated with low lutein and zeaxanthin and elevated malondialdehyde plasma concentrations in RASIG. BB-DNA was also positively correlated with nitric oxide levels. Herein, we provide evidence of a reduced BB-DNA in individuals from long-living families and their spouses, suggesting a decreased microbial dysbiosis and bacterial systemic translocation. BB-DNA was also associated with smoking, CCI, leukocyte subsets, and some redox biomarkers in older participants. Show less
Population-scale expression profiling studies can provide valuable insights into biological and disease-underlying mechanisms. The availability of phenotypic traits is essential for studying... Show morePopulation-scale expression profiling studies can provide valuable insights into biological and disease-underlying mechanisms. The availability of phenotypic traits is essential for studying clinical effects. Therefore, missing, incomplete, or inaccurate phenotypic information can make analyses challenging and prevent RNA-seq or other omics data to be reused. A possible solution are predictors that infer clinical or behavioral phenotypic traits from molecular data. While such predictors have been developed based on different omics data types and are being applied in various studies, metabolomics-based surrogates are less commonly used than predictors based on DNA methylation profiles.In this study, we inferred 17 traits, including diabetes status and exposure to lipid medication, using previously trained metabolomic predictors. We evaluated whether these metabolomic surrogates can be used as an alternative to reported information for studying the respective phenotypes using expression profiling data of four population cohorts. For the majority of the 17 traits, the metabolomic surrogates performed similarly to the reported phenotypes in terms of effect sizes, number of significant associations, replication rates, and significantly enriched pathways.The application of metabolomics-derived surrogate outcomes opens new possibilities for reuse of multi-omics data sets. In studies where availability of clinical metadata is limited, missing or incomplete information can be complemented by these surrogates, thereby increasing the size of available data sets. Additionally, the availability of such surrogates could be used to correct for potential biological confounding. In the future, it would be interesting to further investigate the use of molecular predictors across different omics types and cohorts. Show less
Bizzarri, D.; Reinders, M.J.T.; Beekman, M.; Slagboom, P.E.; Akker, E.B. van den 2022
Motivation: H-1-NMR metabolomics is rapidly becoming a standard resource in large epidemiological studies to acquire metabolic profiles in large numbers of samples in a relatively low-priced and... Show moreMotivation: H-1-NMR metabolomics is rapidly becoming a standard resource in large epidemiological studies to acquire metabolic profiles in large numbers of samples in a relatively low-priced and standardized manner. Concomitantly, metabolomics-based models are increasingly developed that capture disease risk or clinical risk factors. These developments raise the need for user-friendly toolbox to inspect new H-1-NMR metabolomics data and project a wide array of previously established risk models. Results: We present MiMIR (Metabolomics-based Models for Imputing Risk), a graphical user interface that provides an intuitive framework for ad hoc statistical analysis of Nightingale Health's H-1-NMR metabolomics data and allows for the projection and calibration of 24 pre-trained metabolomics-based models, without any pre-required programming knowledge. Availability and implementation: The R-shiny package is available in CRAN or downloadable at , together with an extensive user manual (also available as Supplementary Documents to the article). Show less
Spek, A. van der; Karamujic-Comic, H.; Pool, R.; Bot, M.; Beekman, M.; Garmaeva, S.; ... ; BBMRI Metabolomics Consortium 2022
Telomeres are repetitive DNA sequences located at the end of chromosomes, which are associated to biological aging, cardiovascular disease, cancer and mortality. Lipid and fatty acid metabolism... Show moreTelomeres are repetitive DNA sequences located at the end of chromosomes, which are associated to biological aging, cardiovascular disease, cancer and mortality. Lipid and fatty acid metabolism have been associated with telomere shortening. We have conducted an in-depth study investigating the association of metabolic biomarkers with telomere length (LTL). We performed an association analysis of 226 metabolic biomarkers with LTL using data from 11 775 individuals from six independent population-based cohorts (BBMRI-NL consortium). Metabolic biomarkers include lipoprotein lipids and subclasses, fatty acids, amino acids, glycolysis measures and ketone bodies. LTL was measured by quantitative polymerase chain reaction or F1owFISH. Linear regression analysis was performed adjusting for age, sex, lipid-lowering medication and cohort-specific covariates (model 1) and additionally for body mass index (BMI) and smoking (model 2), followed by inverse variance-weighted meta-analyses (significance threshold P me t a = 6.5 x 10(-4)). We identified four metabolic biomarkers positively associated with LTL, including two cholesterol to lipid ratios in small VLDL (S-VLDL-C % and S-VLDL-CE %) and two omega-6 fatty acid ratios (FAw6/FA and LA/FA). After additionally adjusting for BMI and smoking, these metabolic biomarkers remained associated with LTL with similar effect estimates. In addition, cholesterol esters in very small VLDL (XS-VLDL-CE) became significantly associated with LTL (P = 3.6 x 10(-4)). We replicated the association of FAw6/FA with LTL in an independent dataset of 7845 individuals (P = 1.9 x 10(-4)). To conclude, we identified multiple metabolic biomarkers involved in lipid and fatty acid metabolism that may be involved in LTL biology. Longitudinal studies are needed to exclude reversed causation. Show less
Background Epigenetic clocks use DNA methylation (DNAm) levels of specific sets of CpG dinucleotides to accurately predict individual chronological age. A popular application of these clocks is to... Show moreBackground Epigenetic clocks use DNA methylation (DNAm) levels of specific sets of CpG dinucleotides to accurately predict individual chronological age. A popular application of these clocks is to explore whether the deviation of predicted age from chronological age is associated with disease phenotypes, where this deviation is interpreted as a potential biomarker of biological age. This wide application, however, contrasts with the limited insight in the processes that may drive the running of epigenetic clocks. Results We perform a functional genomics analysis on four epigenetic clocks, including Hannum's blood predictor and Horvath's multi-tissue predictor, using blood DNA methylome and transcriptome data from 3132 individuals. The four clocks result in similar predictions of individual chronological age, and their constituting CpGs are correlated in DNAm level and are enriched for similar histone modifications and chromatin states. Interestingly, DNAm levels of CpGs from the clocks are commonly associated with gene expression in trans. The gene sets involved are highly overlapping and enriched for T cell processes. Further analysis of the transcriptome and methylome of sorted blood cell types identifies differences in DNAm between naive and activated T and NK cells as a probable contributor to the clocks. Indeed, within the same donor, the four epigenetic clocks predict naive cells to be up to 40 years younger than activated cells. Conclusions The ability of epigenetic clocks to predict chronological age involves their ability to detect changes in proportions of naive and activated immune blood cells, an established feature of immuno-senescence. This finding may contribute to the interpretation of associations between clock-derived measures and age-related health outcomes. Show less
Paraschiakos, S.; Sa, C.R. de; Okai, J.; Slagboom, P.E.; Beekman, M.; Knobbe, A. 2022
Through the quantification of physical activity energy expenditure (PAEE), health care monitoring has the potential to stimulate vital and healthy ageing, inducing behavioural changes in older... Show moreThrough the quantification of physical activity energy expenditure (PAEE), health care monitoring has the potential to stimulate vital and healthy ageing, inducing behavioural changes in older people and linking these to personal health gains. To be able to measure PAEE in a health care perspective, methods from wearable accelerometers have been developed, however, mainly targeted towards younger people. Since elderly subjects differ in energy requirements and range of physical activities, the current models may not be suitable for estimating PAEE among the elderly. Furthermore, currently available methods seem to be either simple but non-generalizable or require elaborate (manual) feature construction steps. Because past activities influence present PAEE, we propose a modeling approach known for its ability to model sequential data, the recurrent neural network (RNN). To train the RNN for an elderly population, we used the growing old together validation (GOTOV) dataset with 34 healthy participants of 60 years and older (mean 65 years old), performing 16 different activities. We used accelerometers placed on wrist and ankle, and measurements of energy counts by means of indirect calorimetry. After optimization, we propose an architecture consisting of an RNN with 3 GRU layers and a feedforward network combining both accelerometer and participant-level data. Our efforts included switching mean to standard deviation for down-sampling the input data and combining temporal and static data (person-specific details such as age, weight, BMI). The resulting architecture produces accurate PAEE estimations while decreasing training input and time by a factor of 10. Subsequently, compared to the state-of-the-art, it is capable to integrate longer activity data which lead to more accurate estimations of low intensity activities EE. It can thus be employed to investigate associations of PAEE with vitality parameters of older people related to metabolic and cognitive health and mental well-being. Show less
Bizzarri, D.; Reinders, M.J.T.; Beekman, M.; Slagboom, P.E.; BBMRI-NL; Akker, E.B. van den 2022
Background Missing or incomplete phenotypic information can severely deteriorate the statistical power in epidemiological studies. High-throughput quantification of small-molecules in bio-samples,... Show moreBackground Missing or incomplete phenotypic information can severely deteriorate the statistical power in epidemiological studies. High-throughput quantification of small-molecules in bio-samples, i.e. `metabolomics', is steadily gaining popularity, as it is highly informative for various phenotypical characteristics. Here we aim to leverage metabolomics to impute missing data in clinical variables routinely assessed in large epidemiological and clinical studies.Methods To this end, we have employed similar to 26,000 H-1-NMR metabolomics samples from 28 Dutch cohorts collected within the BBMRI-NL consortium, to create 19 metabolomics-based predictors for clinical variables, including diabetes status (AUC(5-Fold CV) = 0.94) and lipid medication usage (AUC(5-Fold CV) = 0.90).Findings Subsequent application in independent cohorts confirmed that our metabolomics-based predictors can indeed be used to impute a wide array of missing clinical variables from a single metabolomics data resource. In addition, application highlighted the potential use of our predictors to explore the effects of totally unobserved confounders in omics association studies. Finally, we show that our predictors can be used to explore risk factor profiles contributing to mortality in older participants.Interpretation To conclude, we provide H-1-NMR metabolomics-based models to impute clinical variables routinely assessed in epidemiological studies and illustrate their merit in scenarios when phenotypic variables are partially incomplete or totally unobserved. Copyright (C) 2021 The Author(s). Published by Elsevier B.V. Show less
Maas, S.C.E.; Vidaki, A.; Teumer, A.; Costeira, R.; Wilson, R.; Dongen, J. van; ... ; Kayser, M. 2021
Background Information on long-term alcohol consumption is relevant for medical and public health research, disease therapy, and other areas. Recently, DNA methylation-based inference of alcohol... Show moreBackground Information on long-term alcohol consumption is relevant for medical and public health research, disease therapy, and other areas. Recently, DNA methylation-based inference of alcohol consumption from blood was reported with high accuracy, but these results were based on employing the same dataset for model training and testing, which can lead to accuracy overestimation. Moreover, only subsets of alcohol consumption categories were used, which makes it impossible to extrapolate such models to the general population. By using data from eight population-based European cohorts (N = 4677), we internally and externally validated the previously reported biomarkers and models for epigenetic inference of alcohol consumption from blood and developed new models comprising all data from all categories. Results By employing data from six European cohorts (N = 2883), we empirically tested the reproducibility of the previously suggested biomarkers and prediction models via ten-fold internal cross-validation. In contrast to previous findings, all seven models based on 144-CpGs yielded lower mean AUCs compared to the models with less CpGs. For instance, the 144-CpG heavy versus non-drinkers model gave an AUC of 0.78 +/- 0.06, while the 5 and 23 CpG models achieved 0.83 +/- 0.05, respectively. The transportability of the models was empirically tested via external validation in three independent European cohorts (N = 1794), revealing high AUC variance between datasets within models. For instance, the 144-CpG heavy versus non-drinkers model yielded AUCs ranging from 0.60 to 0.84 between datasets. The newly developed models that considered data from all categories showed low AUCs but gave low AUC variation in the external validation. For instance, the 144-CpG heavy and at-risk versus light and non-drinkers model achieved AUCs of 0.67 +/- 0.02 in the internal cross-validation and 0.61-0.66 in the external validation datasets. Conclusions The outcomes of our internal and external validation demonstrate that the previously reported prediction models suffer from both overfitting and accuracy overestimation. Our results show that the previously proposed biomarkers are not yet sufficient for accurate and robust inference of alcohol consumption from blood. Overall, our findings imply that DNA methylation prediction biomarkers and models need to be improved considerably before epigenetic inference of alcohol consumption from blood can be considered for practical applications. Show less
Stokes, C.S.; Weber, D.; Wagenpfeil, S.; Stuetz, W.; Moreno-Villanueva, M.; Dolle, M.E.T.; ... ; Grune, T. 2021
Self-rated health (SRH) is associated with higher risk of death. Since low plasma levels of fat-soluble vitamins are related to mortality, we aimed to assess whether plasma concentrations of... Show moreSelf-rated health (SRH) is associated with higher risk of death. Since low plasma levels of fat-soluble vitamins are related to mortality, we aimed to assess whether plasma concentrations of vitamins A, D and E were associated with SRH in the MARK-AGE study. We included 3158 participants (52 % female) aged between 35 and 75 years. Cross-sectional data were collected via questionnaires. An enzyme immunoassay quantified 25-hydroxyvitamin D and HPLC determined alpha-tocopherol and retinol plasma concentrations. The median 25-hydroxyvitamin D and retinol concentrations differed significantly (P < 0.001) between SRH categories and were lower in the combined fair/poor category v. the excellent, very good and good categories (25-hydroxvitamin D: 40.8 v. 51.9, 49.3, 46.7 nmol/l, respectively; retinol: 1.67 v. 1.75, 1.74, 1.70 mu mol/l, respectively). Both vitamin D and retinol status were independently associated with fair/poor SRH in multiple regression analyses: adjusted OR (95 % CI) for the vitamin D insufficiency, deficiency and severe deficiency categories were 1.33 (1.06-1.68), 1.50 (1.17-1.93) and 1.83 (1.34-2.50), respectively; P = 0.015, P = 0.001 and P < 0.001, and for the second/third/fourth retinol quartiles: 1.44 (1.18-1.75), 1.57 (1. 28-1.93) and 1.49 (1.20-1.84); all P < 0.001. No significant associations were reported for a-tocopherol quartiles. Lower vitamin A and D status emerged as independent markers for fair/poor SRH. Further insights into the long-term implications of these modifiable nutrients on health status are warranted. Show less
Albalak, G.; Stijntjes, M.; Wijsman, C.A.; Slagboom, P.E.; Ouderaa, F.J. van der; Mooijaart, S.P.; ... ; Noordam, R. 2021
Background Little is known about the impact of timing as opposed to frequency and intensity of daily physical activity on metabolic health. Therefore, we assessed the association between... Show moreBackground Little is known about the impact of timing as opposed to frequency and intensity of daily physical activity on metabolic health. Therefore, we assessed the association between accelerometery-based daily timing of physical activity and measures of metabolic health in sedentary older people. Methods Hourly mean physical activity derived from wrist-worn accelerometers over a 6-day period was collected at baseline and after 3 months in sedentary participants from the Active and Healthy Ageing study. A principal component analysis (PCA) was performed to reduce the number of dimensions (e.g. define periods instead of separate hours) of hourly physical activity at baseline and change during follow-up. Cross-sectionally, a multivariable-adjusted linear regression analysis was used to associate the principal components, particularly correlated with increased physical activity in data-driven periods during the day, with body mass index (BMI), fasting glucose and insulin, HbA1c and the homeostatic model assessment for insulin resistance (HOMA-IR). For the longitudinal analyses, we calculated the hourly changes in physical activity and change in metabolic health after follow-up. Results We included 207 individuals (61.4% male, mean age: 64.8 [SD 2.9], mean BMI: 28.9 [4.7]). Higher physical activity in the early morning was associated with lower fasting glucose (-2.22%, 95% CI: -4.19, -0.40), fasting insulin (-13.54%, 95%CI: -23.49, -4.39), and HOMA-IR (-16.07%, 95%CI: -27.63, -5.65). Higher physical activity in the late afternoon to evening was associated with lower BMI (-2.84%, 95% CI: -4.92, -0.70). Higher physical activity at night was associated with higher BMI (2.86%, 95% CI: 0.90, 4.78), fasting glucose (2.57%, 95% CI: 0.70, 4.30), and HbA1c (2.37%, 95% CI: 1.00, 3.82). Similar results were present in the prospective analysis. Conclusion Specific physical activity timing patterns were associated with more beneficial metabolic health, suggesting particular time-dependent physical activity interventions might maximise health benefits. Show less
Background Observational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed... Show moreBackground Observational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed to investigate the potential causal relationship between thyroid status and cardiovascular disease and to characterize the metabolomic profile associated with thyroid status. Methods Multi-cohort two-sample Mendelian randomization (MR) was performed utilizing genome-wide significant variants as instruments for standardized thyrotropin (TSH) and free thyroxine (fT4) within the reference range. Associations between TSH and fT4 and metabolic profile were investigated in a two-stage manner: associations between TSH and fT4 and the full panel of 161 metabolomic markers were first assessed hypothesis-free, then directional consistency was assessed through Mendelian randomization, another metabolic profile platform, and in individuals with biochemically defined thyroid dysfunction. Results Circulating TSH was associated with 52/161 metabolomic markers, and fT4 levels were associated with 21/161 metabolomic markers among 9432 euthyroid individuals (median age varied from 23.0 to 75.4 years, 54.5% women). Positive associations between circulating TSH levels and concentrations of very low-density lipoprotein subclasses and components, triglycerides, and triglyceride content of lipoproteins were directionally consistent across the multivariable regression, MR, metabolomic platforms, and for individuals with hypo- and hyperthyroidism. Associations with fT4 levels inversely reflected those observed with TSH. Among 91,810 CAD cases and 656,091 controls of European ancestry, per 1-SD increase of genetically determined TSH concentration risk of CAD increased slightly, but not significantly, with an OR of 1.03 (95% CI 0.99-1.07; p value 0.16), whereas higher genetically determined fT4 levels were not associated with CAD risk (OR 1.00 per SD increase of fT4; 95% CI 0.96-1.04; p value 0.59). Conclusions Lower thyroid status leads to an unfavorable lipid profile and a somewhat increased cardiovascular disease risk. Show less
Dongen, J. van; Gordon, S.D.; McRae, A.F.; Odintsova, V.V.; Mbarek, H.; Breeze, C.E.; ... ; Genetics DNA Methylation Consortiu 2021
The mechanisms underlying how monozygotic (or identical) twins arise are yet to be determined. Here, the authors investigate this in an epigenome-wide association study, showing that monozygotic... Show moreThe mechanisms underlying how monozygotic (or identical) twins arise are yet to be determined. Here, the authors investigate this in an epigenome-wide association study, showing that monozygotic twinning has a characteristic DNA methylation signature in adult somatic tissues.Monozygotic (MZ) twins and higher-order multiples arise when a zygote splits during pre-implantation stages of development. The mechanisms underpinning this event have remained a mystery. Because MZ twinning rarely runs in families, the leading hypothesis is that it occurs at random. Here, we show that MZ twinning is strongly associated with a stable DNA methylation signature in adult somatic tissues. This signature spans regions near telomeres and centromeres, Polycomb-repressed regions and heterochromatin, genes involved in cell-adhesion, WNT signaling, cell fate, and putative human metastable epialleles. Our study also demonstrates a never-anticipated corollary: because identical twins keep a lifelong molecular signature, we can retrospectively diagnose if a person was conceived as monozygotic twin. Show less
IMPORTANCE In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these... Show moreIMPORTANCE In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings.OBJECTIVE To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia.DESIGN, SETTING, AND PARTICIPANTS This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021.EXPOSURES Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values.MAIN OUTCOMES AND MEASURES The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated.RESULTS Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia.CONCLUSIONS AND RELEVANCE In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines. Show less
Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100... Show moreOsteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation. Show less
