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1.
Artigo em Inglês | MEDLINE | ID: mdl-31702015

RESUMO

CONTEXT: Both thyroid dysfunction and levothyroxine therapy (LT4) have been associated with bone loss, but studies on the effect of LT4 for subclinical hypothyroidism (SHypo) on bone yielded conflicting results. OBJECTIVE: To assess the effect of LT4 treatment on bone mineral density (BMD), Trabecular Bone Score (TBS), and bone turnover markers (BTMs) in older adults with SHypo. DESIGN AND INTERVENTION: Planned nested substudy of the double-blind placebo-controlled TRUST trial. Participants with SHypo were randomized to LT4 with dose titration vs. placebo with computerized mock titration. SETTING AND PARTICIPANTS: 196 community-dwelling adults over 65 years enrolled at the Swiss TRUST sites had baseline and 1-year follow-up bone examinations; 4 participants withdrew due to adverse events not related to treatment. MAIN OUTCOME MEASURES: One-year percent changes of BMD, TBS, and two serum BTMs (sCTX and P1NP). Student's t-test for unadjusted analyses, and linear regression adjusted for clinical center and sex, were performed. RESULTS: Mean age was 74.3y ± 5.7, 45.4% were women, and 19.6% were osteoporotic. The unadjusted 1-year change in lumbar spine BMD was similar between LT4 (+0.8%) and placebo-treated groups (-0.6%; between-groups difference +1.4%: 95%CI -0.1 to 2.9, p=0.059). Likewise, there were no between-group differences in 1-year change in TBS (-1.3%: 95%CI -3.1 to 0.6, p=0.19), total hip BMD (-0.2%: 95%CI -1.1 to 0.1, p=0.61), or BTMs levels (sCTX +24.1%: 95%CI -7.9 to 56.2, p=0.14), or after adjustment for clinical centers and sex. CONCLUSIONS: Over one-year levothyroxine had no effect on bone health in older adults with SHypo. REGISTRATION: ClinicalTrial.gov NCT01660126 and NCT02491008.

2.
JAMA ; : 1-11, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31664429

RESUMO

Importance: It is unclear whether levothyroxine treatment provides clinically important benefits in adults aged 80 years and older with subclinical hypothyroidism. Objective: To determine the association of levothyroxine treatment for subclinical hypothyroidism with thyroid-related quality of life in adults aged 80 years and older. Design, Setting, and Participants: Prospectively planned combined analysis of data involving community-dwelling adults aged 80 years and older with subclinical hypothyroidism. Data from a randomized clinical trial were combined with a subgroup of participants aged 80 years and older from a second clinical trial. The trials were conducted between April 2013 and May 2018. Final follow-up was May 4, 2018. Exposures: Participants were randomly assigned to receive levothyroxine (n = 112; 52 participants from the first trial and 60 from the second trial) or placebo (n = 139; 53 participants from the first trial and 86 from the second trial). Main Outcomes and Measures: Co-primary outcomes were Thyroid-Related Quality of Life Patient-Reported Outcome (ThyPRO) questionnaire scores for the domains of hypothyroid symptoms and tiredness at 1 year (range, 0-100; higher scores indicate worse quality of life; minimal clinically important difference, 9). Results: Of 251 participants (mean age, 85 years; 118 [47%] women), 105 were included from the first clinical trial and 146 were included from the second clinical trial. A total of 212 participants (84%) completed the study. The hypothyroid symptoms score decreased from 21.7 at baseline to 19.3 at 12 months in the levothyroxine group vs from 19.8 at baseline to 17.4 at 12 months in the placebo group (adjusted between-group difference, 1.3 [95% CI, -2.7 to 5.2]; P = .53). The tiredness score increased from 25.5 at baseline to 28.2 at 12 months in the levothyroxine group vs from 25.1 at baseline to 28.7 at 12 months in the placebo group (adjusted between-group difference, -0.1 [95% CI, -4.5 to 4.3]; P = .96). At least 1 adverse event occurred in 33 participants (29.5%) in the levothyroxine group (the most common adverse event was cerebrovascular accident, which occurred in 3 participants [2.2%]) and 40 participants (28.8%) in the placebo group (the most common adverse event was pneumonia, which occurred in 4 [3.6%] participants). Conclusions and Relevance: In this prospectively planned analysis of data from 2 clinical trials involving adults aged 80 years and older with subclinical hypothyroidism, treatment with levothyroxine, compared with placebo, was not significantly associated with improvement in hypothyroid symptoms or fatigue. These findings do not support routine use of levothyroxine for treatment of subclinical hypothyroidism in adults aged 80 years and older. Trial Registration: ClinicalTrials.gov Identifier: NCT01660126; Netherlands Trial Register: NTR3851.

3.
EMBO J ; : e101982, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31633821

RESUMO

Cellular senescence has been shown to contribute to skin ageing. However, the role of melanocytes in the process is understudied. Our data show that melanocytes are the only epidermal cell type to express the senescence marker p16INK4A during human skin ageing. Aged melanocytes also display additional markers of senescence such as reduced HMGB1 and dysfunctional telomeres, without detectable telomere shortening. Additionally, senescent melanocyte SASP induces telomere dysfunction in paracrine manner and limits proliferation of surrounding cells via activation of CXCR3-dependent mitochondrial ROS. Finally, senescent melanocytes impair basal keratinocyte proliferation and contribute to epidermal atrophy in vitro using 3D human epidermal equivalents. Crucially, clearance of senescent melanocytes using the senolytic drug ABT737 or treatment with mitochondria-targeted antioxidant MitoQ suppressed this effect. In conclusion, our study provides proof-of-concept evidence that senescent melanocytes affect keratinocyte function and act as drivers of human skin ageing.

4.
JAMA Netw Open ; 2(9): e1910915, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31539074

RESUMO

Importance: Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations. Objective: To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis. Design, Setting, and Participants: This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included. Main Outcomes and Measures: Type 2 diabetes and glycemic traits. Results: This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P = 4.03 × 10-5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose concentration (ß = 0.189; SE = 0.060; P = .002), but not with fasting insulin, 2-hour glucose, or hemoglobin A1c concentration. Conclusions and Relevance: In this study, a genetic predisposition to lower birth weight was associated with increased risk of T2D and higher fasting glucose concentration, suggesting genetic effects on retarded fetal growth and increased diabetes risk that either are independent of each other or operate through alterations of integrated biological mechanisms.

5.
Ageing Res Rev ; 56: 100964, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31561015

RESUMO

Specific hallmarks are thought to underlie the ageing process and age-related functional decline. In this viewpoint, we put forward the hypothesis that disturbances in the process of tissue maintenance are an important common denominator that may lie in between specific hallmarks of ageing (i.e. damage and responses to damage) and their ultimate (patho)physiological consequences (i.e. functional decline and age-related disease). As a first step towards verifying or falsifying this hypothesis, it will be important to measure biomarkers of tissue maintenance in future studies in different study populations. The main aim of the current paper is to discuss potential biomarkers of tissue maintenance that could be used in such future studies. Among the many tissues that could have been chosen to explore our hypothesis, to keep the paper manageable, we chose to focus on a selected number of tissues, namely bone, cartilage, muscle, and the brain, which are important for mobility and cognition and affected in several common age-related diseases, including osteoporosis, osteoarthritis, sarcopenia, and neurodegenerative diseases. Furthermore, we discuss the advantages and limitations of potential biomarkers for use in (pre)clinical studies. The proposed biomarkers should be validated in future research, for example by measuring these in humans with different rates of ageing.

6.
Eur J Epidemiol ; 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31494793

RESUMO

Inferring a person's smoking habit and history from blood is relevant for complementing or replacing self-reports in epidemiological and public health research, and for forensic applications. However, a finite DNA methylation marker set and a validated statistical model based on a large dataset are not yet available. Employing 14 epigenome-wide association studies for marker discovery, and using data from six population-based cohorts (N = 3764) for model building, we identified 13 CpGs most suitable for inferring smoking versus non-smoking status from blood with a cumulative Area Under the Curve (AUC) of 0.901. Internal fivefold cross-validation yielded an average AUC of 0.897 ± 0.137, while external model validation in an independent population-based cohort (N = 1608) achieved an AUC of 0.911. These 13 CpGs also provided accurate inference of current (average AUCcrossvalidation 0.925 ± 0.021, AUCexternalvalidation0.914), former (0.766 ± 0.023, 0.699) and never smoking (0.830 ± 0.019, 0.781) status, allowed inferring pack-years in current smokers (10 pack-years 0.800 ± 0.068, 0.796; 15 pack-years 0.767 ± 0.102, 0.752) and inferring smoking cessation time in former smokers (5 years 0.774 ± 0.024, 0.760; 10 years 0.766 ± 0.033, 0.764; 15 years 0.767 ± 0.020, 0.754). Model application to children revealed highly accurate inference of the true non-smoking status (6 years of age: accuracy 0.994, N = 355; 10 years: 0.994, N = 309), suggesting prenatal and passive smoking exposure having no impact on model applications in adults. The finite set of DNA methylation markers allow accurate inference of smoking habit, with comparable accuracy as plasma cotinine use, and smoking history from blood, which we envision becoming useful in epidemiology and public health research, and in medical and forensic applications.

7.
Sci Rep ; 9(1): 11623, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31406173

RESUMO

Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10-6), methionine (p-value = 9.2 × 10-5), tyrosine (p-value = 2.1 × 10-4), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10-4), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10-4), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10-4). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.

8.
Nat Commun ; 10(1): 3346, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31431621

RESUMO

Predicting longer-term mortality risk requires collection of clinical data, which is often cumbersome. Therefore, we use a well-standardized metabolomics platform to identify metabolic predictors of long-term mortality in the circulation of 44,168 individuals (age at baseline 18-109), of whom 5512 died during follow-up. We apply a stepwise (forward-backward) procedure based on meta-analysis results and identify 14 circulating biomarkers independently associating with all-cause mortality. Overall, these associations are similar in men and women and across different age strata. We subsequently show that the prediction accuracy of 5- and 10-year mortality based on a model containing the identified biomarkers and sex (C-statistic = 0.837 and 0.830, respectively) is better than that of a model containing conventional risk factors for mortality (C-statistic = 0.772 and 0.790, respectively). The use of the identified metabolic profile as a predictor of mortality or surrogate endpoint in clinical studies needs further investigation.

9.
Physiol Genomics ; 51(8): 311-322, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31199196

RESUMO

Obesity is a causal risk factor for the development of age-related disease conditions, which includes Type 2 diabetes mellitus, cardiovascular disease, and dementia. In genome-wide association studies, genetic variation in FTO is strongly associated with obesity and has been described across different ethnic backgrounds and life stages. To date, much work has been devoted on determining the biological mechanisms via which FTO affects body weight regulation and ultimately contributes to age-related cardiometabolic and brain disease. The main hypotheses of the involved biological mechanisms include the involvement of FTO in habitual food intake and energy expenditure. In this narrative review, our overall aim is to provide an overview on how FTO gene variants could increase the risk of developing age-related disease conditions. Specifically, we will discuss the state of the literature based on the different hypotheses how FTO regulates body weight and ultimately contributes to cardiometabolic disease and brain disease.

10.
Am J Clin Nutr ; 110(2): 437-450, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31165884

RESUMO

BACKGROUND: Folate and vitamin B-12 are essential micronutrients involved in the donation of methyl groups in cellular metabolism. However, associations between intake of these nutrients and genome-wide DNA methylation levels have not been studied comprehensively in humans. OBJECTIVE: The aim of this study was to assess whether folate and/or vitamin B-12 intake are asssociated with genome-wide changes in DNA methylation in leukocytes. METHODS: A large-scale epigenome-wide association study of folate and vitamin B-12 intake was performed on DNA from 5841 participants from 10 cohorts using Illumina 450k arrays. Folate and vitamin B-12 intakes were calculated from food-frequency questionnaires (FFQs). Continuous and categorical (low compared with high intake) linear regression mixed models were applied per cohort, controlling for confounders. A meta-analysis was performed to identify significant differentially methylated positions (DMPs) and regions (DMRs), and a pathway analysis was performed on the DMR annotated genes. RESULTS: The categorical model resulted in 6 DMPs, which are all negatively associated with folate intake, annotated to FAM64A, WRAP73, FRMD8, CUX1, and LCN8 genes, which have a role in cellular processes including centrosome localization, cell proliferation, and tumorigenesis. Regional analysis showed 74 folate-associated DMRs, of which 73 were negatively associated with folate intake. The most significant folate-associated DMR was a 400-base pair (bp) spanning region annotated to the LGALS3BP gene. In the categorical model, vitamin B-12 intake was associated with 29 DMRs annotated to 48 genes, of which the most significant was a 1100-bp spanning region annotated to the calcium-binding tyrosine phosphorylation-regulated gene (CABYR). Vitamin B-12 intake was not associated with DMPs. CONCLUSIONS: We identified novel epigenetic loci that are associated with folate and vitamin B-12 intake. Interestingly, we found a negative association between folate and DNA methylation. Replication of these methylation loci is necessary in future studies.

11.
J Biol Rhythms ; 34(4): 347-363, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31187683

RESUMO

Measurement errors commonly occur in 24-h hormonal data and may affect the outcomes of such studies. Measurement errors often appear as outliers in such data sets; however, no well-established method is available for their automatic detection. In this study, we aimed to compare performances of different methods for outlier detection in hormonal serial data. Hormones (glucose, insulin, thyroid-stimulating hormone, cortisol, and growth hormone) were measured in blood sampled every 10 min for 24 h in 38 participants of the Leiden Longevity Study. Four methods for detecting outliers were compared: (1) eyeballing, (2) Tukey's fences, (3) stepwise approach, and (4) the expectation-maximization (EM) algorithm. Eyeballing detects outliers based on experts' knowledge, and the stepwise approach incorporates physiological knowledge with a statistical algorithm. Tukey's fences and the EM algorithm are data-driven methods, using interquartile range and a mathematical algorithm to identify the underlying distribution, respectively. The performance of the methods was evaluated based on the number of outliers detected and the change in statistical outcomes after removing detected outliers. Eyeballing resulted in the lowest number of outliers detected (1.0% of all data points), followed by Tukey's fences (2.3%), the stepwise approach (2.7%), and the EM algorithm (11.0%). In all methods, the mean hormone levels did not change materially after removing outliers. However, their minima were affected by outlier removal. Although removing outliers affected the correlation between glucose and insulin on the individual level, when averaged over all participants, none of the 4 methods influenced the correlation. Based on our results, the EM algorithm is not recommended given the high number of outliers detected, even where data points are physiologically plausible. Since Tukey's fences is not suitable for all types of data and eyeballing is time-consuming, we recommend the stepwise approach for outlier detection, which combines physiological knowledge and an automated process.

12.
J Am Coll Cardiol ; 73(24): 3118-3131, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31221261

RESUMO

BACKGROUND: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions. OBJECTIVES: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population. METHODS: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs. RESULTS: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals. CONCLUSIONS: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms.

13.
Aging Cell ; 18(4): e12956, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31062498

RESUMO

With advancing age, many organs exhibit functional deterioration. The age-associated accumulation of senescent cells is believed to represent one factor contributing to this phenomenon. While senescent cells are found in several different organ systems, it is not known whether they arise independently in each organ system or whether their prevalence within an individual reflects that individual's intrinsic aging process. To address this question, we studied senescence in two different organ systems in humans, namely skin and T cells in 80 middle-aged and older individuals from the Leiden Longevity Study. Epidermal p16INK4a positivity was associated with neither CD4+ nor CD8+ T-cell immunosenescence phenotype composites (i.e., end-stage differentiated/senescent T cells, including CD45RA+ CCR7- CD28- CD27- CD57+ KLRG1+ T cells). Dermal p16INK4a positivity was significantly associated with the CD4+ , but not with the CD8+ immunosenescence composite. We therefore conclude that there is limited evidence for a link between skin senescence and immunosenescence within individuals.

14.
Metabolomics ; 15(2): 23, 2019 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-30830468

RESUMO

BACKGROUND: We aimed to identify novel metabolite and lipid signatures connected with the metabolic syndrome in a Dutch middle-aged population. METHODS: 115 individuals with a metabolic syndrome score ranging from 0 to 5 [50 cases of the metabolic syndrome (score ≥ 3) and 65 controls] were enrolled from the Leiden Longevity Study, and LC/GC-MS metabolomics and lipidomics profiling were performed on fasting plasma samples. Data were analysed with principal component analysis and orthogonal projections to latent structures (OPLS) to study metabolite/lipid signatures associated with the metabolic syndrome. In addition, univariate analyses were done with linear regression, adjusted for age and sex, for the study of individual metabolites/lipids in relation to the metabolic syndrome. RESULTS: Data was available on 103 metabolites and 223 lipids. In the OPLS model with metabolic syndrome score (Y-variable), 9 metabolites were negatively correlated and 26 metabolites (mostly acylcarnitines, amino acids and keto acids) were positively correlated with the metabolic syndrome score. In addition, a total of 100 lipids (mainly triacylglycerides) were positively correlated and 10 lipids from different lipid classes were negatively correlated with the metabolic syndrome score. In the univariate analyses, the metabolic syndrome (score) was associated with multiple individual metabolites (e.g., valeryl carnitine, pyruvic acid, lactic acid, alanine) and lipids [e.g., diglyceride(34:1), diglyceride(36:2)]. CONCLUSION: In this first study on metabolomics/lipidomics of the metabolic syndrome, we identified multiple novel metabolite and lipid signatures, from different chemical classes, that were connected to the metabolic syndrome and are of interest to cardiometabolic disease biology.

15.
J Clin Endocrinol Metab ; 104(7): 2903-2910, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30759251

RESUMO

CONTEXT: Seasonal variation in cold and light exposure may influence metabolic health. OBJECTIVE: We assessed the associations of bright sunlight and outdoor temperature with measures of glucose and lipid metabolism in two populations of middle-aged European subjects. DESIGN: Cross-sectional study. SETTING: Two population-based European cohorts. PARTICIPANTS: Middle-aged nondiabetic subjects from the Oxford Biobank (OBB; N = 4327; mean age, 41.4 years) and the Netherlands Epidemiology of Obesity (NEO) study (N = 5899; mean age, 55.6 years). INTERVENTIONS: Data on outdoor bright sunlight and temperature collected from local weather stations. MAIN OUTCOME MEASURES: Insulin resistance and fasting lipid levels. Multivariable regression analyses were adjusted for age, sex, percentage body fat, season, and either outdoor temperature or bright sunlight. RESULTS: In the OBB cohort, increased bright sunlight exposure was associated with lower fasting insulin [-1.27% (95% CI, -2.09 to -0.47%) per extra hour of bright sunlight], lower homeostatic model assessment for insulin resistance (-1.36%; 95% CI, -2.23 to -0.50), lower homeostatic model assessment for ß-cell function (-0.80%; 95% CI, -1.31 to -0.30), and lower triglyceride (-1.28%; 95% CI, -2.07 to -0.50) levels. In the NEO cohort generally unidirectional but weaker associations were observed. No associations between outdoor temperature and measures of glucose or lipid metabolism were detected following adjustment for bright sunlight. CONCLUSIONS: Bright sunlight, but not outdoor temperature, might be associated with increased insulin sensitivity and lower triglyceride levels.

16.
Am J Hum Genet ; 104(1): 112-138, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30595373

RESUMO

Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E-04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E-03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E-06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.


Assuntos
DNA Mitocondrial/genética , Genes Mitocondriais/genética , Variação Genética/genética , Metabolismo/genética , Mitocôndrias/genética , Mitocôndrias/metabolismo , Adipócitos/metabolismo , Índice de Massa Corporal , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Estudos de Coortes , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Glucose/metabolismo , Hemoglobina A Glicada/metabolismo , Humanos , Insulina/metabolismo , Locos de Características Quantitativas , Relação Cintura-Quadril
17.
J Alzheimers Dis ; 67(1): 279-289, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30584139

RESUMO

BACKGROUND: An abnormally wide spatial QRS-T angle on an ECG is a marker of heterogeneity in electrical activity of cardiac ventricles and is linked with cardiovascular events. Growing evidence suggests that cardiac dysfunction might signal future cognitive decline. OBJECTIVE: In this study, we investigated whether spatial QRS-T angle associates with future cognitive decline in older subjects at high cardiovascular risk. METHODS: We included 4,172 men and women (mean age 75.2±3.3 years) free of cardiac arrhythmias from the PROSPER cohort. Spatial QRS-T angle was calculated from baseline 12-lead ECGs using a matrix transformation method. Cognitive function was assessed using 4 neuropsychological tests including Stroop test, letter-digit coding test, immediate and delayed picture word learning tests. Cognitive function was assessed at baseline and repeatedly during a mean follow-up time of 3.2 years. Using linear mixed models, we calculated the annual changes of cognitive scores in sex-specific thirds of spatial QRS-T angle. RESULTS: Participants with wider spatial QRS-T angle had a steeper decline in letter-digit coding test (ß= -0.0106, p = 0.004), immediate picture-word learning test (ß= -0.0049, p = 0.001), and delayed picture-word learning test (ß= -0.0055, p = 0.013). All associations were independent of arrhythmias, cardiovascular risk factors, comorbidities, medication use, cardiovascular events, and other ECG abnormalities including QRS duration, QTc interval, T wave abnormalities, and left ventricular hypertrophy. CONCLUSION: Abnormal cardiac electrical activity characterized by wide spatial QRS-T angle associates with accelerated cognitive decline independent of conventional cardiovascular factors. These findings suggest a link between a non-traditional ECG measure of pre-clinical cardiac pathology and future cognitive decline.

18.
Eur J Hum Genet ; 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30420679

RESUMO

According to the current dogma, cholesteryl ester transfer protein (CETP) decreases high-density lipoprotein (HDL)-cholesterol (C) and increases low-density lipoprotein (LDL)-C. However, detailed insight into the effects of CETP on lipoprotein subclasses is lacking. Therefore, we used a Mendelian randomization approach based on a genetic score for serum CETP concentration (rs247616, rs12720922 and rs1968905) to estimate causal effects per unit (µg/mL) increase in CETP on 159 standardized metabolic biomarkers, primarily lipoprotein subclasses. Metabolic biomarkers were measured by nuclear magnetic resonance (NMR) in 5672 participants of the Netherlands Epidemiology of Obesity (NEO) study. Higher CETP concentrations were associated with less large HDL (largest effect XL-HDL-C, P = 6 × 10-22) and more small VLDL components (largest effect S-VLDL cholesteryl esters, P = 6 × 10-6). No causal effects were observed with LDL subclasses. All these effects were replicated in an independent cohort from European ancestry (MAGNETIC NMR GWAS; n ~20,000). Additionally, we assessed observational associations between ELISA-measured CETP concentration and metabolic measures. In contrast to results from Mendelian randomization, observationally, CETP concentration predominantly associated with more VLDL, IDL and LDL components. Our results show that CETP is an important causal determinant of HDL and VLDL concentration and composition, which may imply that the CETP inhibitor anacetrapib decreased cardiovascular disease risk through specific reduction of small VLDL rather than LDL. The contrast between genetic and observational associations might be explained by a high capacity of VLDL, IDL and LDL subclasses to carry CETP, thereby concealing causal effects on HDL.

19.
Nat Commun ; 9(1): 4455, 2018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30367059

RESUMO

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

20.
Artigo em Inglês | MEDLINE | ID: mdl-30321297

RESUMO

Candidate gene studies and genome-wide association studies found that genetic variation in APOE is robustly associated with multiple age-related diseases and longevity. Apolipoprotein E (ApoE) is an apolipoprotein that plays an important role in triglyceride and cholesterol metabolism. In literature, especially the ApoE ɛ4 isoform has been associated with an increased risk of mortality and age-related diseases such as Alzheimer's disease (AD), cardiovascular diseases (CVD), as compared to the "neutral" ApoE ɛ3 isoform. There are, however, large differences in the deleterious effects of the ApoE ɛ4 isoform between ancestries and populations, which might be explained by differences in environmental and lifestyle exposures. In this respect, poor nutrition and physical inactivity are two important lifestyle factors that have been associated with increased risks for AD and CVD. Therefore, in this narrative review, we discuss how omega-3 fatty acid intake and physical activity may modify the impact of ApoE ɛ4 on AD and CVD risk.

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