Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 119
Filtrar
1.
J Lipid Res ; 63(5): 100193, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35278410

RESUMO

Triglyceride (TG)-lowering LPL variants in combination with genetic LDL-C-lowering variants are associated with reduced risk of coronary artery disease (CAD). Genetic variation in the APOA5 gene encoding apolipoprotein A-V also strongly affects TG levels, but the potential clinical impact and underlying mechanisms are yet to be resolved. Here, we aimed to study the effects of APOA5 genetic variation on CAD risk and plasma lipoproteins through factorial genetic association analyses. Using data from 309,780 European-ancestry participants from the UK Biobank, we evaluated the effects of lower TG levels as a result of genetic variation in APOA5 and/or LPL on CAD risk with or without a background of reduced LDL-C. Next, we compared lower TG levels via APOA5 and LPL variation with over 100 lipoprotein measurements in a combined sample from the Netherlands Epidemiology of Obesity study (N = 4,838) and the Oxford Biobank (N = 6,999). We found that lower TG levels due to combined APOA5 and LPL variation and genetically-influenced lower LDL-C levels afforded the largest reduction in CAD risk (odds ratio: 0.78 (0.73-0.82)). Compared to patients with genetically-influenced lower TG via LPL, genetically-influenced lower TG via APOA5 had similar and independent, but notably larger, effects on the lipoprotein profile. Our results suggest that lower TG levels as a result of APOA5 variation have strong beneficial effects on CAD risk and the lipoprotein profile, which suggest apo A-V may be a potential novel therapeutic target for CAD prevention.


Assuntos
Doença da Artéria Coronariana , Apolipoproteína A-V/genética , Apolipoproteínas A/genética , LDL-Colesterol , Doença da Artéria Coronariana/genética , Humanos , Lipoproteínas , Triglicerídeos
2.
Nat Genet ; 54(2): 152-160, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35115687

RESUMO

Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Transtornos de Enxaqueca/genética , Polimorfismo de Nucleotídeo Único , Alelos , Sistema Cardiovascular/metabolismo , Estudos de Casos e Controles , Sistema Nervoso Central/metabolismo , Loci Gênicos , Humanos , Enxaqueca com Aura/genética , Anotação de Sequência Molecular , Locos de Características Quantitativas
3.
Eur J Endocrinol ; 186(3): 407-416, 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35049520

RESUMO

OBJECTIVE: Epidemiological and clinical studies have highlighted important roles for sex hormones in the regulation of fat distribution and systemic metabolism. We investigated the bidirectional associations between bioavailable serum testosterone (BioT) in both sexes and oestradiol (E2) in men and adiposity and metabolic traits using Mendelian randomisation (MR). DESIGN AND METHODS: As genetic instruments for sex hormones, we selected all the genome-wide significant, independent signals from a genome-wide association studies (GWAS) in up to 425 097 European ancestry UK Biobank participants. European population-specific, summary-level data for adiposity, metabolic, and blood pressure traits were obtained from the largest publicly available GWAS. Sex-specific, two-sample MR analyses were used to estimate the associations of sex hormones with these traits and vice versa. RESULTS: In women, higher BioT was associated with obesity, upper-body fat distribution, and low HDL-cholesterol although, based on analyses modelling the sex hormone-binding globulin-independent effects of BioT, the last two associations might be indirect. Conversely, obesity and android fat distribution were associated with elevated serum BioT. In men, higher BioT was associated with lower hip circumference and lower fasting glucose. Reciprocally, obesity was associated with lower BioT and higher E2, while upper-body fat distribution and raised triglycerides were associated with lower E2. CONCLUSIONS: Adipose tissue and metabolic dysfunction are associated with deranged sex hormone levels in both sexes. In women, elevated BioT might be a cause of obesity. Conversely, in men, higher BioT appears to have beneficial effects on adiposity and glucose metabolism.


Assuntos
Adiposidade/genética , Hormônios Esteroides Gonadais/genética , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana
4.
Int J Obes (Lond) ; 46(3): 515-522, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34782736

RESUMO

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 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.


Assuntos
Glicemia , Resistência à Insulina , Idoso , Glicemia/metabolismo , Índice de Massa Corporal , Peso Corporal , Estudos Transversais , Exercício Físico , Feminino , Hemoglobina A Glicada/análise , Humanos , Insulina/metabolismo , Masculino , Pessoa de Meia-Idade
5.
J Clin Endocrinol Metab ; 107(2): e643-e652, 2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-34514498

RESUMO

CONTEXT: Thyroid dysfunction is associated with higher anemia prevalence, although causality remains unclear. OBJECTIVE: This study aimed to investigate the association between thyroid function and anemia. METHODS: This cross-sectional and Mendelian randomization study included 445 482 European participants from the UK Biobank (mean age 56.77 years (SD 8.0); and 54.2% women). Self-reported clinical diagnosis of hypothyroidism was stated by 21 860 (4.9%); self-reported clinical diagnosis of hyperthyroidism by 3431 (0.8%). Anemia, defined as hemoglobin level of < 13 g/dL in men and < 12 g/dL in women, was present in 18 717 (4.2%) participants. RESULTS: In cross-sectional logistic regression analyses, self-reported clinical diagnoses of hypo- and hyperthyroidism were associated with higher odds of anemia (OR 1.12; 95% CI, 1.05-1.19 and OR 1.09; 95% CI, 0.91-1.30), although with wide confidence intervals for hyperthyroidism. We did not observe an association of higher or lower genetically influenced thyrotropin (TSH) with anemia (vs middle tertile: OR for lowest tertile 0.98 [95% CI, 0.95-1.02]; highest tertile 1.02 [95% CI, 0.98-1.06]), nor of genetically influenced free thyroxine (fT4) with anemia. Individuals with genetic variants in the DIO3OS gene implicated in intracellular regulation of thyroid hormones had a higher anemia risk (OR 1.05; 95% CI, 1.02-1.10); no association was observed with variants in DIO1 or DIO2 genes. CONCLUSION: While self-reported clinical diagnosis of hypothyroidism was associated with higher anemia risk, we did not find evidence supporting a causal association with variation of thyroid function within the euthyroid range. However, intracellular regulation of thyroid hormones might play a role in developing anemia.


Assuntos
Anemia/epidemiologia , Hipotireoidismo/genética , Glândula Tireoide/fisiopatologia , Idoso , Anemia/genética , Bancos de Espécimes Biológicos/estatística & dados numéricos , Causalidade , Estudos de Coortes , Estudos Transversais , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hipotireoidismo/diagnóstico , Hipotireoidismo/patologia , Hipotireoidismo/fisiopatologia , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Prevalência , Autorrelato , Tireotropina/sangue , Reino Unido/epidemiologia
6.
Diabetes Care ; 45(3): 674-683, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35085396

RESUMO

OBJECTIVE: Type 2 diabetes (T2D) has heterogeneous patient clinical characteristics and outcomes. In previous work, we investigated the genetic basis of this heterogeneity by clustering 94 T2D genetic loci using their associations with 47 diabetes-related traits and identified five clusters, termed ß-cell, proinsulin, obesity, lipodystrophy, and liver/lipid. The relationship between these clusters and individual-level metabolic disease outcomes has not been assessed. RESEARCH DESIGN AND METHODS: Here we constructed individual-level partitioned polygenic scores (pPS) for these five clusters in 12 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (n = 454,193) and tested for cross-sectional association with T2D-related outcomes, including blood pressure, renal function, insulin use, age at T2D diagnosis, and coronary artery disease (CAD). RESULTS: Despite all clusters containing T2D risk-increasing alleles, they had differential associations with metabolic outcomes. Increased obesity and lipodystrophy cluster pPS, which had opposite directions of association with measures of adiposity, were both significantly associated with increased blood pressure and hypertension. The lipodystrophy and liver/lipid cluster pPS were each associated with CAD, with increasing and decreasing effects, respectively. An increased liver/lipid cluster pPS was also significantly associated with reduced renal function. The liver/lipid cluster includes known loci linked to liver lipid metabolism (e.g., GCKR, PNPLA3, and TM6SF2), and these findings suggest that cardiovascular disease risk and renal function may be impacted by these loci through their shared disease pathway. CONCLUSIONS: Our findings support that genetically driven pathways leading to T2D also predispose differentially to clinical outcomes.


Assuntos
Diabetes Mellitus Tipo 2 , Preparações Farmacêuticas , Alelos , Estudos Transversais , Diabetes Mellitus Tipo 2/genética , Loci Gênicos , Humanos , Obesidade/genética , Preparações Farmacêuticas/metabolismo
7.
Nutrition ; 93: 111440, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34534944

RESUMO

Vitamin E (α-tocopherol [α-TOH]) is transported in lipoprotein particles in blood, but little is known about the transportation of its oxidized metabolites. In the Netherlands Epidemiology of Obesity Study, we aimed to investigate the associations of 147 circulating metabolomic measures obtained through targeted nuclear magnetic resonance with serum α-TOH and its urinary enzymatic (α-CEHC) and oxidized (α-TLHQ) metabolites from 24-h urine quantified by liquid chromatography with tandem mass spectrometry. Multivariable linear regression analyses, in which multiple testing was taken into account, were performed to assess associations between metabolomic measures (determinants; standardized to mean = 0, SD = 1) and vitamin E metabolites (outcomes), adjusted for demographic factors. We analyzed 474 individuals (55% women, 45% men) with a mean (SD) age of 55.7 (6.0) y. Out of 147 metabolomic measures, 106 were associated (P < 1.34 × 10-3) with serum α-TOH (median ß [interquartile range] = 0.416 [0.383-0.466]), predominantly lipoproteins associated with higher α-TOH. The associations of metabolomic measures with urinary α-CEHC have directions similar to those with α-TOH, but effect sizes were smaller and non-significant (median ß [interquartile range] = 0.065 [0.047-0.084]). However, associations of metabolomic measures with urinary α-TLHQ were markedly different from those with both serum α-TOH and urinary α-CEHC, with negative and small-to-null relations to most very-low-density lipoproteins and amino acids. Therefore, our results highlight the differences in the lipoproteins involved in the transportation of circulating α-TOH and oxidized vitamin E metabolites. This indicates that circulating α-TOH may be representative of the enzymatic but not the antioxidative function of vitamin E.


Assuntos
Metaboloma , Vitamina E , alfa-Tocoferol , Antioxidantes , Feminino , Humanos , Lipoproteínas , Masculino , Pessoa de Meia-Idade , Oxirredução , Vitamina E/sangue , Vitamina E/urina , alfa-Tocoferol/sangue , alfa-Tocoferol/urina
8.
Geroscience ; 2021 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-34932184

RESUMO

The significance of classical risk factors in coronary artery disease (CAD) remains unclear in older age due to possible changes in underlying disease pathologies. Therefore, we conducted Mendelian Randomization approaches to investigate the causal relationship between classical risk factors and primary CAD in different age groups. A Mendelian Randomization study was conducted in European-ethnicity individuals from the UK Biobank population. Analyses were performed using data of 22,313 CAD cases (71.6% men) and 407,920 controls (44.5% men). Using logistic regression analyses, we investigated the associations between standardized genetic risk score and primary CAD stratified by age of diagnosis. In addition, feature importance and model accuracy were assessed in different age groups to evaluate predictive power of the genetic risk scores with increasing age. We found age-dependent associations for all classical CAD risk factors. Notably, body mass index (OR 1.22 diagnosis < 50 years; OR 1.02 diagnosis > 70 years), blood pressure (OR 1.12 < 50 years; OR 1.04 > 70 years), LDL cholesterol (OR 1.16 < 50 years; OR 1.02 > 70 years), and triglyceride levels (OR 1.11 < 50 years; 1.04 > 70 years). In line with the Mendelian Randomization analyses, model accuracy and feature importance of the classical risk factors decreased with increasing age of diagnosis. Causal determinants for primary CAD are age dependent with classical CAD risk factors attenuating in relation with primary CAD with increasing age. These results question the need for (some) currently applied cardiovascular disease risk reducing interventions at older age.

9.
BMC Med ; 19(1): 266, 2021 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-34727949

RESUMO

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 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.


Assuntos
Doenças Cardiovasculares , Tireotropina , Adulto , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Feminino , Humanos , Lipídeos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Tiroxina , Adulto Jovem
10.
J Crohns Colitis ; 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34739073

RESUMO

BACKGROUND AND AIMS: Observational studies have suggested a bidirectional association between depression and inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). However, it remains unclear whether observed associations are casual due to the difficulties of determining sequential temporality. We investigated the association between depression and IBD by using bidirectional two-sample Mendelian randomization (MR). METHODS: Independent genetic variants for depression and IBD were selected as instruments from published genome-wide association studies (GWAS) among individuals of predominantly European ancestry. Summary statistics for instrument-outcome associations were retrieved from three separate databases for both depression (Psychiatric Genomics Consortium, FinnGen, and UK Biobank), and IBD (the largest GWAS meta-analysis, FinnGen, and UK Biobank), respectively. MR analyses included inverse-variance weighted method, weighted-median estimator, MR-Egger regression, and sensitivity analyses of Steiger filtering and MR PRESSO. From either direction, analyses were performed per outcome database and were subsequently meta-analyzed using fixed-effect model. RESULTS: Genetically predicted depression (per log-odds ratio increase) was associated with a higher risk of IBD; odds ratios (95% confidence interval) for IBD, CD and UC were 1.20 (1.05, 1.36), 1.29 (1.07, 1.56) and 1.22 (1.01, 1.47) in a combined sample size of 693,183 (36,507 IBD cases), 212,172 (13,714 CD cases) and 219,686 (15,691 UC cases) individuals, respectively. In contrast, no association was observed between genetically influenced IBD and depression in 534,635 individuals (71,466 depression cases). CONCLUSIONS: Our findings corroborated a causal association of depression on IBD, which may impact the clinical decision on the management of depression in patients with IBD. Though our results did not support a causal effect of IBD on depression, further investigations are needed to clarify the effect of IBD activity on depression (with different symptomology).

11.
HGG Adv ; 2(1)2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-34734193

RESUMO

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (PLCL2), synaptic function and neurotransmission (LIN7A, PFIA2), as well as genes previously implicated in neuropsychiatric or stress-related disorders (FSTL5, CHODL). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

12.
J Am Heart Assoc ; 10(23): e022567, 2021 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-34796734

RESUMO

Background Dietary intake and blood concentrations of vitamins E and C, lycopene, and carotenoids have been associated with a lower risk of incident (ischemic) stroke. However, causality cannot be inferred from these associations. Here, we investigated causality by analyzing the associations between genetically influenced antioxidant levels in blood and ischemic stroke using Mendelian randomization. Methods and Results For each circulating antioxidant (vitamins E and C, lycopene, ß-carotene, and retinol), which were assessed as either absolute blood levels and/or high-throughput metabolite levels, independent genetic instrumental variables were selected from earlier genome-wide association studies (P<5×10-8). We used summary statistics for single-nucleotide polymorphisms-stroke associations from 3 European-ancestry cohorts (cases/controls): MEGASTROKE (60 341/454 450), UK Biobank (2404/368 771), and the FinnGen study (8046/164 286). Mendelian randomization analyses were performed on each exposure per outcome cohort using inverse variance-weighted analyses and subsequently meta-analyzed. In a combined sample of 1 058 298 individuals (70 791 cases), none of the genetically influenced absolute antioxidants or antioxidant metabolite concentrations were causally associated with a lower risk of ischemic stroke. For absolute antioxidants levels, the odds ratios (ORs) ranged between 0.94 (95% CI, 0.85-1.05) for vitamin C and 1.04 (95% CI, 0.99-1.08) for lycopene. For metabolites, ORs ranged between 1.01 (95% CI, 0.98-1.03) for retinol and 1.12 (95% CI, 0.88-1.42) for vitamin E. Conclusions This study did not provide evidence for a causal association between dietary-derived antioxidant levels and ischemic stroke. Therefore, antioxidant supplements to increase circulating levels are unlikely to be of clinical benefit to prevent ischemic stroke.


Assuntos
Antioxidantes , Dieta , AVC Isquêmico , Antioxidantes/administração & dosagem , Antioxidantes/análise , Dieta/estatística & dados numéricos , Estudo de Associação Genômica Ampla , Humanos , AVC Isquêmico/sangue , AVC Isquêmico/epidemiologia , AVC Isquêmico/genética , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Medição de Risco
13.
Sci Rep ; 11(1): 19365, 2021 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-34588469

RESUMO

Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV1), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV1. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.


Assuntos
Fumar Cigarros/epidemiologia , Volume Expiratório Forçado/genética , Interação Gene-Ambiente , Adulto , Idoso , Idoso de 80 Anos ou mais , Fumar Cigarros/efeitos adversos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Conjuntos de Dados como Assunto , Éxons/genética , Estudos de Viabilidade , Feminino , Estudo de Associação Genômica Ampla , Humanos , Pulmão/fisiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas G/genética , Fatores de Risco
14.
Aging Cell ; 20(8): e13445, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34312982

RESUMO

Observational studies have revealed associations between short leucocyte telomere length (LTL), a TL marker in somatic tissues and multiple Metabolic Syndrome (MetS) traits. Animal studies have supported these findings by showing that increased telomere attrition leads to adipose tissue dysfunction and insulin resistance. We investigated the associations between genetically instrumented LTL and MetS traits using Mendelian Randomisation (MR). Fifty-two independent variants identified at FDR<0.05 from a genome-wide association study (GWAS) including 78,592 Europeans and collectively accounting for 2.93% of LTL variance were selected as genetic instruments for LTL. Summary-level data for MetS traits and for the MetS as a binary phenotype were obtained from the largest publicly available GWAS and two-sample MR analyses were used to estimate the associations of LTL with these traits. The combined effect of the genetic instruments was modelled using inverse variance weighted regression and sensitivity analyses with MR-Egger, weighted-median and MR-PRESSO were performed to test for and correct horizonal pleiotropy. Genetically instrumented longer LTL was associated with higher waist-to-hip ratio adjusted for body mass index (ß = 0.045 SD, SE = 0.018, p = 0.01), raised systolic (ß = 1.529 mmHg, SE = 0.332, p = 4x10-6 ) and diastolic (ß = 0.633 mmHg, SE = 0.222, p = 0.004) blood pressure, and increased MetS risk (OR = 1.133, 95% CI 1.057-1.215). Consistent results were obtained in sensitivity analyses, which provided no evidence of unbalanced horizontal pleiotropy. Telomere shortening might not be a major driver of cellular senescence and dysfunction in human adipose tissue. Future experimental studies should examine the mechanistic bases for the links between longer LTL and increased upper-body fat distribution and raised blood pressure.


Assuntos
Análise da Randomização Mendeliana/métodos , Síndrome Metabólica/genética , Telômero/genética , Humanos
15.
Atherosclerosis ; 328: 33-37, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34082327

RESUMO

BACKGROUND AND AIMS: The APOE ε4 genotype has a higher risk for developing coronary artery disease (CAD), but there is preliminary evidence that antioxidative lifestyle factors interact with APOE genotype on CAD risk. Here, we assessed the effect modification of physical activity, oily fish and polyunsaturated fatty acid (PUFA) intake with APOE genotype on risk of incident CAD. METHODS: The present study comprised 345,659 white European participants from UK Biobank (mean age: 56.5 years, 45.7% men) without a history of CAD. Information regarding physical activity, oily fish intake and PUFA intake was collected through questionnaires, and information on incident CAD through linkage with hospital admission records. Analyses were performed using Cox proportional hazard models adjusted for age and sex. RESULTS: Higher physical activity level and oily fish intake were both associated with a lower incidence of CAD. However, these associations were similar across the different APOE genotypes (p-values for interaction > 0.05). Most notable, higher PUFA intake was associated with a lower CAD risk in APOE ε4 genotype carriers (hazard ratio: 0.76, 95% confidence interval: 0.63-0.92), and not in APOE ε3/ε3 genotype carriers (0.90; 0.79, 1.02), but without statistical evidence for effect modification (p-valueinteraction = 0.137). CONCLUSIONS: While higher physical activity and high fish and PUFA intake were associated with a lower risk of incident CAD, no evidence for interaction of these lifestyle factors with APOE genotype was observed in UK Biobank participants. Interventions intended to reduce cardiovascular risk might therefore be similarly effective across the APOE genotype carriers.


Assuntos
Doença da Artéria Coronariana , Animais , Apolipoproteínas E/genética , Bancos de Espécimes Biológicos , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/genética , Feminino , Interação Gene-Ambiente , Genótipo , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Reino Unido/epidemiologia
16.
Metabolomics ; 17(6): 57, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34106350

RESUMO

BACKGROUND: Insulin is the key regulator of glucose metabolism, but it is difficult to dissect direct insulin from glucose-induced effects. We aimed to investigate the effects of hyperinsulemia on metabolomic measures under euglycemic conditions in nondiabetic participants. METHODS: We assessed concentrations of 151 metabolomic measures throughout a two-step hyperinsulinemic euglycemic clamp procedure. We included 24 participants (50% women, mean age = 62 [s.d. = 4.2] years) and metabolomic measures were assessed under baseline, low-dose (10 mU/m2/min) and high-dose (40 mU/m2/min) insulin conditions. The effects of low- and high-dose insulin infusion on metabolomic measures were analyzed using linear mixed-effect models for repeated measures. RESULTS: After low-dose insulin infusion, 90 metabolomic measures changed in concentration (p < 1.34e-4), among which glycerol (beta [Confidence Interval] = - 1.41 [- 1.54, - 1.27] s.d., p = 1.28e-95) and three-hydroxybutyrate (- 1.22 [- 1.36, - 1.07] s.d., p = 1.44e-61) showed largest effect sizes. After high-dose insulin infusion, 121 metabolomic measures changed in concentration, among which branched-chain amino acids showed the largest additional decrease compared with low-dose insulin infusion (e.g., Leucine, - 1.78 [- 1.88, - 1.69] s.d., P = 2.7e-295). More specifically, after low- and high-dose insulin infusion, the distribution of the lipoproteins shifted towards more LDL-sized particles with decreased mean diameters. CONCLUSION: Metabolomic measures are differentially insulin sensitive and may thus be differentially affected by the development of insulin resistance. Moreover, our data suggests insulin directly affects metabolomic measures previously associated with increased cardiovascular disease risk.


Assuntos
Resistência à Insulina , Glicemia , Feminino , Técnica Clamp de Glucose , Humanos , Insulina , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade
17.
Nutr Metab Cardiovasc Dis ; 31(8): 2407-2415, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34158242

RESUMO

BACKGROUND AND AIMS: The accumulation of fat increases the formation of lipid peroxides, which are partly scavenged by alpha-tocopherol (α-TOH). Here, we aimed to investigate the associations between different measures of (abdominal) fat and levels of urinary α-TOH metabolites in middle-aged individuals. METHODS AND RESULTS: In this cross-sectional analysis in the Netherlands Epidemiology of Obesity study (N = 511, 53% women; mean [SD] age of 55 [6.1] years), serum α-TOH and α-TOH metabolites from 24-h urine were measured as alpha-tocopheronolactone hydroquinone (α-TLHQ, oxidized) and alpha-carboxymethyl-hydroxychroman (α-CEHC, enzymatically converted) using liquid-chromatography-tandem mass spectrometry. Body mass index and total body fat were measured, and abdominal subcutaneous and visceral adipose tissue (aSAT and VAT) were assessed using magnetic resonance imaging. Using multivariable-adjusted linear regression analyses, we analysed the associations of BMI, TBF, aSAT and VAT with levels of urinary α-TOH metabolites, adjusted for confounders. We observed no evidence for associations between body fat measures and serum α-TOH. Higher BMI and TBF were associated with lower urinary levels of TLHQ (0.95 [95%CI: 0.90, 1.00] and 0.94 [0.88, 1.01] times per SD, respectively) and with lower TLHQ relative to CEHC (0.93 [0.90, 0.98] and 0.93 [0.87, 0.98] times per SD, respectively). We observed similar associations for VAT (TLHQ: 0.94 [0.89, 0.99] times per SD), but not for aSAT. CONCLUSIONS: Opposite to our research hypothesis, higher abdominal adiposity was moderately associated with lower levels of oxidized α-TOH metabolites, which might reflect lower vitamin E antioxidative activity in individuals with higher abdominal fat instead.


Assuntos
Adiposidade , Gordura Intra-Abdominal/fisiopatologia , Obesidade Abdominal/sangue , Obesidade Abdominal/fisiopatologia , alfa-Tocoferol/sangue , Fatores Etários , Biomarcadores/sangue , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Gordura Intra-Abdominal/metabolismo , Peroxidação de Lipídeos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Obesidade Abdominal/diagnóstico , Obesidade Abdominal/epidemiologia
18.
Ann Neurol ; 90(2): 203-216, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34180076

RESUMO

OBJECTIVE: Identifying common genetic variants that confer genetic risk for cluster headache. METHODS: We conducted a case-control study in the Dutch Leiden University Cluster headache neuro-Analysis program (LUCA) study population (n = 840) and unselected controls from the Netherlands Epidemiology of Obesity Study (NEO; n = 1,457). Replication was performed in a Norwegian sample of 144 cases from the Trondheim Cluster headache sample and 1,800 controls from the Nord-Trøndelag Health Survey (HUNT). Gene set and tissue enrichment analyses, blood cell-derived RNA-sequencing of genes around the risk loci and linkage disequilibrium score regression were part of the downstream analyses. RESULTS: An association was found with cluster headache for 4 independent loci (r2 < 0.1) with genomewide significance (p < 5 × 10-8 ), rs11579212 (odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.33-1.72 near RP11-815 M8.1), rs6541998 (OR = 1.53, 95% CI = 1.37-1.74 near MERTK), rs10184573 (OR = 1.43, 95% CI = 1.26-1.61 near AC093590.1), and rs2499799 (OR = 0.62, 95% CI = 0.54-0.73 near UFL1/FHL5), collectively explaining 7.2% of the variance of cluster headache. SNPs rs11579212, rs10184573, and rs976357, as proxy SNP for rs2499799 (r2  = 1.0), replicated in the Norwegian sample (p < 0.05). Gene-based mapping yielded ASZ1 as possible fifth locus. RNA-sequencing indicated differential expression of POLR1B and TMEM87B in cluster headache patients. INTERPRETATION: This genomewide association study (GWAS) identified and replicated genetic risk loci for cluster headache with effect sizes larger than those typically seen in complex genetic disorders. ANN NEUROL 2021;90:203-216.


Assuntos
Cefaleia Histamínica/epidemiologia , Cefaleia Histamínica/genética , Loci Gênicos/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Países Baixos/epidemiologia , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de RNA/métodos
19.
J Clin Endocrinol Metab ; 106(11): e4438-e4447, 2021 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-34181708

RESUMO

CONTEXT: Weight gain during adulthood increases cardiometabolic disease risk, possibly through adipocyte hypertrophy. OBJECTIVE: We aimed to study the specific metabolomic profile of adult weight gain, and to examine its association with adipocyte volume. METHODS: Nuclear magnetic resonance-based metabolomics were measured in the Netherlands Epidemiology of Obesity (NEO) study (n = 6347, discovery) and Oxford Biobank (n = 6317, replication). Adult weight gain was calculated as the absolute difference between body mass index (BMI) at middle age and recalled BMI at age 20 years. We performed linear regression analyses with both exposures BMI at age 20 years and weight gain, and separately with BMI at middle age in relation to 149 serum metabolomic measures, adjusted for age, sex, and multiple testing. Additionally, subcutaneous abdominal adipocyte biopsies were collected in a subset of the Oxford Biobank (n = 114) to estimate adipocyte volume. RESULTS: Mean (SD) weight gain was 4.5 (3.7) kg/m2 in the NEO study and 3.6 (3.7) kg/m2 in the Oxford Biobank. Weight gain, and not BMI at age 20 nor middle age, was associated with concentrations of 7 metabolomic measures after successful replication, which included polyunsaturated fatty acids, small to medium low-density lipoproteins, and total intermediate-density lipoprotein. One SD weight gain was associated with 386 µm3 (95% CI, 143-629) higher median adipocyte volume. Adipocyte volume was associated with lipoprotein particles specific for adult weight gain. CONCLUSION: Adult weight gain is associated with specific metabolomic alterations of which the higher lipoprotein concentrations were likely contributed by larger adipocyte volumes, presumably linking weight gain to cardiometabolic disease.


Assuntos
Adipócitos/patologia , Metaboloma/fisiologia , Ganho de Peso/fisiologia , Gordura Abdominal/patologia , Envelhecimento , Biópsia , Índice de Massa Corporal , Estudos de Coortes , Feminino , Humanos , Lipoproteínas/sangue , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Obesidade/epidemiologia
20.
Atherosclerosis ; 328: 144-152, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34053745

RESUMO

BACKGROUND AND AIMS: Mendelian randomization studies have shown that triglyceride (TG)- lowering lipoprotein lipase (LPL) alleles and low-density lipoprotein-cholesterol (LDL-C)-lowering alleles have independent beneficial associations on cardiovascular disease (CVD) risk. We aimed to provide further insight into this observation by applying Mendelian randomization analyses of genetically-influenced TG and LDL-C levels on plasma metabolomic profiles. METHODS: We quantified over 100 lipoprotein metabolomic measures in the Netherlands Epidemiology of Obesity (NEO) study (N = 4838) and Oxford Biobank (OBB) (N = 6999) by nuclear magnetic resonance (NMR) spectroscopy. Weighted genetic scores for TG via five LPL alleles and LDL-C via 19 alleles were calculated and dichotomized by the median, resulting in four genotype combinations of high/low TG and high/low LDL-C. We performed linear regression analyses using a two × two design with the group with genetically-influenced high TG and LDL-C as a reference. RESULTS: Compared to the individual groups with genetically-influenced lower TG or lower LDL-C only, the group with combined genetically-influenced lower TG and LDL-C showed an overall independent and additive pattern of changes in metabolomic measures. Over 100 measures were different (p < 1.35 × 10-3) compared to the reference, with effect sizes and directionality being similar in NEO and OBB. Most notably, levels of all very-low density lipoprotein (VLDL) and LDL sub-particles were lower. CONCLUSIONS: Our findings provide evidence that TG-lowering on top of LDL-C-lowering has additive beneficial effects on the lipoprotein profile compared to TG-lowering or LDL-C-lowering only, which is in accordance with reported additive genetic effects on CVD risk reduction.


Assuntos
Lipase , Lipase Lipoproteica , Alelos , LDL-Colesterol/genética , Lipase Lipoproteica/genética , Lipoproteínas , Países Baixos , Triglicerídeos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...