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1.
Nutrients ; 13(11)2021 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-34836312

RESUMO

We assessed associations between infant diet (e.g., breastfeeding and introduction to solid foods) and DNA methylation in infancy and childhood. We measured DNA methylation in peripheral blood collected in infancy (9-15 months of age) in 243 children; and in a subset of 50 children, we also measured methylation in childhood (6-9 years of age) to examine persistence, and at birth (in cord blood) to examine temporality. We performed multivariable linear regression of infant diet on the outcome of methylation using epigenome-wide and candidate site approaches. We identified six novel CpG sites associated with breastfeeding duration using an EWAS approach. One differentially methylated site presented directionally consistent associations with breastfeeding (cg00574958, CPT1A) in infancy and childhood but not at birth. Two differentially methylated sites in infancy (cg19693031, TXNIP; cg23307264, KHSRP) were associated with breastfeeding and were not present at birth; however, these associations did not persist into childhood. Associations between infant diet and methylation in infancy at three sites (cg22369607, AP001525.1; cg2409200, TBCD; cg27173510, PGBD5) were also present at birth, suggesting the influence of exposures other than infant diet. Infant diet exposures are associated with persistent methylation differences in CPT1A, which may be one mechanism behind infant diet's long-term health effects.

2.
Front Nutr ; 8: 720041, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34604278

RESUMO

Objectives: An observed variation in the risk of celiac disease, according to the season of birth, suggests that vitamin D may affect the development of the disease. The aim of this study was to investigate if vitamin D concentration is associated with the risk of celiac disease autoimmunity (CDA) in genetically at-risk children. Study Design: Children prospectively followed in the multinational The Environmental Determinants of Diabetes in the Young study, conducted at six centers in Europe and the US, were selected for a 1-to-3 nested case-control study. In total, 281 case-control sets were identified. CDA was defined as positivity for tissue transglutaminase autoantibodies (tTGA) on two or more consecutive visits. Vitamin D was measured as 25-hydroxyvitamin D [25(OH)D] concentrations in all plasma samples prior to, and including, the first tTGA positive visit. Conditional logistic regression was used to examine the association between 25(OH)D and risk of CDA. Results: No significant association was seen between 25(OH)D concentrations (per 5 nmol/L increase) and risk for CDA development during early infancy (odds ratio [OR] 0.99, 95% confidence interval [CI] 0.95-1.04) or childhood (OR 1.02, 95% CI 0.97-1.07). When categorizing 25(OH)D concentrations, there was an increased risk of CDA with 25(OH)D concentrations <30 nmol/L (OR 2.23, 95% CI 1.29, 3.84) and >75 nmol/L (OR 2.10, 95% CI 1.28-3.44) in early infancy, as compared with 50-75 nmol/L. Conclusion: This study indicates that 25(OH)D concentrations <30 nmol/L and >75 nmol/L during early infancy were associated with an increased risk of developing CDA in genetically at-risk children. The non-linear relationship raises the need for more studies on the possible role of 25(OH)D in the relation to celiac disease onset.

3.
BMJ Open ; 11(9): e050883, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34521672

RESUMO

OBJECTIVE: Physical activity (PA) in preclinical rheumatoid arthritis (RA) is associated with lower RA risk and disease severity. As joint signs and symptoms of inflammatory arthritis serve as a barrier to PA in RA, it is important to consider whether they affect PA in the time prior to RA. Therefore, we investigated whether joint swelling, stiffness or pain were associated with PA in first-degree relatives (FDRs) of patients with RA, a population at higher risk for future RA. DESIGN: Prospective study design. SETTING: We recruited FDRs of patients with RA from academic centres, Veterans' hospitals and rheumatology clinics or through responses to advertising from six sites across the USA. PARTICIPANTS: We evaluated associations of joint stiffness, joint swelling and joint pain with PA time in 268 FDRs with ≥2 visits over an average 1.2 years. Clinicians confirmed joint swelling. Participants self-reported joint stiffness and/or pain. PRIMARY OUTCOME MEASURES: PA during a typical 24-hour day was quantified via questionnaire, weighted to reflect metabolic expenditure, where 24 hours was the minimum PA time. Linear mixed models evaluated associations between symptoms and change in PA over time, adjusting for age, sex, race, body mass index, smoking and RA-related autoantibodies. RESULTS: Average weighted PA time was 37±7 hours. In the cross-sectional analysis, PA time was 1.3±0.9 hours higher in FDRs reporting joint pain (p=0.15); and 0.8±1.6 and 0.4±1 hours lower in FDRs with joint swelling (p=0.60) and stiffness (p=0.69), respectively. Longitudinally, adjusting for baseline PA time, baseline symptoms were not significantly associated with changes in PA time. However, on average over time, joint stiffness and pain were associated with lower PA time (pinteraction=0.0002, pinteraction=0.002), and joint swelling was associated with higher PA time (pinteraction <0.0001). CONCLUSION: Baseline symptoms did not predict future PA time, but on average over time, joint symptoms influenced PA time.


Assuntos
Artrite Reumatoide , Artralgia/etiologia , Estudos Transversais , Exercício Físico , Humanos , Estudos Prospectivos
4.
BMC Res Notes ; 14(1): 352, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34496950

RESUMO

OBJECTIVE: Illumina BeadChip arrays are commonly used to generate DNA methylation data for large epidemiological studies. Updates in technology over time create challenges for data harmonization within and between studies, many of which obtained data from the older 450K and newer EPIC platforms. The pre-processing pipeline for DNA methylation is not trivial, and influences the downstream analyses. Incorporating different platforms adds a new level of technical variability that has not yet been taken into account by recommended pipelines. Our study evaluated the performance of various tools on different versions of platform data harmonization at each step of pre-processing pipeline, including quality control (QC), normalization, batch effect adjustment, and genomic inflation. We illustrate our novel approach using 450K and EPIC data from the Diabetes Autoimmunity Study in the Young (DAISY) prospective cohort. RESULTS: We found normalization and probe filtering had the biggest effect on data harmonization. Employing a meta-analysis was an effective and easily executable method for accounting for platform variability. Correcting for genomic inflation also helped with harmonization. We present guidelines for studies seeking to harmonize data from the 450K and EPIC platforms, which includes the use of technical replicates for evaluating numerous pre-processing steps, and employing a meta-analysis.


Assuntos
Metilação de DNA , Ilhas de CpG , Estudos Epidemiológicos , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Estudos Prospectivos
5.
Mol Metab ; 54: 101342, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34563731

RESUMO

OBJECTIVE: Identify and characterize circulating metabolite profiles associated with adiposity to inform precision medicine. METHODS: Untargeted plasma metabolomic profiles in the Insulin Resistance Atherosclerosis Family Study (IRASFS) Mexican American cohort (n = 1108) were analyzed for association with anthropometric (body mass index, BMI; waist circumference, WC; waist-to-hip ratio, WHR) and computed tomography measures (visceral adipose tissue, VAT; subcutaneous adipose tissue, SAT; visceral-to-subcutaneous ratio, VSR) of adiposity. Genetic data, inclusive of genome-wide array-based genotyping, whole exome sequencing (WES) and whole genome sequencing (WGS), were evaluated to identify the genetic contributors. Phenotypic and genetic association signals were replicated across ancestries. Transcriptomic data were analyzed to explore the relationship between genetic and metabolomic data. RESULTS: A partially characterized metabolite, tentatively named metabolonic lactone sulfate (X-12063), was consistently associated with BMI, WC, WHR, VAT, and SAT in IRASFS Mexican Americans (PMA <2.02 × 10-27). Trait associations were replicated in IRASFS African Americans (PAA < 1.12 × 10-07). Expanded analyses revealed associations with multiple phenotypic measures of cardiometabolic health, e.g. insulin sensitivity (SI), triglycerides (TG), diastolic blood pressure (DBP) and plasminogen activator inhibitor-1 (PAI-1) in both ancestries. Metabolonic lactone sulfate levels were heritable (h2 > 0.47), and a significant genetic signal at the ZSCAN25/CYP3A5 locus (PMA = 9.00 × 10-41, PAA = 2.31 × 10-10) was observed, highlighting a putative functional variant (rs776746, CYP3A5∗3). Transcriptomic analysis in the African American Genetics of Metabolism and Expression (AAGMEx) cohort supported the association of CYP3A5 with metabolonic lactone sulfate levels (PFDR = 6.64 × 10-07). CONCLUSIONS: Variant rs776746 is associated with a decrease in the transcript levels of CYP3A5, which in turn is associated with increased metabolonic lactone sulfate levels and poor cardiometabolic health.

6.
Metabolites ; 11(8)2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34436483

RESUMO

Environmental factors including viruses, diet, and the metabolome have been linked with the appearance of islet autoimmunity (IA) that precedes development of type 1 diabetes (T1D). We measured global DNA methylation (DNAm) and untargeted metabolomics prior to IA and at the time of seroconversion to IA in 92 IA cases and 91 controls from the Diabetes Autoimmunity Study in the Young (DAISY). Causal mediation models were used to identify seven DNAm probe-metabolite pairs in which the metabolite measured at IA mediated the protective effect of the DNAm probe measured prior to IA against IA risk. These pairs included five DNAm probes mediated by histidine (a metabolite known to affect T1D risk), one probe (cg01604946) mediated by phostidyl choline p-32:0 or o-32:1, and one probe (cg00390143) mediated by sphingomyelin d34:2. The top 100 DNAm probes were over-represented in six reactome pathways at the FDR <0.1 level (q = 0.071), including transport of small molecules and inositol phosphate metabolism. While the causal pathways in our mediation models require further investigation to better understand the biological mechanisms, we identified seven methylation sites that may improve our understanding of epigenetic protection against T1D as mediated by the metabolome.

7.
Arthritis Rheumatol ; 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34369110

RESUMO

OBJECTIVE: Mechanisms leading to anti-citrullinated protein antibody (ACPA) generation in rheumatoid arthritis (RA) are hypothesized to originate in the lung. We undertook this study to understand associations between neutrophil extracellular trap (NET) formation in the lung and local ACPA generation in subjects at risk of developing RA. METHODS: Induced sputum was collected from 49 subjects at risk of developing RA, 12 patients with RA, and 18 controls. Sputum neutrophils were tested for ex vivo NET formation, and sputum-induced NET formation of control neutrophils was measured using immunofluorescence imaging. Sputum macrophages were tested for ex vivo endocytosis of apoptotic and opsonized cells. Levels of ACPA, NET remnants, and inflammatory proteins were quantified in sputum supernatant. RESULTS: Spontaneous citrullinated histone H3 (Cit-H3)-expressing NET formation was higher in sputum neutrophils from at-risk subjects and RA patients compared to controls (median 12%, 22%, and 0%, respectively; P < 0.01). In at-risk subjects, sputum IgA ACPA correlated with the percentage of neutrophils that underwent Cit-H3+ NET formation (r = 0.49, P = 0.002) and levels of Cit-H3+ NET remnants (r = 0.70, P < 0.001). Reduced endocytic capacity of sputum macrophages was found in at-risk subjects and RA patients compared to controls. Using a mediation model, we found that sputum inflammatory proteins were associated with sputum IgA ACPA through a pathway mediated by Cit-H3+ NET remnants. Sputum-induced Cit-H3+ NET formation also correlated with sputum levels of interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor in at-risk subjects, suggesting a causal relationship. CONCLUSION: These data support a potential mechanism for mucosal ACPA generation in subjects at risk of developing RA, whereby inflammation leads to increased citrullinated protein-expressing NETs that promote local ACPA generation.

8.
Arthritis Res Ther ; 23(1): 163, 2021 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-34092252

RESUMO

BACKGROUND: Mucosal sites are hypothesized to play a role in the development of rheumatoid arthritis (RA). Since serum anti-peptidylarginine deiminase (PAD)4 antibodies, including a subset that cross-react with PAD3 (PAD3/4), are specific for RA and associate with severe disease, we sought to examine whether anti-PAD4 and anti-PAD3/4 antibodies were present in the lung and oral mucosa of subjects with RA and "at-risk" for RA. METHODS: We included 37 RA, 25 healthy control, and 46 subjects "at-risk" for RA based on familial RA and/or serum anti-citrullinated protein antibody (ACPA) positivity. Paired serum, sputum, and saliva were evaluated for anti-PAD4 and anti-PAD3/4 using immunoprecipitation and ACPA using ELISA. Immunoglobulins (Ig) were purified from representative samples, and their effect on citrullination of histone H3 by recombinant human PAD4 was measured by anti-citH3 immunoblot. RESULTS: Anti-PAD4 antibodies were detected in the serum of 6/37 (16.2%), sputum of 3/37 (8.1%), and saliva of 3/33 (9.1%) RA subjects and in the serum and sputum of 1/46 (2.2%) at-risk subjects. None of the healthy controls had anti-PAD4 antibodies at any site. Serum, sputum, and salivary anti-PAD4 antibodies were more prevalent in RA subjects with RA duration >2 years. Purified antibodies from representative anti-PAD4-positive and anti-PAD3/4-positive sputum were primarily of the IgA isotype and able to increase PAD4 enzymatic activity. CONCLUSIONS: Anti-PAD4 antibodies are present in the sputum and saliva of a portion of RA patients and are infrequent in at-risk subjects. Importantly, the ability of anti-PAD4, and particularly anti-PAD3/4, antibodies in the sputum to enhance PAD4 enzymatic activity suggests that anti-PAD4 may play an active role in the RA lung.


Assuntos
Artrite Reumatoide , Autoanticorpos , Histonas , Humanos , Hidrolases , Proteína-Arginina Desiminase do Tipo 4 , Desiminases de Arginina em Proteínas
9.
Genet Epidemiol ; 45(6): 593-603, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34130352

RESUMO

Omics studies frequently use samples collected during cohort studies. Conditioning on sample availability can cause selection bias if sample availability is nonrandom. Inverse probability weighting (IPW) is purported to reduce this bias. We evaluated IPW in an epigenome-wide analysis testing the association between DNA methylation (261,435 probes) and age in healthy adolescent subjects (n = 114). We simulated age and sex to be correlated with sample selection and then evaluated four conditions: complete population/no selection bias (all subjects), naïve selection bias (no adjustment), and IPW selection bias (selection bias with IPW adjustment). Assuming the complete population condition represented the "truth," we compared each condition to the complete population condition. Bias or difference in associations between age and methylation was reduced in the IPW condition versus the naïve condition. However, genomic inflation and type 1 error were higher in the IPW condition relative to the naïve condition. Postadjustment using bacon, type 1 error and inflation were similar across all conditions. Power was higher under the IPW condition compared with the naïve condition before and after inflation adjustment. IPW methods can reduce bias in genome-wide analyses. Genomic inflation is a potential concern that can be minimized using methods that adjust for inflation.


Assuntos
Estudo de Associação Genômica Ampla , Adolescente , Viés , Estudos de Coortes , Humanos , Probabilidade , Viés de Seleção
10.
PLoS One ; 16(5): e0251423, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34014961

RESUMO

Relative to European Americans, African Americans have lower 25-hydroxyvitamin D (25OHD) and vitamin D binding protein (VDBP) concentrations, higher 1,25-dihydroxyvitamin D (1,25(OH)2D3) concentrations and bone mineral density (BMD), and paradoxically reduced burdens of calcified atherosclerotic plaque (subclinical atherosclerosis). To identify genetic factors contributing to vitamin D and BMD measures, association analysis of >14M variants was conducted in a maximum of 697 African American-Diabetes Heart Study participants with type 2 diabetes (T2D). The most significant association signals were detected for VDBP on chromosome 4; variants rs7041 (ß = 0.44, SE = 0.019, P = 9.4x10-86) and rs4588 (ß = 0.17, SE = 0.021, P = 3.5x10-08) in the group-specific component (vitamin D binding protein) gene (GC). These variants were found to be independently associated. In addition, rs7041 was also associated with bioavailable vitamin D (BAVD; ß = 0.16, SE = 0.02, P = 3.3x10-19). Six rare variants were significantly associated with 25OHD, including a non-synonymous variant in HSPG2 (rs116788687; ß = -1.07, SE = 0.17, P = 2.2x10-10) and an intronic variant in TNIK (rs143555701; ß = -1.01, SE = 0.18, P = 9.0x10-10), both biologically related to bone development. Variants associated with 25OHD failed to replicate in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Evaluation of vitamin D metabolism and bone mineral density phenotypes in an African American population enriched for T2D could provide insight into ethnic specific differences in vitamin D metabolism and bone mineral density.


Assuntos
Densidade Óssea , Diabetes Mellitus Tipo 2/sangue , Vitamina D/análogos & derivados , Afro-Americanos/genética , Idoso , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Vitamina D/sangue , Vitamina D/genética , Proteína de Ligação a Vitamina D/sangue , Proteína de Ligação a Vitamina D/genética
11.
Obesity (Silver Spring) ; 29(7): 1195-1202, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33998167

RESUMO

OBJECTIVE: Although increasing evidence suggests that visceral adipose tissue (VAT) is a major underlying cause of metabolic syndrome (MetS), few studies have measured VAT at multiple time points in diverse populations. VAT and insulin resistance were hypothesized to differ by MetS status within BMI category in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study and, further, that baseline VAT and insulin resistance and increases over time are associated with incident MetS. METHODS: Generalized estimating equations were used for differences in body fat distribution and insulin resistance by MetS status. Mixed effects logistic regression was used for the association of baseline and change in adiposity and insulin resistance with incident MetS across 5 years, adjusted for age, sex, race/ethnicity, and family correlation. RESULTS: VAT and insulin sensitivity differed significantly by MetS status and BMI category at baseline. VAT and homeostatic model assessment of insulin resistance (HOMA-IR) at baseline (VAT odds ratio [OR] = 1.16 [95% CI: 1.12-2.31]; HOMA-IR OR = 1.85 [95% CI: 1.32-2.58]) and increases over time (VAT OR = 1.55 [95% CI: 1.22-1.98]; HOMA-IR OR = 3.23 [95% CI: 2.20-4.73]) were associated with incident MetS independent of BMI category. CONCLUSIONS: Differing levels of VAT may be driving metabolic heterogeneity within BMI categories. Both overall and abdominal obesity (VAT) may play a role in the development of MetS. Increased VAT over time contributed additional risk.


Assuntos
Aterosclerose , Resistência à Insulina , Síndrome Metabólica , Humanos , Gordura Intra-Abdominal , Síndrome Metabólica/epidemiologia , Obesidade/epidemiologia
12.
Diabetologia ; 64(8): 1785-1794, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33893822

RESUMO

AIMS/HYPOTHESIS: Oxylipins are lipid mediators derived from polyunsaturated fatty acids. Some oxylipins are proinflammatory (e.g. those derived from arachidonic acid [ARA]), others are pro-resolving of inflammation (e.g. those derived from α-linolenic acid [ALA], docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) and others may be both (e.g. those derived from linoleic acid [LA]). The goal of this study was to examine whether oxylipins are associated with incident type 1 diabetes. METHODS: We conducted a nested case-control analysis in the Diabetes Autoimmunity Study in the Young (DAISY), a prospective cohort study of children at risk of type 1 diabetes. Plasma levels of 14 ARA-derived oxylipins, ten LA-derived oxylipins, six ALA-derived oxylipins, four DHA-derived oxylipins and two EPA-related oxylipins were measured by ultra-HPLC-MS/MS at multiple timepoints related to autoantibody seroconversion in 72 type 1 diabetes cases and 71 control participants, which were frequency matched on age at autoantibody seroconversion (of the case), ethnicity and sample availability. Linear mixed models were used to obtain an age-adjusted mean of each oxylipin prior to type 1 diabetes. Age-adjusted mean oxylipins were tested for association with type 1 diabetes using logistic regression, adjusting for the high risk HLA genotype HLA-DR3/4,DQB1*0302. We also performed principal component analysis of the oxylipins and tested principal components (PCs) for association with type 1 diabetes. Finally, to investigate potential critical timepoints, we examined the association of oxylipins measured before and after autoantibody seroconversion (of the cases) using PCs of the oxylipins at those visits. RESULTS: The ARA-related oxylipin 5-HETE was associated with increased type 1 diabetes risk. Five LA-related oxylipins, two ALA-related oxylipins and one DHA-related oxylipin were associated with decreased type 1 diabetes risk. A profile of elevated LA- and ALA-related oxylipins (PC1) was associated with decreased type 1 diabetes risk (OR 0.61; 95% CI 0.40, 0.94). A profile of elevated ARA-related oxylipins (PC2) was associated with increased diabetes risk (OR 1.53; 95% CI 1.03, 2.29). A critical timepoint analysis showed type 1 diabetes was associated with a high ARA-related oxylipin profile at post-autoantibody-seroconversion but not pre-seroconversion. CONCLUSIONS/INTERPRETATION: The protective association of higher LA- and ALA-related oxylipins demonstrates the importance of both inflammation promotion and resolution in type 1 diabetes. Proinflammatory ARA-related oxylipins may play an important role once the autoimmune process has begun.

13.
Front Nutr ; 8: 600756, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33869260

RESUMO

In recent years the role of the intestinal microbiota in health and disease has come to the forefront of medical research. Alterations in the intestinal microbiota and several of its features have been linked to numerous diseases, including type 1 diabetes (T1D). To date, studies in animal models of T1D, as well as studies in human subjects, have linked several intestinal microbiota alterations with T1D pathogenesis. Features that are most often linked with T1D pathogenesis include decreased microbial diversity, the relative abundance of specific strains of individual microbes, and altered metabolite production. Alterations in these features as well as others have provided insight into T1D pathogenesis and shed light on the potential mechanism by which the microbiota plays a role in T1D pathogenesis, yet the underlying factors leading to these alterations remains unknown. One potential mechanism for alteration of the microbiota is through diet and nutrition. Previous studies have shown associations of diet with islet autoimmunity, but a direct contributing factor has yet to be identified. Diet, through introduction of antigens and alteration of the composition and function of the microbiota, may elicit the immune system to produce autoreactive responses that result in the destruction of the beta cells. Here, we review the evidence associating diet induced changes in the intestinal microbiota and their contribution to T1D pathogenesis. We further provide a roadmap for determining the effect of diet and other modifiable factors on the entire microbiota ecosystem, including its impact on both immune and beta cell function, as it relates to T1D. A greater understanding of the complex interactions between the intestinal microbiota and several interacting systems in the body (immune, intestinal integrity and function, metabolism, beta cell function, etc.) may provide scientifically rational approaches to prevent development of T1D and other childhood immune and allergic diseases and biomarkers to evaluate the efficacy of interventions.

14.
Hum Mol Genet ; 30(15): 1443-1456, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-33856023

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P < 5.30 × 10-7); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction and Alzheimer's disease (AD) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to nonalcoholic steatohepatitis; however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and AD at the exome level in the largest analysis to date.

15.
Am J Clin Nutr ; 114(1): 134-142, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33831944

RESUMO

BACKGROUND: Breastfeeding has beneficial effects on numerous health outcomes. OBJECTIVES: We investigated whether breastfeeding duration is associated with the development of early childhood autoimmunity, allergies, or obesity in a multinational prospective birth cohort. METHODS: Infants with genetic susceptibility for type 1 diabetes (n = 8676) were followed for the development of autoantibodies to islet autoantigens or transglutaminase, allergies, and for anthropometric measurements to a median age of 8.3 y (IQR: 2.8-10.2 y). Information on breastfeeding was collected at 3 mo of age and prospectively thereafter. A propensity score for longer breastfeeding was calculated from the variables that were likely to influence any or exclusive breastfeeding. The risks of developing autoimmunity or allergy were assessed using Cox proportional hazards models, and the risk of obesity at 5.5 y of age was assessed using logistic regression with adjustment by the propensity score. RESULTS: Breastfeeding duration was not associated with a lower risk of either islet or transglutaminase autoimmunity (any breastfeeding >6 mo, adjusted HR: 1.07; 95% CI: 0.96, 1.19; exclusive breastfeeding >3 mo, adjusted HR: 1.03; 95% CI: 0.92, 1.15). Exclusive breastfeeding >3 mo was associated with a decreased risk of seasonal allergic rhinitis (adjusted HR: 0.70; 95% CI: 0.53, 0.92; P < 0.01). Any breastfeeding >6 mo and exclusive breastfeeding >3 mo were associated with decreased risk of obesity (adjusted OR: 0.62; 95% CI: 0.47, 0.81; P < 0.001; and adjusted OR: 0.68; 95% CI: 0.47, 0.95; P < 0.05, respectively). CONCLUSIONS: Longer breastfeeding was not associated with a lower risk of childhood (islet or transglutaminase) autoimmunity in genetically at-risk children but was associated with decreased risk of seasonal allergic rhinitis and obesity at 5.5 y of age.


Assuntos
Aleitamento Materno , Diabetes Mellitus Tipo 1/imunologia , Predisposição Genética para Doença , Hipersensibilidade , Sobrepeso , Autoantígenos/sangue , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Fatores de Risco
16.
Diabetes ; 70(7): 1592-1601, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33863802

RESUMO

Reversion of islet autoimmunity (IA) may point to mechanisms that prevent IA progression. We followed 199 individuals who developed IA during the Diabetes Autoimmunity Study in the Young. Untargeted metabolomics was performed in serum samples following IA. Cox proportional hazards models were used to test whether the metabolites (2,487) predicted IA reversion: two or more consecutive visits negative for all autoantibodies. We conducted a principal components analysis (PCA) of the top metabolites; |hazard ratio (HR) >1.25| and nominal P < 0.01. Phosphatidylcholine (16:0_18:1(9Z)) was the strongest individual metabolite (HR per 1 SD 2.16, false discovery rate (FDR)-adjusted P = 0.0037). Enrichment analysis identified four clusters (FDR P < 0.10) characterized by an overabundance of sphingomyelin (d40:0), phosphatidylcholine (16:0_18:1(9Z)), phosphatidylcholine (30:0), and l-decanoylcarnitine. Overall, 63 metabolites met the criteria for inclusion in the PCA. PC1 (HR 1.4, P < 0.0001), PC2 (HR 0.85, P = 0.0185), and PC4 (HR 1.28, P = 0.0103) were associated with IA reversion. Given the potential influence of diet on the metabolome, we investigated whether nutrients were correlated with PCs. We identified 20 nutrients that were correlated with the PCs (P < 0.05). Total sugar intake was the top nutrient. Overall, we identified an association between phosphatidylcholine, sphingomyelin, and carnitine levels and reversion of IA.


Assuntos
Autoimunidade , Ilhotas Pancreáticas/imunologia , Fosfolipídeos/sangue , Soroconversão , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/imunologia , Feminino , Humanos , Masculino , Metabolômica , Modelos de Riscos Proporcionais
17.
Metabolites ; 11(3)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652624

RESUMO

Oxylipins derived from omega-3 and -6 fatty acids are actively involved in inflammatory and immune processes and play important roles in human disease. However, as the interest in oxylipins increases, questions remain regarding which molecules are detectable in plasma, the best methods of collecting samples, and if molecules are stable during collection and storage. We thereby built upon existing studies by examining the stability of an expanded panel of 90 oxylipins, including specialized pro-resolving lipid mediators (SPMs), in human plasma (n = 5 subjects) during sample collection, processing, and storage at -80 °C. Oxylipins were quantified using liquid chromatography-tandem mass spectrometry (LC/MS/MS). Blood samples collected in ethylenediaminetetraacetic acid (EDTA) or heparin followed by up to 2 h at room temperature prior to processing showed no significant differences in oxylipin concentrations compared to immediately processed samples, including the SPMs lipoxin A4 and resolvin D1. The majority of molecules, including SPMs, remained stable following storage for up to 1 year. However, in support of previous findings, changes were seen in a small subset of oxylipins including 12-HETE, TXB2, 14-HDHA, and 18-HEPE. Overall, this study showed that accurate measurements of most oxylipins can be obtained from stored EDTA or heparin plasma samples using LC/MS/MS.

18.
Diabetologia ; 64(7): 1604-1612, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33783586

RESUMO

AIMS/HYPOTHESIS: We aimed to investigate the association between maternal consumption of gluten-containing foods and other selected foods during late pregnancy and offspring risk of islet autoimmunity (IA) and type 1 diabetes in The Environmental Determinants of Diabetes in the Young (TEDDY) study. METHODS: The TEDDY study recruited children at high genetic risk for type 1 diabetes at birth, and prospectively follows them for the development of IA and type 1 diabetes (n = 8556). A questionnaire on the mother's diet in late pregnancy was completed by 3-4 months postpartum. The maternal daily intake was estimated from a food frequency questionnaire for eight food groups: gluten-containing foods, non-gluten cereals, fresh milk, sour milk, cheese products, soy products, lean/medium-fat fish and fatty fish. For each food, we described the distribution of maternal intake among the four participating countries in the TEDDY study and tested the association of tertile of maternal food consumption with risk of IA and type 1 diabetes using forward selection time-to-event Cox regression. RESULTS: By 28 February 2019, 791 cases of IA and 328 cases of type 1 diabetes developed in TEDDY. There was no association between maternal late-pregnancy consumption of gluten-containing foods or any of the other selected foods and risk of IA, type 1 diabetes, insulin autoantibody-first IA or GAD autoantibody-first IA (all p ≥ 0.01). Maternal gluten-containing food consumption in late pregnancy was higher in Sweden (242 g/day), Germany (247 g/day) and Finland (221 g/day) than in the USA (199 g/day) (pairwise p < 0.05). CONCLUSIONS/INTERPRETATION: Maternal food consumption during late pregnancy was not associated with offspring risk for IA or type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00279318.

19.
Sci Rep ; 11(1): 3627, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-33574451

RESUMO

Our aim was to investigate the associations between erythrocyte fatty acids and the risk of islet autoimmunity in children. The Environmental Determinants of Diabetes in the Young Study (TEDDY) is a longitudinal cohort study of children at high genetic risk for type 1 diabetes (n = 8676) born between 2004 and 2010 in the U.S., Finland, Sweden, and Germany. A nested case-control design comprised 398 cases with islet autoimmunity and 1178 sero-negative controls matched for clinical site, family history, and gender. Fatty acids composition was measured in erythrocytes collected at the age of 3, 6, and 12 months and then annually up to 6 years of age. Conditional logistic regression models were adjusted for HLA risk genotype, ancestry, and weight z-score. Higher eicosapentaenoic and docosapentaenoic acid (n - 3 polyunsaturated fatty acids) levels during infancy and conjugated linoleic acid after infancy were associated with a lower risk of islet autoimmunity. Furthermore, higher levels of some even-chain saturated (SFA) and monounsaturated fatty acids (MUFA) were associated with increased risk. Fatty acid status in early life may signal the risk for islet autoimmunity, especially n - 3 fatty acids may be protective, while increased levels of some SFAs and MUFAs may precede islet autoimmunity.


Assuntos
Autoimunidade , Eritrócitos/metabolismo , Ácidos Graxos/metabolismo , Ilhotas Pancreáticas/imunologia , Aleitamento Materno , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Fatores de Risco
20.
J Diabetes ; 13(2): 143-153, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33124145

RESUMO

BACKGROUND: The Environmental Determinants of the Diabetes in the Young (TEDDY) study has prospectively followed, from birth, children at increased genetic risk of type 1 diabetes. TEDDY has collected heterogenous data longitudinally to gain insights into the environmental and biological mechanisms driving the progression to persistent islet autoantibodies. METHODS: We developed a machine learning model to predict imminent transition to the development of persistent islet autoantibodies based on time-varying metabolomics data integrated with time-invariant risk factors (eg, gestational age). The machine learning was initiated with 221 potential features (85 genetic, 5 environmental, 131 metabolomic) and an ensemble-based feature evaluation was utilized to identify a small set of predictive features that can be interrogated to better understand the pathogenesis leading up to persistent islet autoimmunity. RESULTS: The final integrative machine learning model included 42 disparate features, returning a cross-validated receiver operating characteristic area under the curve (AUC) of 0.74 and an AUC of ~0.65 on an independent validation dataset. The model identified a principal set of 20 time-invariant markers, including 18 genetic markers (16 single nucleotide polymorphisms [SNPs] and two HLA-DR genotypes) and two demographic markers (gestational age and exposure to a prebiotic formula). Integration with the metabolome identified 22 supplemental metabolites and lipids, including adipic acid and ceramide d42:0, that predicted development of islet autoantibodies. CONCLUSIONS: The majority (86%) of metabolites that predicted development of islet autoantibodies belonged to three pathways: lipid oxidation, phospholipase A2 signaling, and pentose phosphate, suggesting that these metabolic processes may play a role in triggering islet autoimmunity.


Assuntos
Autoanticorpos , Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/imunologia , Predisposição Genética para Doença , Ilhotas Pancreáticas/imunologia , Autoimunidade/genética , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Feminino , Genótipo , Idade Gestacional , Humanos , Lactente , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de Risco
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