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1.
Clin Nutr ; 42(2): 173-181, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36599272

RESUMO

BACKGROUND & AIMS: Evidence suggests that adherence to the Mediterranean diet (MedDiet) affects human metabolism and may contribute to better cognitive performance. However, the underlying mechanisms are not clear. OBJECTIVE: We generated a metabolite profile for adherence to MedDiet and evaluated its cross-sectional association with aspects of cognitive performance. METHODS: A total of 1250 healthy Greek middle-aged adults from the Epirus Health Study cohort were included in the analysis. Adherence to the MedDiet was assessed using the 14-point Mediterranean Diet Adherence Screener (MEDAS); cognition was measured using the Trail Making Test, the Verbal Fluency test and the Logical Memory test. A targeted metabolite profiling (n = 250 metabolites) approach was applied, using a high-throughput nuclear magnetic resonance platform. We used elastic net regularized regressions, with a 10-fold cross-validation procedure, to identify a metabolite profile for MEDAS. We evaluated the associations of the identified metabolite profile and MEDAS with cognitive tests, using multivariable linear regression models. RESULTS: We identified a metabolite profile composed of 42 metabolites, mainly lipoprotein subclasses and fatty acids, significantly correlated with MedDiet adherence (Pearson r = 0.35, P-value = 5.5 × 10-37). After adjusting for known risk factors and accounting for multiple testing, the metabolite profile and MEDAS were not associated with the cognitive tests. CONCLUSIONS: A plasma metabolite profile related to better adherence to the MedDiet was not associated with the tested aspects of cognitive performance, in a middle-aged Mediterranean population.

2.
Nutrients ; 14(23)2022 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-36501061

RESUMO

Variation in vitamin B12 levels has been associated with a range of diseases across the life-course, the causal nature of which remains elusive. We aimed to interrogate genetically predicted vitamin B12 status in relation to a plethora of clinical outcomes available in the UK Biobank. Genome-wide association study (GWAS) summary data obtained from a Danish and Icelandic cohort of 45,576 individuals were used to identify 8 genetic variants associated with vitamin B12 levels, serving as genetic instruments for vitamin B12 status in subsequent analyses. We conducted a Mendelian randomisation (MR)-phenome-wide association study (PheWAS) of vitamin B12 status with 945 distinct phenotypes in 439,738 individuals from the UK Biobank using these 8 genetic instruments to proxy alterations in vitamin B12 status. We used external GWAS summary statistics for replication of significant findings. Correction for multiple testing was taken into consideration using a 5% false discovery rate (FDR) threshold. MR analysis identified an association between higher genetically predicted vitamin B12 status and lower risk of vitamin B deficiency (including all B vitamin deficiencies), serving as a positive control outcome. We further identified associations between higher genetically predicted vitamin B12 status and a reduced risk of megaloblastic anaemia (OR = 0.35, 95% CI: 0.20-0.50) and pernicious anaemia (0.29, 0.19-0.45), which was supported in replication analyses. Our study highlights that higher genetically predicted vitamin B12 status is potentially protective of risk of vitamin B12 deficiency associated with pernicious anaemia diagnosis, and reduces risk of megaloblastic anaemia. The potential use of genetically predicted vitamin B12 status in disease diagnosis, progression and management remains to be investigated.


Assuntos
Anemia Megaloblástica , Anemia Perniciosa , Deficiência de Vitamina B 12 , Humanos , Anemia Megaloblástica/complicações , Anemia Perniciosa/complicações , Estudo de Associação Genômica Ampla , Vitamina B 12 , Deficiência de Vitamina B 12/genética , Deficiência de Vitamina B 12/complicações , Vitaminas , Análise da Randomização Mendeliana
3.
Nat Commun ; 13(1): 7652, 2022 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-36496454

RESUMO

Metformin, a diabetes drug with anti-aging cellular responses, has complex actions that may alter dementia onset. Mixed results are emerging from prior observational studies. To address this complexity, we deploy a causal inference approach accounting for the competing risk of death in emulated clinical trials using two distinct electronic health record systems. In intention-to-treat analyses, metformin use associates with lower hazard of all-cause mortality and lower cause-specific hazard of dementia onset, after accounting for prolonged survival, relative to sulfonylureas. In parallel systems pharmacology studies, the expression of two AD-related proteins, APOE and SPP1, was suppressed by pharmacologic concentrations of metformin in differentiated human neural cells, relative to a sulfonylurea. Together, our findings suggest that metformin might reduce the risk of dementia in diabetes patients through mechanisms beyond glycemic control, and that SPP1 is a candidate biomarker for metformin's action in the brain.


Assuntos
Demência , Diabetes Mellitus Tipo 2 , Metformina , Humanos , Metformina/farmacologia , Metformina/uso terapêutico , Reposicionamento de Medicamentos , Farmacologia em Rede , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Compostos de Sulfonilureia , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Demência/tratamento farmacológico , Demência/etiologia , Registros Médicos
4.
PLoS Med ; 19(12): e1004141, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36580444

RESUMO

BACKGROUND: Fatty acids are important dietary factors that have been extensively studied for their implication in health and disease. Evidence from epidemiological studies and randomised controlled trials on their role in cardiovascular, inflammatory, and other diseases remains inconsistent. The objective of this study was to assess whether genetically predicted fatty acid concentrations affect the risk of disease across a wide variety of clinical health outcomes. METHODS AND FINDINGS: The UK Biobank (UKB) is a large study involving over 500,000 participants aged 40 to 69 years at recruitment from 2006 to 2010. We used summary-level data for 117,143 UKB samples (base dataset), to extract genetic associations of fatty acids, and individual-level data for 322,232 UKB participants (target dataset) to conduct our discovery analysis. We studied potentially causal relationships of circulating fatty acids with 845 clinical diagnoses, using mendelian randomisation (MR) approach, within a phenome-wide association study (PheWAS) framework. Regression models in PheWAS were adjusted for sex, age, and the first 10 genetic principal components. External summary statistics were used for replication. When several fatty acids were associated with a health outcome, multivariable MR and MR-Bayesian method averaging (MR-BMA) was applied to disentangle their causal role. Genetic predisposition to higher docosahexaenoic acid (DHA) was associated with cholelithiasis and cholecystitis (odds ratio per mmol/L: 0.76, 95% confidence interval: 0.66 to 0.87). This was supported in replication analysis (FinnGen study) and by the genetically predicted omega-3 fatty acids analyses. Genetically predicted linoleic acid (LA), omega-6, polyunsaturated fatty acids (PUFAs), and total fatty acids (total FAs) showed positive associations with cardiovascular outcomes with support from replication analysis. Finally, higher genetically predicted levels of DHA (0.83, 0.73 to 0.95) and omega-3 (0.83, 0.75 to 0.92) were found to have a protective effect on obesity, which was supported using body mass index (BMI) in the GIANT consortium as replication analysis. Multivariable MR analysis suggested a direct detrimental effect of LA (1.64, 1.07 to 2.50) and omega-6 fatty acids (1.81, 1.06 to 3.09) on coronary heart disease (CHD). MR-BMA prioritised LA and omega-6 fatty acids as the top risk factors for CHD. Although we present a range of sensitivity analyses to the address MR assumptions, horizontal pleiotropy may still bias the reported associations and further evaluation in clinical trials is needed. CONCLUSIONS: Our study suggests potentially protective effects of circulating DHA and omega-3 concentrations on cholelithiasis and cholecystitis and on obesity, highlighting the need to further assess them as prevention treatments in clinical trials. Moreover, our findings do not support the supplementation of unsaturated fatty acids for cardiovascular disease prevention.


Assuntos
Ácidos Graxos Ômega-3 , Ácidos Graxos Ômega-6 , Predisposição Genética para Doença , Humanos , Teorema de Bayes , Colelitíase/epidemiologia , Colelitíase/genética , Doença das Coronárias/epidemiologia , Doença das Coronárias/genética , Ácidos Docosa-Hexaenoicos/sangue , Ácidos Docosa-Hexaenoicos/genética , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-3/genética , Ácidos Graxos Ômega-6/sangue , Ácidos Graxos Ômega-6/genética , Análise da Randomização Mendeliana/métodos , Obesidade/epidemiologia , Obesidade/genética , Colecistite/epidemiologia , Colecistite/genética , Adulto , Pessoa de Meia-Idade , Idoso , Masculino , Feminino
5.
Neurology ; 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36384659

RESUMO

OBJECTIVES: Whether chronic autoimmune inflammatory diseases causally affect the risk of AD is controversial. We characterised the relationship between inflammatory diseases and the risk of AD and explore the role of circulating inflammatory biomarkers in the relationships between inflammatory diseases and AD. METHODS: We performed observational analyses for chronic autoimmune inflammatory diseases and risk of AD using data from 2,047,513 participants identified in the UK Clinical Practice Research Datalink (CPRD). Using data of a total of more than 1,100,000 individuals from 15 large scale genome-wide association study (GWAS) datasets, we performed two-sample Mendelian randomisation (MR) to investigate the relationships between chronic autoimmune inflammatory diseases, circulating inflammatory biomarker levels, and risk of AD. RESULTS: Cox regression models using CPRD data showed that overall incidence of AD was higher among patients with inflammatory bowel disease (IBD) (hazard ratio (HR)=1.17; 95%CI 1.15 to 1.19; P-value=2.1×10-4), other inflammatory polyarthropathies & systematic connective tissue disorders (OID) (HR=1.13; 95%CI 1.12 to 1.14; P-value=8.6×10-5), psoriasis (HR=1.13; 95%CI 1.10 to 1.16; P-value=2.6×10-4), rheumatoid arthritis (RA) (HR=1.08; 95%CI 1.06 to 1.11; P-value=4.0×10-4), and multiple sclerosis (MS) (HR=1.06; 95%CI 1.04 to 1.07; P-value=2.8×10-4) compared to the age (± 5 years) and sex-matched comparison groups free from all inflammatory diseases under investigation. Bidirectional MR analysis identified relationships between chronic autoimmune inflammatory diseases and circulating inflammatory biomarkers. Particularly, circulating monokine induced by gamma interferon (MIG) level was suggestively associated with a higher risk of AD (odds ratio from inverse variance weighted (ORIVW)=1.23; 95%CI 1.06 to 1.42; PIVW=0.007), and lower risk of Crohn's disease (ORIVW=0.73; 95%CI -0.62, 0.86; PIVW=1.3×10-4). Colocalisation supported a common causal SNP for MIG and Crohn's disease (posterior probability=0.74) but not AD (posterior probability=0.03). Using a two-sample MR approach, genetically predicted risks of inflammatory diseases were not associated with higher AD risk. CONCLUSION: Our data suggest that the association between inflammatory diseases and risk of AD is unlikely to be causal and may be a result of confounding. In support, while inflammatory biomarkers showed evidence for causal associations with inflammatory diseases, evidence was weak that they affected both inflammatory disease and AD.

6.
J Am Acad Dermatol ; 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36370904

RESUMO

BACKGROUND: Potentially modifiable risk factors have previously been investigated only in conventional observational studies. OBJECTIVE: To assess whether genetically predicted exposures to modifiable factors are associated with the risk of psoriasis. METHODS: Two-sample Mendelian randomization (MR) analysis. RESULTS: An increased risk of psoriasis was noted for genetically predicted lifetime smoking index (odds ratio [OR]MR-IVW = 2.11; 95% confidence interval [CI], 1.28-3.51), childhood (OR MR-IVW = 1.40; 95% CI, 1.14-1.71) and adult body mass index (OR MR-IVW = 1.63; 95% CI, 1.32-2), waist (OR IVW = 1.86; 95% CI, 1.31-2.64), and hip circumference (OR MR-IVW = 1.55; 95% CI, 1.15-2.07). Protective association was also reported between genetically predicted longer sleep duration (OR MR-IVW = 0.56; 95% CI 0.37-0.84) and increased years of education (OR MR-IVW = 0.78; 95% CI, 0.62-0.98). This effect of education persisted in multivariable MR after adjusting for genetic predictors of smoking and adult body mass index (ORMVMR-IVW = 0.72; 95% CI, 0.56-0.92). LIMITATIONS: It was not possible to stratify for psoriasis severity. CONCLUSION: Smoking cessation and prevention of obesity are important strategies for decreasing the incidence of psoriasis. Similarly, targeting education inequality is expected to lead further to reductions in cases of psoriasis.

7.
Nat Commun ; 13(1): 6939, 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36376304

RESUMO

C-reactive protein is involved in a plethora of pathophysiological conditions. Many genetic loci associated with C-reactive protein are annotated to lipid and glucose metabolism genes supporting common biological pathways between inflammation and metabolic traits. To identify novel pleiotropic loci, we perform multi-trait analysis of genome-wide association studies on C-reactive protein levels along with cardiometabolic traits, followed by a series of in silico analyses including colocalization, phenome-wide association studies and Mendelian randomization. We find 41 novel loci and 19 gene sets associated with C-reactive protein with various pleiotropic effects. Additionally, 41 variants colocalize between C-reactive protein and cardiometabolic risk factors and 12 of them display unexpected discordant effects between the shared traits which are translated into discordant associations with clinical outcomes in subsequent phenome-wide association studies. Our findings provide insights into shared mechanisms underlying inflammation and lipid metabolism, representing potential preventive and therapeutic targets.


Assuntos
Proteína C-Reativa , Estudo de Associação Genômica Ampla , Humanos , Proteína C-Reativa/genética , Polimorfismo de Nucleotídeo Único , Pleiotropia Genética , Loci Gênicos , Inflamação/genética , Predisposição Genética para Doença , Análise da Randomização Mendeliana
8.
J Neurochem ; 2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36326588

RESUMO

Alzheimer´s Disease (AD) is a highly prevalent neurodegenerative disorder. Despite increasing evidence of the importance of metabolic dysregulation in AD, the underlying metabolic changes that may impact amyloid plaque formation are not understood, particularly for late onset AD. This study analyzed genome-wide association studies (GWAS), transcriptomics and proteomics data obtained from several data repositories to obtain differentially expressed (DE) multi-omics elements in mouse models of AD. We characterized the metabolic modulation in these datasets using gene ontology, transcription factor, pathway, and cell-type enrichment analyses. A predicted lipid signature was extracted from genome-scale metabolic networks (GSMN) and subsequently validated in a lipidomic dataset derived from cortical tissue of ABCA-7 null mice, a mouse model of one of the genes associated with late onset AD. Moreover, a metabolome-wide association study (MWAS) was performed to further characterize the association between dysregulated lipid metabolism in human blood serum and genes associated with AD risk. We found 203 DE transcripts, 164 DE proteins and 58 DE GWAS-derived mouse orthologs associated with significantly enriched metabolic biological processes. Lipid and bioenergetics metabolic pathways were significantly over-represented across the AD multi-omics datasets. Microglia and astrocytes were significantly enriched in the lipid-predominant AD-metabolic transcriptome. We also extracted a predicted lipid signature that was validated and robustly modelled class separation in the ABCA7 mice cortical lipidome, with 11 of these lipid species exhibiting statistically significant modulations. MWAS revealed 298 AD single nucleotide polymorphisms (SNP)-metabolite associations, of which 70% corresponded to lipid classes. These results support the importance of lipid metabolism dysregulation in AD and highlight the suitability of mapping AD multi-omics data into GSMNs to identify metabolic alterations.

10.
Proc Natl Acad Sci U S A ; 119(43): e2206083119, 2022 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-36269859

RESUMO

Genome-wide association studies (GWASs) have identified genetic loci associated with the risk of Alzheimer's disease (AD), but the molecular mechanisms by which they confer risk are largely unknown. We conducted a metabolome-wide association study (MWAS) of AD-associated loci from GWASs using untargeted metabolic profiling (metabolomics) by ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). We identified an association of lactosylceramides (LacCer) with AD-related single-nucleotide polymorphisms (SNPs) in ABCA7 (P = 5.0 × 10-5 to 1.3 × 10-44). We showed that plasma LacCer concentrations are associated with cognitive performance and genetically modified levels of LacCer are associated with AD risk. We then showed that concentrations of sphingomyelins, ceramides, and hexosylceramides were altered in brain tissue from Abca7 knockout mice, compared with wild type (WT) (P = 0.049-1.4 × 10-5), but not in a mouse model of amyloidosis. Furthermore, activation of microglia increases intracellular concentrations of hexosylceramides in part through induction in the expression of sphingosine kinase, an enzyme with a high control coefficient for sphingolipid and ceramide synthesis. Our work suggests that the risk for AD arising from functional variations in ABCA7 is mediated at least in part through ceramides. Modulation of their metabolism or downstream signaling may offer new therapeutic opportunities for AD.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Doença de Alzheimer , Ceramidas , Animais , Camundongos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Ceramidas/metabolismo , Cromatografia Líquida , Estudo de Associação Genômica Ampla , Lactosilceramidas , Metaboloma , Camundongos Knockout , Esfingomielinas , Espectrometria de Massas em Tandem
12.
Circulation ; 146(15): 1123-1134, 2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36154167

RESUMO

BACKGROUND: Acute myocarditis is an inflammatory condition that may herald the onset of dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis. METHODS: This was a population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterized cardiomyopathy-associated genes with comparison to healthy controls (n=1053) sequenced on the same platform. Case ascertainment in England was assessed against national hospital admission data. The primary outcome was all-cause mortality. RESULTS: Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared with <1% of healthy controls (P=0.0097). In the London cohort (n=230; median age, 33 years; 84% men), patients were representative of national myocarditis admissions (median age, 32 years; 71% men; 66% case ascertainment), and there was enrichment of rare truncating variants (tv) in ACM-associated genes (3.1% of cases versus 0.4% of controls; odds ratio, 8.2; P=0.001). This was driven predominantly by DSP-tv in patients with normal LV ejection fraction and ventricular arrhythmia. In Maastricht (n=106; median age, 54 years; 61% men), there was enrichment of rare truncating variants in DCM-associated genes, particularly TTN-tv, found in 7% (all with left ventricular ejection fraction <50%) compared with 1% in controls (odds ratio, 3.6; P=0.0116). Across both cohorts over a median of 5.0 years (interquartile range, 3.9-7.8 years), all-cause mortality was 5.4%. Two-thirds of deaths were cardiovascular, attributable to worsening heart failure (92%) or sudden cardiac death (8%). The 5-year mortality risk was 3.3% in genotype-negative patients versus 11.1% for genotype-positive patients (Padjusted=0.08). CONCLUSIONS: We identified DCM- or ACM-associated genetic variants in 8% of patients with acute myocarditis. This was dominated by the identification of DSP-tv in those with normal left ventricular ejection fraction and TTN-tv in those with reduced left ventricular ejection fraction. Despite differences between cohorts, these variants have clinical implications for treatment, risk stratification, and family screening. Genetic counseling and testing should be considered in patients with acute myocarditis to help reassure the majority while improving the management of those with an underlying genetic variant.


Assuntos
Cardiomiopatia Dilatada , Miocardite , Adulto , Cardiomiopatia Dilatada/genética , Feminino , Coração , Humanos , Masculino , Pessoa de Meia-Idade , Miocardite/diagnóstico , Miocardite/genética , Volume Sistólico , Função Ventricular Esquerda
13.
Neurol Genet ; 8(5): e200014, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36046424

RESUMO

Background and Objectives: Angiotensin-converting enzyme (ACE) inhibitors are a commonly prescribed class of medication used to treat heart failure, hypertension, and chronic kidney disease. However, previous observational studies have shown conflicting directions of associations between ACE inhibitors and risk of Alzheimer disease. Genetic evidence has supported a protective effect of cerebral ACE against Alzheimer disease (AD). However, it is unclear whether this effect is mediated through blood pressure and extends to other neurodegenerative diseases. Methods: We performed genetic colocalization investigating an effect of cortical ACE expression on AD risk in people of European ancestry. We further investigated whether any effect of ACE expression on AD risk is mediated through changes in blood pressure and whether effects extend to Parkinson disease, small-vessel disease, or cognitive function in a Mendelian randomization paradigm. Results: There was genetic evidence supporting a protective effect of cortical ACE expression on AD risk in people of European ancestry. Although higher cortical ACE expression was associated with higher blood pressure, there was no strong evidence to support that its association with AD was mediated through blood pressure nor that ACE expression affected risk of other neurodegenerative traits. Discussion: Genetic evidence supports protective effects of cerebral ACE expression on AD, but not other neurodegenerative outcomes in people of European ancestry. Further work is required to investigate whether therapeutic inhibition of ACE increases risk of Alzheimer disease.

14.
Int J Cancer ; 151(11): 1935-1946, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-35830197

RESUMO

It is unclear whether diet, and in particular certain foods or nutrients, are associated with lung cancer risk. We assessed associations of 92 dietary factors with lung cancer risk in 327 790 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cox regression yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) per SD higher intake/day of each food/nutrient. Correction for multiple comparisons was performed using the false discovery rate and identified associations were evaluated in the Netherlands Cohort Study (NLCS). In EPIC, 2420 incident lung cancer cases were identified during a median of 15 years of follow-up. Higher intakes of fibre (HR per 1 SD higher intake/day = 0.91, 95% CI 0.87-0.96), fruit (HR = 0.91, 95% CI 0.86-0.96) and vitamin C (HR = 0.91, 95% CI 0.86-0.96) were associated with a lower risk of lung cancer, whereas offal (HR = 1.08, 95% CI 1.03-1.14), retinol (HR = 1.06, 95% CI 1.03-1.10) and beer/cider (HR = 1.04, 95% CI 1.02-1.07) intakes were positively associated with lung cancer risk. Associations did not differ by sex and there was less evidence for associations among never smokers. None of the six associations with overall lung cancer risk identified in EPIC were replicated in the NLCS (2861 cases), however in analyses of histological subtypes, inverse associations of fruit and vitamin C with squamous cell carcinoma were replicated in the NLCS. Overall, there is little evidence that intakes of specific foods and nutrients play a major role in primary lung cancer risk, but fruit and vitamin C intakes seem to be inversely associated with squamous cell lung cancer.


Assuntos
Neoplasias Pulmonares , Vitamina A , Ácido Ascórbico , Estudos de Coortes , Dieta/efeitos adversos , Europa (Continente)/epidemiologia , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/etiologia , Países Baixos/epidemiologia , Nutrientes , Estudos Prospectivos , Fatores de Risco
16.
Anal Chem ; 94(14): 5493-5503, 2022 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-35360896

RESUMO

Integration of multiple datasets can greatly enhance bioanalytical studies, for example, by increasing power to discover and validate biomarkers. In liquid chromatography-mass spectrometry (LC-MS) metabolomics, it is especially hard to combine untargeted datasets since the majority of metabolomic features are not annotated and thus cannot be matched by chemical identity. Typically, the information available for each feature is retention time (RT), mass-to-charge ratio (m/z), and feature intensity (FI). Pairs of features from the same metabolite in separate datasets can exhibit small but significant differences, making matching very challenging. Current methods to address this issue are too simple or rely on assumptions that cannot be met in all cases. We present a method to find feature correspondence between two similar LC-MS metabolomics experiments or batches using only the features' RT, m/z, and FI. We demonstrate the method on both real and synthetic datasets, using six orthogonal validation strategies to gauge the matching quality. In our main example, 4953 features were uniquely matched, of which 585 (96.8%) of 604 manually annotated features were correct. In a second example, 2324 features could be uniquely matched, with 79 (90.8%) out of 87 annotated features correctly matched. Most of the missed annotated matches are between features that behave very differently from modeled inter-dataset shifts of RT, MZ, and FI. In a third example with simulated data with 4755 features per dataset, 99.6% of the matches were correct. Finally, the results of matching three other dataset pairs using our method are compared with a published alternative method, metabCombiner, showing the advantages of our approach. The method can be applied using M2S (Match 2 Sets), a free, open-source MATLAB toolbox, available at https://github.com/rjdossan/M2S.


Assuntos
Metabolômica , Biomarcadores/análise , Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Metabolômica/métodos
17.
Nat Commun ; 13(1): 2198, 2022 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-35459240

RESUMO

Chronic low-grade inflammation is linked to a multitude of chronic diseases. We report the largest genome-wide association study (GWAS) on C-reactive protein (CRP), a marker of systemic inflammation, in UK Biobank participants (N = 427,367, European descent) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (total N = 575,531 European descent). We identify 266 independent loci, of which 211 are not previously reported. Gene-set analysis highlighted 42 gene sets associated with CRP levels (p ≤ 3.2 ×10-6) and tissue expression analysis indicated a strong association of CRP related genes with liver and whole blood gene expression. Phenome-wide association study identified 27 clinical outcomes associated with genetically determined CRP and subsequent Mendelian randomisation analyses supported a causal association with schizophrenia, chronic airway obstruction and prostate cancer. Our findings identified genetic loci and functional properties of chronic low-grade inflammation and provided evidence for causal associations with a range of diseases.


Assuntos
Proteína C-Reativa , Estudo de Associação Genômica Ampla , Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Loci Gênicos , Humanos , Inflamação/genética , Masculino , Análise da Randomização Mendeliana , Fenômica , Polimorfismo de Nucleotídeo Único
18.
BMC Med ; 20(1): 34, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35101027

RESUMO

BACKGROUND: Greater maternal adiposity before or during pregnancy is associated with greater offspring adiposity throughout childhood, but the extent to which this is due to causal intrauterine or periconceptional mechanisms remains unclear. Here, we use Mendelian randomisation (MR) with polygenic risk scores (PRS) to investigate whether associations between maternal pre-/early pregnancy body mass index (BMI) and offspring adiposity from birth to adolescence are causal. METHODS: We undertook confounder adjusted multivariable (MV) regression and MR using mother-offspring pairs from two UK cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) and Born in Bradford (BiB). In ALSPAC and BiB, the outcomes were birthweight (BW; N = 9339) and BMI at age 1 and 4 years (N = 8659 to 7575). In ALSPAC only we investigated BMI at 10 and 15 years (N = 4476 to 4112) and dual-energy X-ray absorptiometry (DXA) determined fat mass index (FMI) from age 10-18 years (N = 2659 to 3855). We compared MR results from several PRS, calculated from maternal non-transmitted alleles at between 29 and 80,939 single nucleotide polymorphisms (SNPs). RESULTS: MV and MR consistently showed a positive association between maternal BMI and BW, supporting a moderate causal effect. For adiposity at most older ages, although MV estimates indicated a strong positive association, MR estimates did not support a causal effect. For the PRS with few SNPs, MR estimates were statistically consistent with the null, but had wide confidence intervals so were often also statistically consistent with the MV estimates. In contrast, the largest PRS yielded MR estimates with narrower confidence intervals, providing strong evidence that the true causal effect on adolescent adiposity is smaller than the MV estimates (Pdifference = 0.001 for 15-year BMI). This suggests that the MV estimates are affected by residual confounding, therefore do not provide an accurate indication of the causal effect size. CONCLUSIONS: Our results suggest that higher maternal pre-/early-pregnancy BMI is not a key driver of higher adiposity in the next generation. Thus, they support interventions that target the whole population for reducing overweight and obesity, rather than a specific focus on women of reproductive age.


Assuntos
Adiposidade/genética , Obesidade/genética , Adolescente , Alelos , Índice de Massa Corporal , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Estudos Longitudinais , Obesidade/etiologia , Gravidez , Fatores de Risco , Reino Unido
19.
Open Heart ; 9(1)2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35086919

RESUMO

OBJECTIVES: (1) To evaluate the prevalence and hospitalisation rate of COVID-19 infections among patients with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) in the Royal Brompton and Harefield Hospital Cardiovascular Research Centre (RBHH CRC) Biobank. (2) To evaluate the indirect impact of the pandemic on patients with cardiomyopathy through the Heart Hive COVID-19 study. (3) To assess the impact of the pandemic on national cardiomyopathy-related hospital admissions. METHODS: (1) 1236 patients (703 DCM, 533 HCM) in the RBHH CRC Biobank were assessed for COVID-19 infections and hospitalisations; (2) 207 subjects (131 cardiomyopathy, 76 without heart disease) in the Heart Hive COVID-19 study completed online surveys evaluating physical health, psychological well-being, and behavioural adaptations during the pandemic and (3) 11 447 cardiomyopathy-related hospital admissions across National Health Service (NHS) England were studied from NHS Digital Hospital Episode Statistics over 2019-2020. RESULTS: A comparable proportion of patients with cardiomyopathy in the RBHH CRC Biobank had tested positive for COVID-19 compared with the UK population (1.1% vs 1.6%, p=0.14), but a higher proportion of those infected were hospitalised (53.8% vs 16.5%, p=0.002). In the Heart Hive COVID-19 study, more patients with cardiomyopathy felt their physical health had deteriorated due to the pandemic than subjects without heart disease (32.3% vs 13.2%, p=0.004) despite only 4.6% of the cardiomyopathy cohort reporting COVID-19 symptoms. A 17.9% year-on-year reduction in national cardiomyopathy-related hospital admissions was observed in 2020. CONCLUSION: Patients with cardiomyopathy had similar reported rates of testing positive for COVID-19 to the background population, but those with test-proven infection were hospitalised more frequently. Deterioration in physical health amongst patients could not be explained by COVID-19 symptoms, inferring a significant contribution of the indirect consequences of the pandemic. TRIAL REGISTRATION NUMBER: NCT04468256.


Assuntos
COVID-19 , Cardiomiopatia Dilatada , Cardiomiopatia Hipertrófica , Acesso aos Serviços de Saúde , Hospitalização/estatística & dados numéricos , Saúde Mental , Medicina Estatal/estatística & dados numéricos , COVID-19/epidemiologia , COVID-19/psicologia , COVID-19/terapia , Cardiomiopatia Dilatada/epidemiologia , Cardiomiopatia Dilatada/terapia , Cardiomiopatia Hipertrófica/epidemiologia , Cardiomiopatia Hipertrófica/terapia , Comorbidade , Ajustamento Emocional , Feminino , Acesso aos Serviços de Saúde/estatística & dados numéricos , Acesso aos Serviços de Saúde/tendências , Necessidades e Demandas de Serviços de Saúde , Humanos , Masculino , Saúde Mental/estatística & dados numéricos , Saúde Mental/tendências , Pessoa de Meia-Idade , Prevalência , SARS-CoV-2/isolamento & purificação , Análise de Sobrevida , Reino Unido/epidemiologia
20.
Eur Respir J ; 59(2)2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34172467

RESUMO

INTRODUCTION: The individual prognostic factors for coronavirus disease 2019 (COVID-19) are unclear. For this reason, we aimed to present a state-of-the-art systematic review and meta-analysis on the prognostic factors for adverse outcomes in COVID-19 patients. METHODS: We systematically reviewed PubMed from 1 January 2020 to 26 July 2020 to identify non-overlapping studies examining the association of any prognostic factor with any adverse outcome in patients with COVID-19. Random-effects meta-analysis was performed, and between-study heterogeneity was quantified using I2 statistic. Presence of small-study effects was assessed by applying the Egger's regression test. RESULTS: We identified 428 eligible articles, which were used in a total of 263 meta-analyses examining the association of 91 unique prognostic factors with 11 outcomes. Angiotensin-converting enzyme inhibitors, obstructive sleep apnoea, pharyngalgia, history of venous thromboembolism, sex, coronary heart disease, cancer, chronic liver disease, COPD, dementia, any immunosuppressive medication, peripheral arterial disease, rheumatological disease and smoking were associated with at least one outcome and had >1000 events, p<0.005, I2<50%, 95% prediction interval excluding the null value, and absence of small-study effects in the respective meta-analysis. The risk of bias assessment using the Quality in Prognosis Studies tool indicated high risk of bias in 302 out of 428 articles for study participation, 389 articles for adjustment for other prognostic factors and 396 articles for statistical analysis and reporting. CONCLUSIONS: Our findings could be used for prognostic model building and guide patient selection for randomised clinical trials.


Assuntos
COVID-19 , Viés , Humanos , Prognóstico , SARS-CoV-2
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