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Article ; Online: Genetic determinants of plasma protein levels in the Estonian population.

Kalnapenkis, Anette / Jõeloo, Maarja / Lepik, Kaido / Kukuškina, Viktorija / Kals, Mart / Alasoo, Kaur / Mägi, Reedik / Esko, Tõnu / Võsa, Urmo

Scientific reports

2024 Volume 14, Issue 1, Page(s) 7694

Abstract: The proteome holds great potential as an intermediate layer between the genome and phenome. Previous protein quantitative trait locus studies have focused mainly on describing the effects of common genetic variations on the proteome. Here, we assessed ... ...

Abstract	The proteome holds great potential as an intermediate layer between the genome and phenome. Previous protein quantitative trait locus studies have focused mainly on describing the effects of common genetic variations on the proteome. Here, we assessed the impact of the common and rare genetic variations as well as the copy number variants (CNVs) on 326 plasma proteins measured in up to 500 individuals. We identified 184 cis and 94 trans signals for 157 protein traits, which were further fine-mapped to credible sets for 101 cis and 87 trans signals for 151 proteins. Rare genetic variation contributed to the levels of 7 proteins, with 5 cis and 14 trans associations. CNVs were associated with the levels of 11 proteins (7 cis and 5 trans), examples including a 3q12.1 deletion acting as a hub for multiple trans associations; and a CNV overlapping NAIP, a sensor component of the NAIP-NLRC4 inflammasome which is affecting pro-inflammatory cytokine interleukin 18 levels. In summary, this work presents a comprehensive resource of genetic variation affecting the plasma protein levels and provides the interpretation of identified effects.
MeSH term(s)	Humans ; Genome-Wide Association Study ; Proteome/genetics ; Estonia ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci/genetics ; Blood Proteins/genetics ; DNA Copy Number Variations/genetics
Chemical Substances	Proteome ; Blood Proteins
Language	English
Publishing date	2024-04-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-57966-3
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Article ; Online: Self- and informant-reported personality traits and vaccination against COVID-19.

Arumäe, Kadri / Realo, Anu / Ausmees, Liisi / Allik, Jüri / Esko, Tõnu / Fischer, Krista / Vainik, Uku / Mõttus, René

PloS one

2024 Volume 19, Issue 3, Page(s) e0287413

Abstract: As COVID-19 vaccines' accessibility has grown, so has the role of personal choice in vaccination, and not everybody is willing to vaccinate. Exploring personality traits' associations with vaccination could highlight some person-level drivers of, and ... ...

Abstract	As COVID-19 vaccines' accessibility has grown, so has the role of personal choice in vaccination, and not everybody is willing to vaccinate. Exploring personality traits' associations with vaccination could highlight some person-level drivers of, and barriers to, vaccination. We used self- and informant-ratings of the Five-Factor Model domains and their subtraits (a) measured approximately at the time of vaccination with the 100 Nuances of Personality (100NP) item pool (N = 56,575) and (b) measured on average ten years before the pandemic with the NEO Personality Inventory-3 (NEO-PI-3; N = 3,168). We tested individual domains' and either items' (in the 100NP sample) or facets' (in the NEO-PI-3 sample) associations with vaccination, as well as their collective ability to predict vaccination using elastic net models trained and tested in independent sample partitions. Although the NEO-PI-3 domains and facets did not predict vaccination ten years later, the domains correlated with vaccination in the 100NP sample, with vaccinated people scoring slightly higher on neuroticism and agreeableness and lower on openness, controlling for age, sex, and education. Collectively, the five domains predicted vaccination with an accuracy of r = .08. Associations were stronger at the item level. Vaccinated people were, on average, more science-minded, politically liberal, respectful of rules and authority, and anxious but less spiritual, religious, and self-assured. The 100NP items collectively predicted vaccination with r = .31 accuracy. We conclude that unvaccinated people may be a psychologically heterogeneous group and highlight some potential areas for action in vaccination campaigns.
MeSH term(s)	Humans ; COVID-19 Vaccines ; COVID-19/prevention & control ; Personality ; Personality Inventory ; Personality Tests
Chemical Substances	COVID-19 Vaccines
Language	English
Publishing date	2024-03-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0287413
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Article ; Online: Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2.

Pérez-Jurado, Luis A / Cáceres, Alejandro / Balagué-Dobón, Laura / Esko, Tonu / López de Heredia, Miguel / Quintela, Inés / Cruz, Raquel / Lapunzina, Pablo / Carracedo, Ángel / González, Juan R

Communications biology

2024 Volume 7, Issue 1, Page(s) 202

Abstract: The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals ...

Abstract	The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people.
MeSH term(s)	Male ; Humans ; Aged ; SARS-CoV-2/genetics ; Mosaicism ; COVID-19/genetics ; Chromosomes, Human, Y ; Aging
Language	English
Publishing date	2024-02-19
Publishing country	England
Document type	Journal Article
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-024-05805-6
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Article ; Online: Extreme downregulation of chromosome Y and Alzheimer's disease in men.

Caceres, Alejandro / Jene, Aina / Esko, Tonu / Perez-Jurado, Luis A / Gonzalez, Juan R

Neurobiology of aging

2020 Volume 90, Page(s) 150.e1–150.e4

Abstract: Research has revealed scarcely any biological factors of Alzheimer's disease (AD) that are specific to men. Here, we found that the extreme downregulation of chromosome Y (EDY) increases the age-related risk of AD in men. We considered that EDY was a ... ...

Abstract	Research has revealed scarcely any biological factors of Alzheimer's disease (AD) that are specific to men. Here, we found that the extreme downregulation of chromosome Y (EDY) increases the age-related risk of AD in men. We considered that EDY was a possible male-specific pathway toward AD because EDY is the most likely consequence of the mosaic loss of chromosome Y, which has been recently associated with AD. We studied EDY in the undiseased brain of 371 individuals and observed that it co-occurred across multiple brain regions (p < 10
MeSH term(s)	Aging/genetics ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Chromosomes, Human, Y/genetics ; Chromosomes, Human, Y/metabolism ; Down-Regulation/genetics ; Female ; Genetic Predisposition to Disease/genetics ; Humans ; Male ; Mosaicism ; Sex Characteristics
Chemical Substances	Amyloid beta-Peptides
Language	English
Publishing date	2020-02-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604505-4
ISSN	1558-1497 ; 0197-4580
ISSN (online)	1558-1497
ISSN	0197-4580
DOI	10.1016/j.neurobiolaging.2020.02.003
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Article ; Online: Extreme Downregulation of Chromosome Y and Cancer Risk in Men.

Cáceres, Alejandro / Jene, Aina / Esko, Tonu / Pérez-Jurado, Luis A / González, Juan R

Journal of the National Cancer Institute

2020 Volume 112, Issue 9, Page(s) 913–920

Abstract: Background: Understanding the biological differences between sexes in cancer is essential for personalized treatment and prevention. We hypothesized that the extreme downregulation of chromosome Y gene expression (EDY) is a signature of cancer risk in ... ...

Abstract	Background: Understanding the biological differences between sexes in cancer is essential for personalized treatment and prevention. We hypothesized that the extreme downregulation of chromosome Y gene expression (EDY) is a signature of cancer risk in men and the functional mediator of the reported association between the mosaic loss of chromosome Y (LOY) and cancer. Methods: We advanced a method to measure EDY from transcriptomic data. We studied EDY across 47 nondiseased tissues from the Genotype Tissue-Expression Project (n = 371) and its association with cancer status across 12 cancer studies from The Cancer Genome Atlas (n = 1774) and seven other studies (n = 7562). Associations of EDY with cancer status and presence of loss-off function mutations in chromosome X were tested with logistic regression models, and a Fisher's test was used to assess genome-wide association of EDY with the proportion of copy number gains. All statistical tests were two-sided. Results: EDY was likely to occur in multiple nondiseased tissues (P < .001) and was statistically significantly associated with the EGFR tyrosine kinase inhibitor resistance pathway (false discovery rate = 0.028). EDY strongly associated with cancer risk in men (odds ratio [OR] = 3.66, 95% confidence interval [CI] = 1.58 to 8.46, P = .002), adjusted by LOY and age, and its variability was largely explained by several genes of the nonrecombinant region whose chromosome X homologs showed loss-of-function mutations that co-occurred with EDY during cancer (OR = 2.82, 95% CI = 1.32 to 6.01, P = .007). EDY associated with a high proportion of EGFR amplifications (OR = 5.64, 95% CI = 3.70 to 8.59, false discovery rate < 0.001) and EGFR overexpression along with SRY hypomethylation and nonrecombinant region hypermethylation, indicating alternative causes of EDY in cancer other than LOY. EDY associations were independently validated for different cancers and exposure to smoking, and its status was accurately predicted from individual methylation patterns. Conclusions: EDY is a male-specific signature of cancer susceptibility that supports the escape from X-inactivation tumor suppressor hypothesis for genes that protect women compared with men from cancer risk.
MeSH term(s)	Case-Control Studies ; Chromosomes, Human, Y/genetics ; DNA Methylation/physiology ; Down-Regulation/genetics ; Female ; Gene Expression Regulation ; Genes, Tumor Suppressor ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Male ; Neoplasms/epidemiology ; Neoplasms/genetics ; Polymorphism, Single Nucleotide ; Risk Factors ; Sex Characteristics ; Transcriptome
Language	English
Publishing date	2020-01-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2992-0
ISSN	1460-2105 ; 0027-8874 ; 0198-0157
ISSN (online)	1460-2105
ISSN	0027-8874 ; 0198-0157
DOI	10.1093/jnci/djz232
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Article ; Online: OTTERS: a powerful TWAS framework leveraging summary-level reference data.

Dai, Qile / Zhou, Geyu / Zhao, Hongyu / Võsa, Urmo / Franke, Lude / Battle, Alexis / Teumer, Alexander / Lehtimäki, Terho / Raitakari, Olli T / Esko, Tõnu / Epstein, Michael P / Yang, Jingjing

Nature communications

2023 Volume 14, Issue 1, Page(s) 1271

Abstract: Most existing TWAS tools require individual-level eQTL reference data and thus are not applicable to summary-level reference eQTL datasets. The development of TWAS methods that can harness summary-level reference data is valuable to enable TWAS in ... ...

Abstract	Most existing TWAS tools require individual-level eQTL reference data and thus are not applicable to summary-level reference eQTL datasets. The development of TWAS methods that can harness summary-level reference data is valuable to enable TWAS in broader settings and enhance power due to increased reference sample size. Thus, we develop a TWAS framework called OTTERS (Omnibus Transcriptome Test using Expression Reference Summary data) that adapts multiple polygenic risk score (PRS) methods to estimate eQTL weights from summary-level eQTL reference data and conducts an omnibus TWAS. We show that OTTERS is a practical and powerful TWAS tool by both simulations and application studies.
MeSH term(s)	Animals ; Otters ; Multifactorial Inheritance ; Risk Factors ; Sample Size ; Transcriptome
Language	English
Publishing date	2023-03-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-36862-w
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Article ; Online: Impact of the gut microbiota and associated metabolites on cardiometabolic traits, chronic diseases and human longevity: a Mendelian randomization study.

Gagnon, Eloi / Mitchell, Patricia L / Manikpurage, Hasanga D / Abner, Erik / Taba, Nele / Esko, Tõnu / Ghodsian, Nooshin / Thériault, Sébastien / Mathieu, Patrick / Arsenault, Benoit J

Journal of translational medicine

2023 Volume 21, Issue 1, Page(s) 60

Abstract: Features of the gut microbiota have been associated with several chronic diseases and longevity in preclinical models as well as in observational studies. Whether these relations underlie causal effects in humans remains to be established. We aimed to ... ...

Abstract	Features of the gut microbiota have been associated with several chronic diseases and longevity in preclinical models as well as in observational studies. Whether these relations underlie causal effects in humans remains to be established. We aimed to determine whether the gut microbiota influences cardiometabolic traits as well as the risk of chronic diseases and human longevity using a comprehensive 2-Sample Mendelian randomization approach. We included as exposures 10 gut-associated metabolites and pathways and 57 microbial taxa abundance. We included as outcomes nine cardiometabolic traits (fasting glucose, fasting insulin, systolic blood pressure, diastolic blood pressure, HDL cholesterol, LDL cholesterol, triglycerides, estimated glomerular filtration rate, body mass index [BMI]), eight chronic diseases previously linked with the gut microbiota in observational studies (Alzheimer's disease, depression, type 2 diabetes, non-alcoholic fatty liver disease, coronary artery disease (CAD), stroke, osteoporosis and chronic kidney disease), as well as parental lifespan and longevity. We found 7 associations with evidence of causality before and after sensitivity analyses, but not after multiple testing correction (1198 tests). Most effect sizes (4/7) were small. The two largest exposure-outcome effects were markedly attenuated towards the null upon inclusion of BMI or alcohol intake frequency in multivariable MR analyses. While finding robust genetic instruments for microbiota features is challenging hence potentially inflating type 2 errors, these results do not support a large causal impact of human gut microbita features on cardiometabolic traits, chronic diseases or longevity. These results also suggest that the previously documented associations between gut microbiota and human health outcomes may not always underly causal relations.
MeSH term(s)	Humans ; Diabetes Mellitus, Type 2 ; Longevity/genetics ; Gastrointestinal Microbiome/genetics ; Mendelian Randomization Analysis ; Coronary Artery Disease/genetics ; Body Mass Index ; Chronic Disease ; Polymorphism, Single Nucleotide ; Genome-Wide Association Study
Language	English
Publishing date	2023-01-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2118570-0
ISSN	1479-5876 ; 1479-5876
ISSN (online)	1479-5876
ISSN	1479-5876
DOI	10.1186/s12967-022-03799-5
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Article ; Online: Genome-wide association study of obstructive sleep apnoea in the Million Veteran Program uncovers genetic heterogeneity by sex.

Sofer, Tamar / Kurniansyah, Nuzulul / Murray, Michael / Ho, Yuk-Lam / Abner, Erik / Esko, Tõnu / Huffman, Jennifer E / Cho, Kelly / Wilson, Peter W F / Gottlieb, Daniel J

EBioMedicine

2023 Volume 90, Page(s) 104536

Abstract: Background: Genome-wide association studies (GWAS) for obstructive sleep apnoea (OSA) are limited due to the underdiagnosis of OSA, leading to misclassification of OSA, which consequently reduces statistical power. We performed a GWAS of OSA in the ... ...

Abstract	Background: Genome-wide association studies (GWAS) for obstructive sleep apnoea (OSA) are limited due to the underdiagnosis of OSA, leading to misclassification of OSA, which consequently reduces statistical power. We performed a GWAS of OSA in the Million Veteran Program (MVP) of the U.S. Department of Veterans Affairs (VA) healthcare system, where OSA prevalence is close to its true population prevalence. Methods: We performed GWAS of 568,576 MVP participants, stratified by biological sex and by harmonized race/ethnicity and genetic ancestry (HARE) groups of White, Black, Hispanic, and Asian individuals. We considered both BMI adjusted (BMI-adj) and unadjusted (BMI-unadj) models. We replicated associations in independent datasets, and analysed the heterogeneity of OSA genetic associations across HARE and sex groups. We finally performed a larger meta-analysis GWAS of MVP, FinnGen, and the MGB Biobank, totalling 916,696 individuals. Findings: MVP participants are 91% male. OSA prevalence is 21%. In MVP there were 18 and 6 genome-wide significant loci in BMI-unadj and BMI-adj analyses, respectively, corresponding to 21 association regions. Of these, 17 were not previously reported in association with OSA, and 13 replicated in FinnGen (False Discovery Rate p-value < 0.05). There were widespread significant differences in genetic effects between men and women, but less so across HARE groups. Meta-analysis of MVP, FinnGen, and MGB biobank revealed 17 additional, previously unreported, genome-wide significant regions. Interpretation: Sex differences in genetic associations with OSA are widespread, likely associated with multiple OSA risk factors. OSA shares genetic underpinnings with several sleep phenotypes, suggesting shared aetiology and causal pathways. Funding: Described in acknowledgements.
MeSH term(s)	Humans ; Animals ; Male ; Female ; Genome-Wide Association Study ; Veterans ; Genetic Heterogeneity ; Hares/genetics ; Sleep Apnea, Obstructive/epidemiology ; Sleep Apnea, Obstructive/genetics
Language	English
Publishing date	2023-03-28
Publishing country	Netherlands
Document type	Meta-Analysis ; Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2023.104536
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Article ; Online: Proteome-Wide Mendelian Randomization Identifies Causal Links Between Blood Proteins and Acute Pancreatitis.

Bourgault, Jérôme / Abner, Erik / Manikpurage, Hasanga D / Pujol-Gualdo, Natàlia / Laisk, Triin / Gobeil, Émilie / Gagnon, Eloi / Girard, Arnaud / Mitchell, Patricia L / Thériault, Sébastien / Esko, Tõnu / Mathieu, Patrick / Arsenault, Benoit J

Gastroenterology

2023 Volume 164, Issue 6, Page(s) 953–965.e3

Abstract: Background & aims: Acute pancreatitis (AP) is a complex disease and the leading cause of gastrointestinal disease-related hospital admissions. Few therapeutic options exist for AP prevention. Blood proteins with causal evidence may represent promising ... ...

Abstract	Background & aims: Acute pancreatitis (AP) is a complex disease and the leading cause of gastrointestinal disease-related hospital admissions. Few therapeutic options exist for AP prevention. Blood proteins with causal evidence may represent promising drug targets, but few have been causally linked with AP. Our objective was to identify blood proteins linked with AP by combining genome-wide association meta-analysis and proteome-wide Mendelian randomization (MR) studies. Methods: We performed a genome-wide association meta-analysis totalling 10,630 patients with AP and 844,679 controls and a series of inverse-variance weighted MR analyses using cis-acting variants on 4719 blood proteins from the deCODE study (N = 35,559) and 4979 blood proteins from the Fenland study (N = 10,708). Results: The meta-analysis identified genome-wide significant variants (P <5 × 10 Conclusions: This large genome-wide association study meta-analysis for AP identified new variants linked with AP as well as several blood proteins that may be causally associated with AP. This study provides new information on the genetic architecture of this disease and identified pathways related to AP, which may be further explored as possible therapeutic targets for AP.
MeSH term(s)	Humans ; Proteome/genetics ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; Acute Disease ; Pancreatitis/genetics ; Blood Proteins ; Polymorphism, Single Nucleotide ; Trypsin/genetics ; Trypsinogen/genetics ; Trypsin Inhibitor, Kazal Pancreatic/genetics ; Nuclear Proteins/genetics
Chemical Substances	Proteome ; Blood Proteins ; PRSS2 protein, human (103964-84-7) ; Trypsin (EC 3.4.21.4) ; Trypsinogen (9002-08-8) ; SPINK1 protein, human ; Trypsin Inhibitor, Kazal Pancreatic (50936-63-5) ; MORC4 protein, human ; Nuclear Proteins
Language	English
Publishing date	2023-02-01
Publishing country	United States
Document type	Meta-Analysis ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80112-4
ISSN	1528-0012 ; 0016-5085
ISSN (online)	1528-0012
ISSN	0016-5085
DOI	10.1053/j.gastro.2023.01.028
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Article: Mendelian Randomization Identifies the Potential Causal Impact of Dietary Patterns on Circulating Blood Metabolites.

Taba, Nele / Valge, Hanna-Kristel / Metspalu, Andres / Esko, Tõnu / Wilson, James F / Fischer, Krista / Pirastu, Nicola

Frontiers in genetics

2021 Volume 12, Page(s) 738265

Abstract: Nutrition plays an important role in the development and progress of several health conditions, but the exact mechanism is often still unclear. Blood metabolites are likely candidates to be mediating these relationships, as their levels are strongly ... ...

Abstract	Nutrition plays an important role in the development and progress of several health conditions, but the exact mechanism is often still unclear. Blood metabolites are likely candidates to be mediating these relationships, as their levels are strongly dependent on the frequency of consumption of several foods/drinks. Understanding the causal effect of food on metabolites is thus of extreme importance. To establish these effects, we utilized two-sample Mendelian randomization using the genetic variants associated with dietary traits as instrumental variables. The estimates of single-nucleotide polymorphisms' effects on exposures were obtained from a recent genome-wide association study (GWAS) of 25 individual and 15 principal-component dietary traits, whereas the ones for outcomes were obtained from a GWAS of 123 blood metabolites measured by nuclear magnetic resonance spectroscopy. We identified 413 potentially causal links between food and metabolites, replicating previous findings, such as the association between increased oily fish consumption and higher DHA, and highlighting several novel associations. Most of the associations were related to very-low-density, intermediate-density (IDL), and low-density lipoproteins (LDL). For example, we found that constituents of IDL particles and large LDL particles were raised by coffee and alcohol while lowered by an overall healthier diet and fruit consumption. Our findings provide a strong base of evidence for planning future RCTs aimed at understanding the role of diet in determining blood metabolite levels.
Language	English
Publishing date	2021-11-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2021.738265
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