Publications
20 results found
Wang N, Mustafa R, Zuber V, et al., 2023, Association between systolic blood pressure and low-density lipoprotein cholesterol with coronary heart disease according to age, PLoS One, Vol: 18, ISSN: 1932-6203
BACKGROUND: The impact of elevated systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) at different stages of life is unclear. We aimed to investigate whether genetically mediated SBP/LDL-C is associated with the risk of CHD throughout life. METHODS AND FINDINGS: We conducted a three-sample Mendelian randomization analysis using data from the UK Biobank including 136,648 participants for LDL-C, 135,431 participants for SBP, and 24,052 cases for CHD to assess the effect of duration of exposure to the risk factors on risk of CHD. Analyses were stratified by age at enrolment. In univariable analyses, there was a consistent association between exposure to higher LDL-C and SBP with increased odds of incident CHD in individuals aged ≤55 years, ≤60 years, and ≤65 years (p-value for heterogeneity = 1.00 for LDL-C and 0.67 for SBP, respectively). In multivariable Mendelian randomization analyses, exposure to elevated LDL-C/SBP early in life (age ≤55 years) was associated with a higher risk of CHD independent of later life levels (age >55 years) (odds ratio 1.68, 95% CI 1.20-2.34 per 1 mmol/L LDL-C, and odds ratio 1.33, 95% CI 1.18-1.51 per 10 mmHg SBP). CONCLUSIONS: Genetically predicted SBP and LDL-C increase the risk of CHD independent of age. Elevated SBP and LDL-C in early to middle life is associated with increased CHD risk independent of later-life SBP and LDL-C levels. These findings support the importance of lifelong risk factor control in young individuals, whose risk of CHD accumulates throughout life.
Mustafa R, Ghanbari M, Karhunen V, et al., 2023, Phenome-wide association study on miRNA-related sequence variants: the UK Biobank, Human Genomics, Vol: 17, ISSN: 1479-7364
Background:Genetic variants in the coding region could directly affect the structure and expression levels of genes and proteins. However, the importance of variants in the non-coding region, such as microRNAs (miRNAs), remain to be elucidated. Genetic variants in miRNA-related sequences could affect their biogenesis or functionality and ultimately affect disease risk. Yet, their implications and pleiotropic effects on many clinical conditions remain unknown.Methods:Here, we utilised genotyping and hospital records data in the UK Biobank (N = 423,419) to investigate associations between 346 genetic variants in miRNA-related sequences and a wide range of clinical diagnoses through phenome-wide association studies. Further, we tested whether changes in blood miRNA expression levels could affect disease risk through colocalisation and Mendelian randomisation analysis.Results:We identified 122 associations for six variants in the seed region of miRNAs, nine variants in the mature region of miRNAs, and 27 variants in the precursor miRNAs. These included associations with hypertension, dyslipidaemia, immune-related disorders, and others. Nineteen miRNAs were associated with multiple diagnoses, with six of them associated with multiple disease categories. The strongest association was reported between rs4285314 in the precursor of miR-3135b and celiac disease risk (odds ratio (OR) per effect allele increase = 0.37, P = 1.8 × 10–162). Colocalisation and Mendelian randomisation analysis highlighted potential causal role of miR-6891-3p in dyslipidaemia.Conclusions:Our study demonstrates the pleiotropic effect of miRNAs and offers insights to their possible clinical importance.
O'Farrell F, Aleyakpo B, Mustafa R, et al., 2023, Evidence for involvement of the alcohol consumption WDPCP gene in lipid metabolism, and liver cirrhosis, Scientific Reports, Vol: 13, ISSN: 2045-2322
Biological pathways between alcohol consumption and alcohol liver disease (ALD) are not fully understood. We selected genes with known effect on (1) alcohol consumption, (2) liver function, and (3) gene expression. Expression of the orthologs of these genes in Caenorhabditis elegans and Drosophila melanogaster was suppressed using mutations and/or RNA interference (RNAi). In humans, association analysis, pathway analysis, and Mendelian randomization analysis were performed to identify metabolic changes due to alcohol consumption. In C. elegans, we found a reduction in locomotion rate after exposure to ethanol for RNAi knockdown of ACTR1B and MAPT. In Drosophila, we observed (1) a change in sedative effect of ethanol for RNAi knockdown of WDPCP, TENM2, GPN1, ARPC1B, and SCN8A, (2) a reduction in ethanol consumption for RNAi knockdown of TENM2, (3) a reduction in triradylglycerols (TAG) levels for RNAi knockdown of WDPCP, TENM2, and GPN1. In human, we observed (1) a link between alcohol consumption and several metabolites including TAG, (2) an enrichment of the candidate (alcohol-associated) metabolites within the linoleic acid (LNA) and alpha-linolenic acid (ALA) metabolism pathways, (3) a causal link between gene expression of WDPCP to liver fibrosis and liver cirrhosis. Our results imply that WDPCP might be involved in ALD.
Kim KW, Han SH, 2023, Association of strict targets of systolic blood pressure, low-density lipoprotein cholesterol level with albuminuria in patients with chronic kidney disease, Hypertension Research, Vol: 46, Pages: 1823-1824, ISSN: 0916-9636
Kojouri M, Pinto R, Mustafa R, et al., 2023, Metabolome-wide association study on physical activity, Scientific Reports, Vol: 13, Pages: 1-9, ISSN: 2045-2322
The underlying mechanisms linking physical activity to better health are not fully understood. Here we examined the associations between physical activity and small circulatory molecules, the metabolome, to highlight relevant biological pathways. We examined plasma metabolites associated with self-reported physical activity among 2217 participants from the Airwave Health Monitoring Study. Metabolic profiling was conducted using the mass spectrometry-based Metabolon platform (LC/GC–MS), measuring 828 known metabolites. We replicated our findings in an independent subset of the study (n = 2971) using untargeted LC–MS. Mendelian randomisation was carried out to investigate potential causal associations between physical activity, body mass index, and metabolites. Higher vigorous physical activity was associated (P < 0.05/828 = 6.03 × 10–5) with circulatory levels of 28 metabolites adjusted for age, sex and body mass index. The association was inverse for glutamate and diacylglycerol lipids, and direct for 3–4-hydroxyphenyllactate, phenyl lactate (PLA), alpha-hydroxy isovalerate, tiglylcarnitine, alpha-hydroxyisocaproate, 2-hydroxy-3-methylvalerate, isobutyrylcarnitine, imidazole lactate, methionine sulfone, indole lactate, plasmalogen lipids, pristanate and fumarate. In the replication panel, we found 23 untargeted LC–MS features annotated to the identified metabolites, for which we found nominal associations with the same direction of effect for three features annotated to 1-(1-enyl-palmitoyl)-2-oleoyl-GPC (P-16:0/18:1), 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2), 1-stearoyl-2-dihomo-linolenoyl-GPC (18:0/20:3n3 or 6). Using Mendelian randomisation, we showed a potential causal relationship between body mass index and three identified metabolites. Circulatory metabolites are associated with physical activity and may play a role in mediating its health effects.
Ghanbari M, Mustafa R, Mens M, et al., 2022, An atlas of genetic regulation and disease associations of microRNAs
<jats:title>Abstract</jats:title> <jats:p>MicroRNAs (miRNAs) are small non<jats:italic>-</jats:italic>coding RNAs that post-transcriptionally regulate gene expression. Identification of genetic variants influencing the transcription of miRNAs can provide an understanding of their genetic regulation and implication in human disease. Here we present genome-wide association studies of 2,083 plasma circulating miRNAs measured by next-generation sequencing in 2,178 participants of the Rotterdam Study to identify miRNA-expression quantitative trait loci (miR-eQTLs). We report 4,310 cis- and trans-miR-eQTLs for 64 miRNAs that have been replicated across independent studies. Many of these miR-eQTLs overlap with gene expression, protein, and metabolite-QTLs and with disease-associated variants. The consequences of perturbation in miRNA transcription on a wide range of clinical conditions are systematically investigated in phenome-wide association studies, with their causality tested using Mendelian randomization. Integration of genomics and miRNAs enables interrogation of the genetic architecture of miRNAs, revealing their clinical importance, and providing valuable resources for future studies of miRNAs in human disease.</jats:p>
Dehghan A, Pinto RC, Karaman I, et al., 2022, Metabolome-wide association study on ABCA7 indicates a role of ceramide metabolism in Alzheimer's disease., Proceedings of the National Academy of Sciences of USA, Vol: 119, Pages: 1-12, ISSN: 0027-8424
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.
Whittaker C, Watson O, Alvarez-Moreno C, et al., 2022, Understanding the Potential Impact of Different Drug Properties On SARS-CoV-2 Transmission and Disease Burden: A Modelling Analysis, Clinical Infectious Diseases, Vol: 75, Pages: e224-e233, ISSN: 1058-4838
BackgroundThe public health impact of the COVID-19 pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear.MethodsUsing a mathematical model of SARS-CoV-2 transmission, COVID-19 disease and clinical care, we explore the public-health impact of different potential therapeutics, under a range of scenarios varying healthcare capacity, epidemic trajectories; and drug efficacy in the absence of supportive care.ResultsThe impact of drugs like dexamethasone (delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R=1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalisation) could have much greater benefits, particularly in resource-poor settings facing large epidemics.ConclusionsAdvances in the treatment of COVID-19 to date have been focussed on hospitalised-patients and predicated on an assumption of adequate access to supportive care. Therapeutics delivered earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority.
Jarvelin M-R, 2022, DNA methylation signature of chronic low-gradeinflammation and its role in cardio-respiratorydiseases, Nature Communications, Vol: 13, ISSN: 2041-1723
We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.
van Vliet NA, Bos MM, Thesing CS, et al., 2021, Higher thyrotropin leads to unfavorable lipid profile and somewhat higher cardiovascular disease risk: evidence from multi-cohort Mendelian randomization and metabolomic profiling, BMC Medicine, Vol: 19, Pages: 1-13, ISSN: 1741-7015
BackgroundObservational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed to investigate the potential causal relationship between thyroid status and cardiovascular disease and to characterize the metabolomic profile associated with thyroid status.MethodsMulti-cohort two-sample Mendelian randomization (MR) was performed utilizing genome-wide significant variants as instruments for standardized thyrotropin (TSH) and free thyroxine (fT4) within the reference range. Associations between TSH and fT4 and metabolic profile were investigated in a two-stage manner: associations between TSH and fT4 and the full panel of 161 metabolomic markers were first assessed hypothesis-free, then directional consistency was assessed through Mendelian randomization, another metabolic profile platform, and in individuals with biochemically defined thyroid dysfunction.ResultsCirculating TSH was associated with 52/161 metabolomic markers, and fT4 levels were associated with 21/161 metabolomic markers among 9432 euthyroid individuals (median age varied from 23.0 to 75.4 years, 54.5% women). Positive associations between circulating TSH levels and concentrations of very low-density lipoprotein subclasses and components, triglycerides, and triglyceride content of lipoproteins were directionally consistent across the multivariable regression, MR, metabolomic platforms, and for individuals with hypo- and hyperthyroidism. Associations with fT4 levels inversely reflected those observed with TSH. Among 91,810 CAD cases and 656,091 controls of European ancestry, per 1-SD increase of genetically determined TSH concentration risk of CAD increased slightly, but not significantly, with an OR of 1.03 (95% CI 0.99–1.07; p value 0.16), whereas higher genetically determined fT4 levels were not associated with CAD risk (OR 1.00 per SD increase of fT4; 95% CI 0.96–1.04;
Mustafa R, Mens MMJ, Huang J, et al., 2021, Associations of Circulatory MicroRNAs and Clinical Traits: A Phenome-wide Mendelian Randomization Analysis, Publisher: WILEY, Pages: 777-778, ISSN: 0741-0395
Wielscher M, Mandaviya P, Kuehnel B, et al., 2021, DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases
<jats:title>Abstract</jats:title> <jats:p>We performed a trans-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We found 1,511 independent differentially methylated loci associated with CRP. These CpG sites showed correlation structures across chromosomes, and were primarily situated in euchromatin, depleted in CpG islands and enriched in transcription factor binding sites and genomic enhancer regions. Mendelian randomisation analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis revealed obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we found that a fully activated CpG signature, meaning that if all novel discovered CpGs would either be fully methylated or unmethylated depending on their CRP associated direction of effect, the risk of myocardial infarction would be increased by 20.3%, risk of T2D by 11.3% and the risk of COPD by 5.6%.</jats:p>
Van Vliet NA, Bos MM, Thesing CS, et al., 2021, HIGHER THYROID STIMULATING HORMONE LEADS TO CARDIOVASCULAR DISEASE AND AN UNFAVORABLE LIPID PROFILE: EVIDENCE FROM MULTI-COHORT MENDELIAN RANDOMIZATION AND METABOLOMIC PROFILING, Publisher: ELSEVIER IRELAND LTD, Pages: E40-E40, ISSN: 0021-9150
Bos MM, Goulding NJ, Lee M, et al., 2021, INVESTIGATING THE RELATIONSHIPS BETWEEN UNFAVORABLE SLEEP AND METABOLOMIC TRAITS: EVIDENCE FROM MULTI-COHORT MULTIVARIABLE REGRESSION AND MENDELIAN RANDOMIZATION ANALYSES, Publisher: ELSEVIER IRELAND LTD, Pages: E42-E42, ISSN: 0021-9150
Bos MM, Goulding NJ, Lee MA, et al., 2021, Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses, BMC MEDICINE, Vol: 19, ISSN: 1741-7015
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- Citations: 8
Mustafa R, Mens M, Pinto R, et al., 2020, Identifying metabolomic fingerprints of microRNAs in cardiovascular disorders, Publisher: SPRINGERNATURE, Pages: 277-277, ISSN: 1018-4813
Mustafa R, Mens M, Pinto RJ, et al., 2020, Metabolomic signatures of microRNAs in cardiovascular traits: A Mendelian randomization analysis, Annual Meeting of the International-Genetic-Epidemiology-Society, Publisher: WILEY, Pages: 506-506, ISSN: 0741-0395
Mustafa R, Ghanbari M, Evangelou M, et al., 2018, An enrichment analysis for cardiometabolic traits suggests non-random assignment of genes to microRNAs, International Journal of Molecular Sciences, Vol: 19, ISSN: 1422-0067
MicroRNAs (miRNAs) regulate the expression of majority of genes. However, it is not known whether they regulate genes in random or are organized according to their function. To this end, we chose cardiometabolic disorders as an example and investigated whether genes associated with cardiometabolic disorders are regulated by a random set of miRNAs or a limited number of them. Single-nucleotide polymorphisms (SNPs) reaching genome-wide level significance were retrieved from most recent genome-wide association studies on cardiometabolic traits, which were cross-referenced with Ensembl to identify related genes and combined with miRNA target prediction databases (TargetScan, miRTarBase, or miRecords) to identify miRNAs that regulate them. We retrieved 520 SNPs, of which 355 were intragenic, corresponding to 304 genes. While we found a higher proportion of genes reported from all GWAS that were predicted targets for miRNAs in comparison to all protein coding genes (75.1%), the proportion was even higher for cardiometabolic genes (80.6%). Enrichment analysis was performed within each database. We found that cardiometabolic genes were over-represented in target genes for 29 miRNAs (based on TargetScan) and 3 miRNAs (miR-181a, miR-302d, and miR-372) (based on miRecords) after Benjamini-Hochberg correction for multiple testing. Our work provides evidence for non-random assignment of genes to miRNAs and supports the idea that miRNAs regulate sets of genes that are functionally related.
Sattwika PD, Mustafa R, Paramaiswari A, et al., 2018, Stem cells for lupus nephritis: a concise review of current knowledge, LUPUS, Vol: 27, Pages: 1881-1897, ISSN: 0961-2033
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- Citations: 13
Cremin Í, Watson O, Heffernan A, et al., 2018, An infectious way to teach students about outbreaks, Epidemics, Vol: 23, Pages: 42-48, ISSN: 1755-4365
The study of infectious disease outbreaks is required to train today’s epidemiologists. A typical way to introduce and explain key epidemiological concepts is through the analysis of a historical outbreak. There are, however, few training options that explicitly utilise real-time simulated stochastic outbreaks where the participants themselves comprise the dataset they subsequently analyse. In this paper, we present a teaching exercise in which an infectious disease outbreak is simulated over a five-day period and subsequently analysed. We iteratively developed the teaching exercise to offer additional insight into analysing an outbreak. An R package for visualisation, analysis and simulation of the outbreak data was developed to accompany the practical to reinforce learning outcomes. Computer simulations of the outbreak revealed deviations from observed dynamics, highlighting how simplifying assumptions conventionally made in mathematical models often differ from reality. Here we provide a pedagogical tool for others to use and adapt in their own settings.
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