Epigenetics meets proteomics in an epigenome-wide association study with circulating blood plasma protein traits

Zaghlool, Shaza B.; Kühnel, Brigitte; Elhadad, Mohamed A.; Kader, Sara Abdul; Halama, Anna; Thareja, Gaurav; Engelke, Rudolf; Sarwath, Hina; Al-Dous, Eman K.; Mohamoud, Yasmin Ali; Meitinger, Thomas; Wilson, Rory; Strauch, Konstantin; Peters, Annette; Mook‐Kanamori, Dennis O.; Graumann, Johannes; Malek, Joel A.; Gieger, Christian; Waldenberger, Mélanie; Suhre, Karsten

doi:10.1038/s41467-019-13831-w

Cited by 65 publications

(69 citation statements)

References 74 publications

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“…NLRC5 acts as a potent regulator of the inflammasome [44,95]. Zaghlool et al showed that altered methylation at the NLRC5 locus associates with several inflammatory markers, including CXCL10 and CXCL11, with pathway analyses linking it to disease states in which NLRC5 dysfunction is implicated such as cancer and cardiovascular disease [43].…”

Section: Discussionmentioning

confidence: 99%

“…A number of studies have also carried out epigenome-wide association studies (EWAS) on the levels of a small set of inflammatory proteins, including C-reactive protein, interleukins-(1β, 4, 6, 9 and 10), interferon-gamma, transforming growth factor-beta and tumour necrosis factor [37][38][39][40][41][42]. Zaghlool et al performed an EWAS of 1123 proteins, which pointed towards networks of chronic low-grade inflammatory biomarkers (n = 944 individuals) [43]. In an integrative approach, Ahsan et al aimed to identify genetic and epigenetic markers associated with protein biomarkers including inflammatory mediators (n ≤ 1033 individuals) [44].…”

Section: Introductionmentioning

confidence: 99%

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Multi-method genome- and epigenome-wide studies of inflammatory protein levels in healthy older adults

et al. 2020

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Background: The molecular factors which control circulating levels of inflammatory proteins are not well understood. Furthermore, association studies between molecular probes and human traits are often performed by linear modelbased methods which may fail to account for complex structure and interrelationships within molecular datasets. Methods: In this study, we perform genome-and epigenome-wide association studies (GWAS/EWAS) on the levels of 70 plasma-derived inflammatory protein biomarkers in healthy older adults (Lothian Birth Cohort 1936; n = 876; Olink® inflammation panel). We employ a Bayesian framework (BayesR+) which can account for issues pertaining to data structure and unknown confounding variables (with sensitivity analyses using ordinary least squares-(OLS) and mixed model-based approaches). Results: We identified 13 SNPs associated with 13 proteins (n = 1 SNP each) concordant across OLS and Bayesian methods. We identified 3 CpG sites spread across 3 proteins (n = 1 CpG each) that were concordant across OLS, mixedmodel and Bayesian analyses. Tagged genetic variants accounted for up to 45% of variance in protein levels (for MCP2, 36% of variance alone attributable to 1 polymorphism). Methylation data accounted for up to 46% of variation in protein levels (for CXCL10). Up to 66% of variation in protein levels (for VEGFA) was explained using genetic and epigenetic data combined. We demonstrated putative causal relationships between CD6 and IL18R1 with inflammatory bowel disease and between IL12B and Crohn's disease. Conclusions: Our data may aid understanding of the molecular regulation of the circulating inflammatory proteome as well as causal relationships between inflammatory mediators and disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multi-method genome- and epigenome-wide studies of inflammatory protein levels in healthy older adults

et al. 2020

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“…The components were identified based on the extracted raw data using Metabolon's proprietary software. Metabolon's compound annotations and data have been independently validated by many previous studies, including several genetic association studies by our own group 23,47 .…”

Section: Sample Collectionmentioning

confidence: 96%

The metabolic footprint of compromised insulin sensitivity under fasting and hyperinsulinemic-euglycemic clamp conditions in an Arab population

Halama

Suleiman

Kuliński

et al. 2020

Sci Rep

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Metabolic pathways that are corrupted at early stages of insulin resistance (IR) remain elusive. This study investigates changes in body metabolism in clinically healthy and otherwise asymptomatic subjects that may become apparent already under compromised insulin sensitivity (IS) and prior to IR. 47 clinically healthy Arab male subjects with a broad range of IS, determined by hyperinsulinemic-euglycemic clamp (HIEC), were investigated. Untargeted metabolomics and complex lipidomics were conducted on serum samples collected under fasting and HIEC conditions. Linear models were used to identify associations between metabolites concentrations and IS levels. Among 1896 identified metabolites, 551 showed significant differences between fasting and HIEC, reflecting the metabolic switch in energy utilization. At fasting, 336 metabolites, predominantly di- and tri-acylglycerols, showed significant differences between subjects with low and high levels of IS. Changes in amino acid, carbohydrate and fatty acid metabolism in response to insulin were impaired in subjects with low IS. Association of altered mannose and amino acids with IS was also replicated in an independent cohort of T2D patients. We identified metabolic phenotypes that characterize clinically healthy Arab subjects with low levels of IS at their fasting state. Our study is providing further insights into the metabolic pathways that precede IR.

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“…NRLC5 acts as a potent regulator of the inflammasome (40,41). Zaghlool et al showed that altered methylation at the NLRC5 locus associates with several inflammatory markers, including CXCL10 and CXCL11, with pathway analyses linking it to disease states in which NLRC5 dysfunction is implicated such as cancer and cardiovascular disease (9).…”

Section: Discussionmentioning

confidence: 99%

“…To date, few studies have characterised genetic factors which are associated with circulating inflammatory protein levels (also known as protein quantitative trait loci or pQTLs) (n = 9-83 proteins, 65-6,861 individuals) (6)(7)(8). Zaghlool et al performed an epigenome-wide association study (EWAS) of 1123 proteins, which pointed towards networks of chronic low-grade inflammatory biomarkers (n = 944 individuals) (9). In an integrative approach, Ahsan et al identified epigenetic, as well as genetic, markers associated with protein biomarkers including inflammatory mediators (n ≤ 1,033 individuals) (10).…”

Section: Introductionmentioning

confidence: 99%

Integrative omics approach to identify the molecular architecture of inflammatory protein levels in healthy older adults

Hillary

Baños

Kousathanas

et al. 2020

Preprint

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The molecular factors which control circulating levels of inflammatory proteins are not well understood. Furthermore, association studies between molecular probes and human traits are often performed by linear model-based methods which may fail to account for complex structure and interrelationships within molecular datasets. Therefore, in this study, we perform genome-and epigenome-wide association studies (GWAS/EWAS) on the levels of 70 plasma-derived inflammatory protein biomarkers in healthy older adults (Lothian Birth Cohort 1936; n = 876; Olink® inflammation panel). We employ a Bayesian framework (BayesR+) which can account for issues pertaining to data structure and unknown confounding variables (with sensitivity analyses using ordinary least squares-(OLS) and mixed model-based approaches). We identified 13 SNPs associated with 13 proteins (n = 1 SNP each) concordant across OLS and Bayesian methods. We identified three CpG sites spread across three proteins (n = 1 CpG each) that were concordant across OLS, mixed-model and Bayesian analyses. Tagged genetic variants accounted for up to 45% of variance in protein levels (for MCP2, 36% of variance alone attributable to one polymorphism). Methylation data accounted for up to 46% of variation in protein levels (for CXCL10). Up to 66% of variation in protein levels (for VEGFA) was explained using genetic and epigenetic data combined. We demonstrated putative causal relationships between CD6 and IL18R1 with inflammatory bowel disease, and between IL12B and Crohn's disease. Our data may aid understanding of the molecular regulation of the circulating inflammatory proteome as well as causal relationships between inflammatory mediators and disease.

show abstract

Epigenetics meets proteomics in an epigenome-wide association study with circulating blood plasma protein traits

Cited by 65 publications

References 74 publications

Multi-method genome- and epigenome-wide studies of inflammatory protein levels in healthy older adults

Multi-method genome- and epigenome-wide studies of inflammatory protein levels in healthy older adults

The metabolic footprint of compromised insulin sensitivity under fasting and hyperinsulinemic-euglycemic clamp conditions in an Arab population

Integrative omics approach to identify the molecular architecture of inflammatory protein levels in healthy older adults

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