2017

DOI: 10.1111/joim.12655

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Integrative studies implicate matrix metalloproteinase‐12 as a culprit gene for large‐artery atherosclerotic stroke

Hovsep Mahdessian

¹

,

²

,

Mariette Lengquist

³

et al.

Abstract: Our study supports the notion that MMP12 is implicated in large-artery atherosclerotic stroke, functionally by enhancing elastin degradation and macrophage invasion in plaques.

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Cited by 40 publications

(38 citation statements)

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“…As an example of discrepancies between observational and MR estimates, we found serum levels of MMP12 to be increased in T2DM, consistent with previous reports 18 , whereas the MR estimate for MMP12 suggested a protective effect for T2DM. These findings are similar to the reported protective MR estimate for MMP12 and risk of coronary heart disease 19 whereas clinical and experimental studies have shown higher levels of MMP12 in cardiovascular disease 18,20 .…”

Section: Resultssupporting

confidence: 89%

Deep serum proteomics reveal biomarkers and causal candidates for type 2 diabetes

Guðmundsdóttir

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,

²

,

³

et al. 2019

Preprint

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18The prevalence of type 2 diabetes mellitus (T2DM) is expected to increase rapidly in the next 19 decades, posing a major challenge to societies worldwide. The emerging era of precision 20 medicine calls for the discovery of biomarkers of clinical value for prediction of disease 21 onset, where causal biomarkers can furthermore provide actionable targets. Blood-based 22 factors like serum proteins are in contact with every organ in the body to mediate global 23 homeostasis and may thus directly regulate complex processes such as aging and the 24 development of common chronic diseases. We applied a data-driven proteomics approach 25 measuring serum levels of 4,137 proteins in 5,438 Icelanders to discover novel biomarkers for 26 incident T2DM and describe the serum protein profile of prevalent T2DM. We identified 536 27 proteins associated with incident or prevalent T2DM. Through LASSO penalized logistic 28 regression analysis combined with bootstrap resampling, a panel of 20 protein biomarkers that 29 accurately predicted incident T2DM was identified with a significant incremental 30 improvement over traditional risk factors. Finally, a Mendelian randomization analysis 31 provided support for a causal role of 48 proteins in the development of T2DM, which could 32 be of particular interest as novel therapeutic targets. 33 34 for age and sex, we identified 520 unique proteins that were significantly associated with 84 prevalent T2DM after Bonferroni correction for multiple hypothesis testing (P adj < 0.05), with 85 the strongest associations observed for ARFIP2, MXRA8 and CPM ( Fig. 1a, Table S2). In a 86 second model including adjustment for body mass index (BMI), 322 proteins remained 87 statistically significant ( Table S2). Many of the proteins were inter-correlated, with pairwise 88 Pearson's r ranging from -0.60 to 0.97 ( Fig. S2a). A pathway and gene ontology (GO) 89 enrichment analysis of all 520 proteins associated with prevalent T2DM revealed an 90 enrichment of proteins involved in extracellular matrix (ECM)-receptor interaction, 91 complement and coagulation cascades, metabolic processes and extracellular region (Fig. 92 S3a, Table S3). We furthermore found the genes encoding the 520 prevalent T2DM-93 associated proteins to be enriched for high expression in liver, followed by other tissues that 94 included kidney, gastrointestinal tract and pancreas ( Fig. S4a). Thus, the diabetic state is 95 reflected in a major shift in the serum proteome that is involved in metabolic, inflammatory 96 and ECM processes. 97 98 Serum protein profile of incident T2DM 99The serum protein profiles of T2DM patients observed in the cross-sectional analysis 100 described above may represent shifts that occurred either before or after the onset of the 101 disease. To identify serum protein signatures that preceded the onset of T2DM, we next 102 focused our analysis on the 2,940 non-diabetic AGES participants who participated in a 103 second study visit (AGESII) 5-years after the baseline visit, of which 112 develop...

“…As an example of discrepancies between observational and MR estimates, we found serum levels of MMP12 to be increased in T2DM, consistent with previous reports 18 , whereas the MR estimate for MMP12 suggested a protective effect for T2DM. These findings are similar to the reported protective MR estimate for MMP12 and risk of coronary heart disease 19 whereas clinical and experimental studies have shown higher levels of MMP12 in cardiovascular disease 18,20 .…”

Section: Resultssupporting

confidence: 89%

Deep serum proteomics reveal biomarkers and causal candidates for type 2 diabetes

Guðmundsdóttir

¹

,

²

,

³

et al. 2019

Preprint

View full text Add to dashboard Cite

18The prevalence of type 2 diabetes mellitus (T2DM) is expected to increase rapidly in the next 19 decades, posing a major challenge to societies worldwide. The emerging era of precision 20 medicine calls for the discovery of biomarkers of clinical value for prediction of disease 21 onset, where causal biomarkers can furthermore provide actionable targets. Blood-based 22 factors like serum proteins are in contact with every organ in the body to mediate global 23 homeostasis and may thus directly regulate complex processes such as aging and the 24 development of common chronic diseases. We applied a data-driven proteomics approach 25 measuring serum levels of 4,137 proteins in 5,438 Icelanders to discover novel biomarkers for 26 incident T2DM and describe the serum protein profile of prevalent T2DM. We identified 536 27 proteins associated with incident or prevalent T2DM. Through LASSO penalized logistic 28 regression analysis combined with bootstrap resampling, a panel of 20 protein biomarkers that 29 accurately predicted incident T2DM was identified with a significant incremental 30 improvement over traditional risk factors. Finally, a Mendelian randomization analysis 31 provided support for a causal role of 48 proteins in the development of T2DM, which could 32 be of particular interest as novel therapeutic targets. 33 34 for age and sex, we identified 520 unique proteins that were significantly associated with 84 prevalent T2DM after Bonferroni correction for multiple hypothesis testing (P adj < 0.05), with 85 the strongest associations observed for ARFIP2, MXRA8 and CPM ( Fig. 1a, Table S2). In a 86 second model including adjustment for body mass index (BMI), 322 proteins remained 87 statistically significant ( Table S2). Many of the proteins were inter-correlated, with pairwise 88 Pearson's r ranging from -0.60 to 0.97 ( Fig. S2a). A pathway and gene ontology (GO) 89 enrichment analysis of all 520 proteins associated with prevalent T2DM revealed an 90 enrichment of proteins involved in extracellular matrix (ECM)-receptor interaction, 91 complement and coagulation cascades, metabolic processes and extracellular region (Fig. 92 S3a, Table S3). We furthermore found the genes encoding the 520 prevalent T2DM-93 associated proteins to be enriched for high expression in liver, followed by other tissues that 94 included kidney, gastrointestinal tract and pancreas ( Fig. S4a). Thus, the diabetic state is 95 reflected in a major shift in the serum proteome that is involved in metabolic, inflammatory 96 and ECM processes. 97 98 Serum protein profile of incident T2DM 99The serum protein profiles of T2DM patients observed in the cross-sectional analysis 100 described above may represent shifts that occurred either before or after the onset of the 101 disease. To identify serum protein signatures that preceded the onset of T2DM, we next 102 focused our analysis on the 2,940 non-diabetic AGES participants who participated in a 103 second study visit (AGESII) 5-years after the baseline visit, of which 112 develop...

“…Several published MR findings were confirmed, including that IL6RA variants associated with higher circulating levels of interleukin-6 (IL-6) and soluble IL6-RA were associated with lower risk of coronary heart disease (CHD), rheumatoid arthritis (RA) and atrial fibrillation but higher risks of atopy, such as asthma and eczema 19 . We also replicated previous findings suggesting a causal contribution of IL-1ra to rheumatoid arthritis (RA) but an inverse causal relationship with cholesterol levels 20 , and a protective role of genetically higher MMP-12 against stroke 4,21 .…”

Section: Resultssupporting

confidence: 89%

Genomic evaluation of circulating proteins for drug target characterisation and precision medicine

¹

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²

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³

et al. 2020

Preprint

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Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. By mapping and replicating protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, we identified 467 pQTLs for 85 proteins. The pQTLs were used in combination with other sources of information to evaluate known drug targets, and suggest new target candidates or repositioning opportunities, underpinned by a) causality assessment using Mendelian randomization, b) pathway mapping using trans-pQTL gene assignments, and c) protein-centric polygenic risk scores enabling matching of plausible target mechanisms to sub-groups of individuals enabling precision medicine.

“…Similarly, in vitro macro-calcification has been shown to increase cellular resistance to fluid sheer stress through enhanced cell-matrix interactions [35] and SMCs have a well-documented capacity to respond to physical forces and mechanical stretch [36]. Previous studies have already demonstrated elevated serum-titers of degraded elastin in patients with symptomatic carotid stenosis [37], increased stroke risk associated with low carotid plaque elastin content [38,39], and reduced elastin expression in plaques from S vs. AS patients [40].…”

Section: Discussionmentioning

confidence: 99%

Correlation of computed tomography with carotid plaque transcriptomes associates calcification with lesion-stabilization

¹

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²

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³

et al. 2019

Atherosclerosis

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A B S T R A C TBackground and aims: Unstable carotid atherosclerosis causes stroke, but methods to identify patients and lesions at risk are lacking. We recently found enrichment of genes associated with calcification in carotid plaques from asymptomatic patients. Here, we hypothesized that calcification represents a stabilising feature of plaques and investigated how macro-calcification, as estimated by computed tomography (CT), correlates with gene expression profiles in lesions. Methods: Plaque calcification was measured in pre-operative CT angiographies. Plaques were sorted into high-and lowcalcified, profiled with microarrays, followed by bioinformatic analyses. Immunohistochemistry and qPCR were performed to evaluate the findings in plaques and arteries with medial calcification from chronic kidney disease patients. Results: Smooth muscle cell (SMC) markers were upregulated in high-calcified plaques and calcified plaques from symptomatic patients, whereas macrophage markers were downregulated. The most enriched processes in high-calcified plaques were related to SMCs and extracellular matrix (ECM) organization, while inflammation, lipid transport and chemokine signaling were repressed. These findings were confirmed in arteries with high medial calcification. Proteoglycan 4 (PRG4) was identified as the most upregulated gene in association with plaque calcification and found in the ECM, SMA+ and CD68+/TRAP + cells. Conclusions: Macro-calcification in carotid lesions correlated with a transcriptional profile typical for stable plaques, with altered SMC phenotype and ECM composition and repressed inflammation. PRG4, previously not described in atherosclerosis, was enriched in the calcified ECM and localized to activated macrophages and smooth muscle-like cells. This study strengthens the notion that assessment of calcification may aid evaluation of plaque phenotype and stroke risk.

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