Genetics of Atherosclerotic Cardiovascular Disease

Qasim, Atif

doi:10.1016/b978-0-12-383834-6.00061-6

Cited by 3 publications

(1 citation statement)

References 408 publications

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“…However, the rs687621 polymorphism is located at the ABO locus, which is known to associate with the expression of many plasma proteins 22,24,41,42 . Such an association hotspot could be explained by the glycosyltransferase activity of ABO proteins 75 , which by transferring glycosyl residuals on target proteins may potentially alter its binding affinity of the associated antibody in immunoassays 76 , thus constituting a technical artefact. In light of these potential caveats, the biological relevance of the FAS-associated trans -pQTL identified should be taken with caution, prior to replication.…”

Section: Discussionmentioning

confidence: 99%

Integrative genetic and immune cell analysis of plasma proteins in healthy donors identifies novel associations involving primary immune deficiency genes

Caron

Patin

Rotival

et al. 2021

Preprint

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Blood plasma proteins play an important role in immune defense against pathogens, including cytokine signaling, the complement system and the acute-phase response. Recent large-scale studies have reported genetic (i.e. quantitative trait loci, pQTLs) and non-genetic factors, such as age and sex, as major determinants to inter-individual variability in immune response variation. However, the contribution of blood cell composition to plasma protein heterogeneity has not been fully characterized and may act as a confounding factor in association studies. Here, we evaluated plasma protein levels from 400 unrelated healthy individuals of western European ancestry, who were stratified by sex and two decades of life (20-29 and 60-69 years), from the Milieu Interieur cohort. We quantified 297 proteins by Luminex in a clinically certified laboratory and their levels of variation were analysed together with 5.2M single-nucleotide polymorphisms. With respect to non-genetic variables, we included more than 700 lifestyle and biochemical factors, as well as counts of seven circulating immune cell populations measured by hemogram and standardized flow cytometry. Collectively, we found 152 significant associations involving 49 proteins and 20 non-genetic variables. Consistent with previous studies, age and sex showed a global, pervasive impact on plasma protein heterogeneity, while body mass index and other health status variables were among the non-genetic factors with the highest number of associations. After controlling for these covariates, we identified 100 and 12 pQTLs acting in cis and trans, respectively, collectively associated with 87 plasma proteins and including 30 novel genetic associations. Genetic factors explained the largest fraction of the variability of plasma protein levels, as compared to non-genetic factors. In addition, blood cell fractions, including leukocytes, lymphocytes and three types of polymorphonuclear cells, had a larger contribution to inter-individual variability than age and sex, and appeared as confounders of specific genetic associations. Finally, we identified new genetic associations with plasma protein levels of eight monogenic Mendelian disease genes including three primary immunodeficiency genes (Ficolin-3, Interleukine-2 Receptor alpha and FAS). Our study identified novel genetic and non-genetic factors associated to plasma protein levels which may inform health status and disease management.

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Section: Discussionmentioning

confidence: 99%

Integrative genetic and immune cell analysis of plasma proteins in healthy donors identifies novel associations involving primary immune deficiency genes

Caron

Patin

Rotival

et al. 2021

Preprint

View full text Add to dashboard Cite

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Integrative genetic and immune cell analysis of plasma proteins in healthy donors identifies novel associations involving primary immune deficiency genes

Caron

Rotival²,

Charbit³

et al. 2022

Genome Med

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Background Blood plasma proteins play an important role in immune defense against pathogens, including cytokine signaling, the complement system, and the acute-phase response. Recent large-scale studies have reported genetic (i.e., protein quantitative trait loci, pQTLs) and non-genetic factors, such as age and sex, as major determinants to inter-individual variability in immune response variation. However, the contribution of blood-cell composition to plasma protein heterogeneity has not been fully characterized and may act as a mediating factor in association studies. Methods Here, we evaluated plasma protein levels from 400 unrelated healthy individuals of western European ancestry, who were stratified by sex and two decades of life (20–29 and 60–69 years), from the Milieu Intérieur cohort. We quantified 229 proteins by Luminex in a clinically certified laboratory and their levels of variation were analyzed together with 5.2 million single-nucleotide polymorphisms. With respect to non-genetic variables, we included 254 lifestyle and biochemical factors, as well as counts of seven circulating immune cell populations measured by hemogram and standardized flow cytometry. Results Collectively, we found 152 significant associations involving 49 proteins and 20 non-genetic variables. Consistent with previous studies, age and sex showed a global, pervasive impact on plasma protein heterogeneity, while body mass index and other health status variables were among the non-genetic factors with the highest number of associations. After controlling for these covariates, we identified 100 and 12 pQTLs acting in cis and trans, respectively, collectively associated with 87 plasma proteins and including 19 novel genetic associations. Genetic factors explained the largest fraction of the variability of plasma protein levels, as compared to non-genetic factors. In addition, blood-cell fractions, including leukocytes, lymphocytes, monocytes, neutrophils, eosinophils, basophils, and platelets, had a larger contribution to inter-individual variability than age and sex and appeared as confounders of specific genetic associations. Finally, we identified new genetic associations with plasma protein levels of five monogenic Mendelian disease genes including two primary immunodeficiency genes (Ficolin-3 and FAS). Conclusions Our study identified novel genetic and non-genetic factors associated to plasma protein levels which may inform health status and disease management.

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The Inflammatory Pattern of Chronic Limb-Threatening Ischemia in Muscles: The TNF-α Hypothesis

et al. 2022

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Background: Vascular inflammation plays a crucial role in peripheral arterial disease (PAD), although the role of the mediators involved has not yet been properly defined. The aim of this work is to investigate gene expression and plasma biomarkers in chronic limb-threating ischemia (CLTI). Methods: Using patients from the GHAS trial, both blood and ischemic muscle samples were obtained to analyze plasma markers and mRNA expression, respectively. Statistical analysis was performed by using univariate (Spearman, t-Student, and X2) and multivariate (multiple logistic regression) tests. Results: A total of 35 patients were available at baseline (29 for mRNA expression). Baseline characteristics (mean): Age: 71.4 ± 12.4 years (79.4% male); TNF-α: 10.7 ± 4.9 pg/mL; hsCRP:1.6 ± 2.2 mg/dL; and neutrophil-to-lymphocyte ratio (NLR): 3.5 ± 2.8. Plasma TNF-α was found elevated (≥8.1) in 68.6% of patients, while high hsCRP (≥0.5) was found in 60.5%. Diabetic patients with a high level of inflammation showed significantly higher levels of NOX4 expression at baseline (p = 0.0346). Plasma TNF-α had a negative correlation with NOS3 (eNOS) expression (−0.5, p = 0.015) and plasma hsCRP with VEGFA (−0.63, p = 0.005). The expression of NOX4 was parallel to that of plasma TNF-α (0.305, p = 0.037), especially in DM. Cumulative mortality at 12 months was related to NLR ≥ 3 (p = 0.019) and TNF-α ≥ 8.1 (p = 0.048). The best cutoff point for NLR to predict mortality was 3.4. Conclusions: NOX4 and TNF-α are crucial for the development and complications of lower limb ischemia, especially in DM. hsCRP could have a negative influence on angiogenesis too. NLR and TNF-α represent suitable markers of mortality in CLTI. These results are novel because they connect muscle gene expression and plasma information in patients with advanced PAD, deepening the search for new and accurate targets for this condition.

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Genetics of Atherosclerotic Cardiovascular Disease

Cited by 3 publications

References 408 publications

Integrative genetic and immune cell analysis of plasma proteins in healthy donors identifies novel associations involving primary immune deficiency genes

Integrative genetic and immune cell analysis of plasma proteins in healthy donors identifies novel associations involving primary immune deficiency genes

Integrative genetic and immune cell analysis of plasma proteins in healthy donors identifies novel associations involving primary immune deficiency genes

The Inflammatory Pattern of Chronic Limb-Threatening Ischemia in Muscles: The TNF-α Hypothesis

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