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Implications of genetic polymorphisms in inflammation-induced atherosclerosis.

ABSTRACT: Inflammation is the mainstay of atherosclerosis and is an important governing factor at all stages of the disease process from lesion formation to plaque build-up and final end-stage rupture and thrombosis. An overview of the numerous clinico-epidemiological studies on the association between inflammatory gene polymorphisms and Cardiovascular disease (CVD) and its co-morbidities have shown that the risk associated with any single genotype is modest while the haplotypes, especially those defined on the basis of tag-SNP approach, have better coverage of the gene and show moderately higher impact on disease risk. Nevertheless, even these associations have been inconsistent with low cross-race repeatability. This has been attributed to many plausible causes such as clinical heterogeneity, sample selection criteria, variable genetic landscapes across different ethnic groups, confounding effect of co-morbidities etc. On the other hand, unbiased studies such as the family-based linkage and case-control based associations that have taken into account, thousands of genotypic markers spanning the whole genome, have had the ability to identify novel genetic loci for coronary artery disease. These studies have shown that many inflammatory genes are involved in the regulation of specific biomarkers of inflammation that collectively contribute to the disease-associated risk. In addition, there appears to be considerable cross talk between the different biochemical and metabolic processes. Therefore, consideration of all these factors can build towards an 'atherosclerotic bionetwork' that can refine our quest for developing a robust risk stratification tool for cardiovascular disease.

SUBMITTER: Shanker J

PROVIDER: S-EPMC2840586 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Implications of genetic polymorphisms in inflammation-induced atherosclerosis.

Shanker Jayashree J Kakkar Vijay V VV

The open cardiovascular medicine journal 20100223

Inflammation is the mainstay of atherosclerosis and is an important governing factor at all stages of the disease process from lesion formation to plaque build-up and final end-stage rupture and thrombosis. An overview of the numerous clinico-epidemiological studies on the association between inflammatory gene polymorphisms and Cardiovascular disease (CVD) and its co-morbidities have shown that the risk associated with any single genotype is modest while the haplotypes, especially those defined ...[more]

PMID: 21804639

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Project description:PurposeBranch retinal vein occlusion (BRVO) is a common vision-threatening disease. Compression of the underlying retinal vein due to increased rigidity of the crossing artery has been implicated in the pathogenesis of BRVO. Among others, arterial hypertension and hypercholesterolemia, both of which contribute to atherogenesis, have been identified as risk factors. Atherosclerosis itself is a chronic low-grade inflammatory disease with a distinct pro-inflammatory cytokine pattern. In addition to their role in atherogenesis, some cytokines have been shown to exert procoagulatory effects, and may thus contribute to the development of BRVO by a second mechanism. Gene polymorphisms affecting the expression of inflammation-related cytokines are therefore candidates as potential risk factors for BRVO. The purpose of the present study was to investigate hypothesized associations between cytokine gene polymorphisms and the presence of BRVO.MethodsThe study comprised 398 patients with BRVO and 355 control subjects. Using 5'exonuclease assays (TaqMan), genotypes of the following functional single nucleotide polymorphisms were determined: interleukin 1 beta (IL1B) -511C>T, interleukin 1 receptor antagonist (IL1RN) 1018T>C, interleukin 4 (IL4) -584C>T, interleukin 6 (IL6) -174G>C, interleukin 8 (IL8) -251A>T, interleukin 10 (IL10) -592C>A, interleukin 18 (IL18) 183A>G, tumor necrosis factor (TNF) -308G>A, monocyte chemoattractant protein 1 (CCL2) -2518A>G, and RANTES (CCL5) -403G>A.ResultsNeither genotype distributions nor allele frequencies of any of the investigated polymorphisms differed significantly between BRVO patients and controls (p>0.05). Arterial hypertension was found to be significantly more prevalent in BRVO patients than in controls (p<0.001). In a logistic regression analysis presence of arterial hypertension was associated with an odds ratio of 3.33 (95% confidence interval: 2.42-4.57) for BRVO.ConclusionsAs none of the investigated gene variants was significantly more prevalent in BRVO patients than among control subjects, our data suggest that these polymorphisms themselves are unlikely major risk factors for BRVO.

Project description:Atherosclerosis is fueled by a failure to resolve lipid-driven inflammation within the vasculature that drives plaque formation. Therapeutic approaches to reverse atherosclerotic inflammation are needed to address the rising global burden of cardiovascular disease (CVD). Recently, metabolites have gained attention for their immunomodulatory properties, including itaconate, which is generated from the tricarboxylic acid-intermediate cis-aconitate by the enzyme Immune Responsive Gene 1 (IRG1/ACOD1). Here, we tested the therapeutic potential of the IRG1-itaconate axis for human atherosclerosis. Using single-cell RNA sequencing (scRNA-seq), we found that IRG1 is up-regulated in human coronary atherosclerotic lesions compared to patient-matched healthy vasculature, and in mouse models of atherosclerosis, where it is primarily expressed by plaque monocytes, macrophages, and neutrophils. Global or hematopoietic Irg1-deficiency in mice increases atherosclerosis burden, plaque macrophage and lipid content, and expression of the proatherosclerotic cytokine interleukin (IL)-1β. Mechanistically, absence of Irg1 increased macrophage lipid accumulation, and accelerated inflammation via increased neutrophil extracellular trap (NET) formation and NET-priming of the NLRP3-inflammasome in macrophages, resulting in increased IL-1β release. Conversely, supplementation of the Irg1-itaconate axis using 4-octyl itaconate (4-OI) beneficially remodeled advanced plaques and reduced lesional IL-1β levels in mice. To investigate the effects of 4-OI in humans, we leveraged an ex vivo systems-immunology approach for CVD drug discovery. Using CyTOF and scRNA-seq of peripheral blood mononuclear cells treated with plasma from CVD patients, we showed that 4-OI attenuates proinflammatory phospho-signaling and mediates anti-inflammatory rewiring of macrophage populations. Our data highlight the relevance of pursuing IRG1-itaconate axis supplementation as a therapeutic approach for atherosclerosis in humans.

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Implications of genetic polymorphisms in inflammation-induced atherosclerosis.

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Implications of genetic polymorphisms in inflammation-induced atherosclerosis.

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