Variations In Inflammatory Genes Research Articles

Genetic variation in satiety signaling and hypothalamic inflammation: merging fields for the study of obesity

Although obesity has been a longstanding health crisis, the genetic architecture of the disease remains poorly understood. Genome-wide association studies have identified many genomic loci associated with obesity, with genes being enriched in the brain, particularly in the hypothalamus. This points to the role of the central nervous system (CNS) in predisposition to obesity, and we emphasize here several key genes along the satiety signaling pathway involved in genetic susceptibility. Interest has also risen regarding the chronic, low-grade obesity-associated inflammation, with a growing concern toward inflammation in the hypothalamus as a precursor to obesity. Recent studies have found that genetic variation in inflammatory genes play a role in obesity susceptibility, and we highlight here several key genes. Despite the interest in the genetic variants of these pathways individually, there is a lack of research that investigates the relationship between the two. Understanding the interplay between genetic variation in obesity genes enriched in the CNS and inflammation genes will advance our understanding of obesity etiology and heterogeneity, improve genetic risk prediction analyses, and highlight new drug targets for the treatment of obesity. Additionally, this increased knowledge will assist in physician's ability to develop personalized nutrition and medication strategies for combating the obesity epidemic. Though it often seems to present universally, obesity is a highly individual disease, and there remains a need in the field to develop methods to treat at the individual level.

Role of inflammation and genes associations with Prostate cancer risk.

The pathogenesis of cancer involves environmental factors in addition to hereditary factors. Recent studies have pointed to a potential role for inflammation in prostatic carcinogenesis and tumor progression. An important factor is the development of chronic inflammation in the prostate due to a number of potential causes including infections, dietary factors, hormonal changes and/or other unknown environmental exposures. In this study we investigated the possible association between single nucleotide polymorphisms in the interleukin IL‐1B (C>T), tumor necrosis factor (308G>A), RANTES‐403, GSTP1 exon 5 polymorphic site (Ile105àVal), PPARG (Pro12Ala) genes also two STR polymorphic marker GSTP1 (penta‐nucleotide repeat at promoter regions) and a pyrimidine‐rich penta‐nucleotide repeat length polymorphism, CD4‐1188 (TTTTC) and the risk for developing prostate cancer. Our study is comprised of 134 prostate cancer cases and age, gender and race matched 178 normal healthy controls. These genes are known to be important for inflammation of prostate and common allelic variants have been shown to have a biological effect. Hence, we searched for a possible association between SNP polymorphisms and STR polymorphic allele gene frequencies obtained in prostate cancer patients and compared with those of a normal control population, looking for allelic associations between any of these polymorphic loci and prostate cancer risk. Strong association between GSTP1, CD4, RANTES (p<0.001), a high variation in allelic frequency of mutant IL1B, TNF and PPARG (p=NS) and prostate cancer risk are observed. Genetic associations of disease and genetic variations in inflammatory genes are often relatively modest, it is likely that polymorphisms in multiple inflammatory genes cooperate in an additive or synergistic manner to impact disease risk Because genetic associations of disease and genetic variations in inflammatory genes are often relatively modest, it is likely that polymorphisms in multiple inflammatory genes cooperate in an additive or synergistic manner to impact disease risk. The possible role of inflammation and gene associations with prostate cancer risk will be discussed.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Variations in inflammatory genes as molecular markers for prediction of inflammatory bowel disease occurrence.

Research on inflammatory bowel disease (IBD) has highlighted genes involved in the regulation of inflammatory responses as contributors to disease pathogenesis. This study aimed to evaluate the associations between IBD and variations in NOD2, TLR4, TNF-α, IL-6, IL-1β and IL-1RN genes, and to use the genetic data obtained in predictive modeling. A total of 167 IBD patients and 101 healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Using the genotype data attained as the input to various classification algorithms, IBD prediction models were designed. The area under the receiver operating characteristic curve (AUROC) was used to measure their performance. Significant associations were found between Crohn's disease (CD) and minor NOD2 variants, as well as TLR4 299Gly, TNF-α G-308A, IL-6 G-174C and IL-1RN VNTR A2 variants, while ulcerative colitis (UC) was associated only with IL-1RN VNTR A2 variants. CD and UC showed highly significant difference in the allelic distribution of TNF-α G-308A, where the A allele was found to be related to CD, and the G allele to UC. A combined effect of patients' gender and TLR4 variants was observed among CD patients. When all analyzed genotype and gender data were used, prediction performance achieved a maximum AUROC of 0.690 for CD and 0.601 for UC dataset. Variations in the genes involved in immune regulation are genetic factors of importance in IBD susceptibility that could potentially be used as predictors of disease development.

The role of inflammation-related genes in osteoarthritis

In this review article we examine the role of inflammation-related genes in osteoarthritis (OA) from the perspective of genetics, epigenetics and gene expression. There have been great strides in such genomic analyses of OA in recent years thanks to the study of adequately powered patient cohorts, the detailed analysis of candidate genes, and the application of genome-wide approaches. These have led to some unexpected and therefore exciting discoveries, implicating pathways that would not necessarily have been predicted to have a role in this common arthritis. Inflammatory-related genes sit firmly in the candidate camp based on prior observations that the OA disease process can have an inflammatory component. What is clear from the genetic studies published to date is that there is no compelling evidence that DNA variation in inflammatory genes is an OA risk factor. This conclusion may of course change as ever more powerful association studies are conducted. There is, however, compelling evidence that epigenetic effects involving inflammatory genes are a component of OA and that alteration in the expression of these genes is also highly relevant to the disease process. We may in fact be close to demonstrating, at the genomic level, a clear separation of OA patients into those in whom inflammation is a key driver of the disease and those in whom it is not. This has obvious implications for the design of trials of novel OA interventions and may also guide the intelligent re-purposing of anti-inflammatory therapies.

E-selectin gene (S128R) polymorphism in hemorrhagic stroke: Comparison with ischemic stroke

Increasing evidence suggests that genetic variation in inflammatory genes plays a pivotal role in pathogenesis of stroke. The aim of the present study was to evaluate the association of E-selectin S128R polymorphism with hemorrhagic stroke and also to evaluate the genotypic and allelic variation with ischemic stroke in a South Indian population from Andhra Pradesh. In this study, we recruited 250 hemorrhagic stroke patients along with 250 age and sex matched controls. The genotypes were determined using PCR-RFLP method and the strength of association between genotypes and hemorrhagic stroke was determined by odds ratio with 95% confidence interval (CI) and chi-square analysis. Allelic and genotypic frequencies of the polymorphism differed significantly between hemorrhagic stroke patients and controls (p<0.001). Significant association was also found following dominant (p<0.001) and co-dominant (p<0.001) models. On comparing the genotypic and allelic frequencies between ischemic and hemorrhagic stroke significant difference was found between the two stroke types (p<0.001). In conclusion, we found the AC genotype to be a significant risk factor for hemorrhagic stroke and we also found significant differences in AC genotype and C allele among the two stroke types. The genotypic and allelic variation between the ischemic and hemorrhagic stroke, suggests that E-selectin S128R mediated amplification of leukocytes onto endothelial cells, leading to secondary damage of brain cells is more pronounced in hemorrhagic stroke.

Gene‐diet interaction effects during a supplementation with n‐3 PUFA on both plasma and gene expression levels of inflammatory markers (1037.9)

Objective: To test whether gene expression of inflammatory genes is altered following an n‐3 PUFA supplementation and to test for any possible gene‐diet interactions modulating plasma inflammatory biomarker levels. Methods: 210 subjects completed a 6‐wk n‐3 PUFA supplementation with 5g/d of fish oil. Gene expression of TNF and IL6 was assessed in peripheral blood mononuclear cells (PBMC) using the TaqMan technology adjusted for the endogenous control (GAPDH). Genotyping of 20 SNPs from the TNF‐LTA gene cluster, IL1β, IL6 and CRP genes was performed. Results: Gene expression of TNF and IL6 increased after the 6‐wk n‐3 PUFA supplementation as shown by 2‐ΔΔCt values &gt;1 (mean±SD, 1.05±0.39 and 1.18±0.50, respectively). In a MIXED model for repeated measures adjusted for the effects of age, sex and BMI, gene by supplementation interactions effects were observed for rs1143627, rs16944, rs1800797, and rs2069840 on IL6 levels, for rs2229094 on TNF‐alpha levels and for rs1800629 on CRP levels (p&lt;0.05 for all). Conclusions: An n‐3 PUFA supplementation could alter gene expression levels of TNF and IL6 in PBMC. Also, the large inter‐individual variability in plasma inflammatory markers following an n‐3 PUFA supplementation may be influenced by genetic variations in inflammatory genes.Grant Funding Source: CIHR

Variations in inflammatory genes are associated with periodontitis

BackgroundPeriodontitis is a multi-factorial disease and several risk-factors such as infections, inflammatory responses, oral hygiene, smoke, aging and individual predisposition are involved in the disease. Pathogens trigger chronic inflammation with cytokines release which in turn leads to the destruction of the connective and the teeth supporting bone. The identification of genetic factors controlling oral inflammation may increase our understanding of genetic predisposition to periodontitis.Single nucleotide polymorphisms in the promoter region of Vascular Endothelial Growth Factor, Alpha-1-Antichymotripsin, hydroxy-methyl-glutaryl CoA reductase, Interferon alpha, Interleukin-1 Beta, Interleukin 10, Interleukin 6 and Tumor Necrosis Factor- alpha genes from a case/control study were investigated.ResultsThe C allele of Vascular Endothelial Growth Factor, A allele of Interleukin 10 and GG genotype of Tumor Necrosis Factor-α were individually associated with chronic periodontitis. However, the concomitant presence of the three genetic markers in the same subjects appeared to play a synergistic role and increased several folds the risk of the disease.ConclusionsOur findings offer new tools to implement the screening of unaffected subjects with an increased susceptibility of periodontitis and increase our understanding regarding the genetic inflammatory background related to familiarity of the disease.

Non-Steroidal Anti-Inflammatory Drugs, Variation in Inflammatory Genes, and Aggressive Prostate Cancer

Increasing evidence suggests that prostatic inflammation plays a key role in the development of prostate cancer. It remains controversial whether non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of prostate cancer. Here, we investigate how a previously reported inverse association between NSAID use and the risk of aggressive prostate cancer is modulated by variants in several inflammatory genes. We found that NSAIDs may have differential effects on prostate cancer development, depending on one’s genetic makeup. Further study of these inflammatory pathways may clarify the mechanisms through which NSAIDs impact prostate cancer risk.

The interleukin-1 cluster, dyslipidaemia and risk of myocardial infarction

Coronary heart disease (CHD) is among the most serious worldwide health problems. Recent genetic studies have robustly identified a number of polymorphic loci throughout the genome that are associated with disease risk but it is certain that more remain to be discovered. It is well established that inflammation plays a key role in the pathophysiology of CHD. Determining whether or not polymorphisms in genes involved in the inflammatory cascade affect the risk of CHD is of considerable interest with respect to understanding the direction of the causal arrow between increased expression of inflammatory genes and CHD. Establishing an association between the variation in inflammatory genes and CHD would provide conceptual support for the use of appropriately specific anti-inflammatory agents in CHD prevention and, potentially, suggest new therapeutic targets. This month in BMC Medicine, Benjamin Brown and colleagues adopt a family-based case-control association study design to address this question. In a large number of CHD cases and healthy sibling controls genotyped for 51 mainly coding single nucleotide polymorphisms (SNPs), they find evidence for the association of a common haplotype at the Interleukin-1 (IL-1) cluster with CHD which appears to be stronger in younger cases without hypercholesterolaemia. They also find suggestive evidence for an association between this same haplotype and hypercholesterolaemia. If replicated in other cohorts, these results could be of substantial importance in advancing the understanding of the way in which inflammatory genes affect coronary heart disease risk.See the associated research paper by Brown et al: http://www.biomedcentral.com/1741-7015/8/5

EVIDENCE OF INFLAMMATORY CELL INVOLVEMENT IN BRAIN ARTERIOVENOUS MALFORMATIONS

Brain arteriovenous malformations (AVM) have high matrix metalloproteinase-9, interleukin-6, and myeloperoxidase (MPO) expression, and polymorphic variations in inflammatory genes are associated with an increased risk of hemorrhage. In this study, we characterized the presence of inflammatory cells in AVM lesional tissue specimens. Immunohistochemistry was used to identify and localize neutrophils (MPO as marker), macrophages/microglia (CD68 as marker), T lymphocytes (CD3 as marker), and B lymphocytes (CD20 as marker). Endothelial cell (EC) marker CD31 was used as an index to assess vascular mass (EC mass). Surgical specimens from 20 unruptured, nonembolized AVMs were examined; seven cortical samples from temporal lobectomy were used as controls. Positive signals for inflammatory cell markers were counted and analyzed by normalizing to the area of the tissue section and the amount of endothelial cells (cells/mm/EC mass pixels). Levels of MPO and matrix metalloproteinase 9 were determined by enzyme-linked immunosorbent assay. Neutrophils and macrophages are all frequently identified in the vascular wall of AVM tissue. In contrast, T and B lymphocytes are rarely observed in AVM tissue. AVM tissue displayed more neutrophil and macrophage/microglia markers than epilepsy control tissue (MPO: 434 +/- 333 versus 5 +/- 4, P = 0.0001; CD68: 454 +/- 404 versus 4 +/- 2, P = 0.0001; cells/mm/EC mass pixels). In ex vivo studies, neutrophil quantity, MPO, and matrix metalloproteinase-9 levels were all colinear (R = 0.98-0.99). Our study demonstrates that inflammatory cells are present in AVM tissue. Taken together with previous genetic and cytokine studies, these data are consistent with a novel view that inflammation is associated with AVM disease progression and rupture.

EVIDENCE OF INFLAMMATORY CELL INVOLVEMENT IN BRAIN ARTERIOVENOUS MALFORMATIONS

OBJECTIVE Brain arteriovenous malformations (AVM) have high matrix metalloproteinase-9, interleukin-6, and myeloperoxidase (MPO) expression, and polymorphic variations in inflammatory genes are associated with an increased risk of hemorrhage. In this study, we characterized the presence of inflammatory cells in AVM lesional tissue specimens. METHODS Immunohistochemistry was used to identify and localize neutrophils (MPO as marker), macrophages/microglia (CD68 as marker), T lymphocytes (CD3 as marker), and B lymphocytes (CD20 as marker). Endothelial cell (EC) marker CD31 was used as an index to assess vascular mass (EC mass). Surgical specimens from 20 unruptured, nonembolized AVMs were examined; seven cortical samples from temporal lobectomy were used as controls. Positive signals for inflammatory cell markers were counted and analyzed by normalizing to the area of the tissue section and the amount of endothelial cells (cells/mm2/EC mass pixels). Levels of MPO and matrix metalloproteinase 9 were determined by enzyme-linked immunosorbent assay. RESULTS Neutrophils and macrophages are all frequently identified in the vascular wall of AVM tissue. In contrast, T and B lymphocytes are rarely observed in AVM tissue. AVM tissue displayed more neutrophil and macrophage/microglia markers than epilepsy control tissue (MPO: 434 ± 333 versus 5 ± 4, P = 0.0001; CD68: 454 ± 404 versus 4 ± 2, P = 0.0001; cells/mm2/EC mass pixels). In ex vivo studies, neutrophil quantity, MPO, and matrix metalloproteinase-9 levels were all colinear (R2 = 0.98–0.99). CONCLUSION Our study demonstrates that inflammatory cells are present in AVM tissue. Taken together with previous genetic and cytokine studies, these data are consistent with a novel view that inflammation is associated with AVM disease progression and rupture.

Role of Proinflammatory Alleles in Longevity and Atherosclerosis

Centenarians are characterized by marked delay or escape from age-associated diseases that cause mortality at earlier ages. Jointly, atherosclerosis and its complications, such as myocardial infarction (AMI), significantly contribute to mortality in the elderly. Inflammation is a key component of atherosclerosis and inflammatory genes are good candidates for the risk of the development of atherosclerosis. Genetic traits contribute to the risk of AMI and allelic variations in inflammatory genes should boost the risk of disease. If proinflammatory genotypes significantly contribute to the risk of AMI, alleles associated with disease susceptibility should not be included in the genetic background favoring longevity. Hence, genotypes of natural immunity should play an opposite role in atherosclerosis and longevity. Metalloproteinase (MMPs) are involved in tissue remodeling and therefore play a remarkable role in inflammation-based disease. MMPs are a family of Zn(2+)-dependent enzymes with proteolytic activity against connective tissue proteins such as collagens, proteoglycans, and elastin, which appear to play important roles in the development and progression of the atherosclerotic lesion. There is evidence indicating a role played by the MMPs in the weakening of atherosclerotic plaque which predisposes to lesion disruption. In this study we performed a genetic study on -1562C/T MMP-9 single nucleotide polymorphism (SNP) in order to discern a possible role in AMI. We analyzed the distribution of this SNP in 115 AMI patients, 123 controls, and 34 centenarians from Sicily. We found no significant differences in the genetic distribution and allelic frequency of -1562C/T MMP-9 SNP between the studied groups. The present results are not in agreement with our previous findings, strengthening our hypothesis that genetic background protection against cardiovascular disease is a relevant component of the longevity trait, at least in the generation of Italian male centenarians under study. However, present results do not exclude that differential expression of MMP-9 playing an opposite role in AMI and longevity because other kinds of regulation might be more relevant than those linked to the SNP under study.

The Pharmacogenetic Impact of Inflammatory Genes on Bladder Cancer Recurrence

Although superficial bladder cancer can generally be treated successfully, tumor recurrence is a serious clinical problem, with a recurrence rate of approximately 70%. Clinicopathologic markers for superficial bladder cancer recurrence remain the best prognostic predictors in clinical decision making. Biomarkers that may complement clinicopathological parameters and increase the accuracy of outcome prediction have been extensively studied. A large number of molecular markers, including inflammatory genes, have been suggested to have predictive value for bladder cancer recurrence. The role of inflammation in the development and progression of bladder cancer, as in other malignancies, is gaining increased recognition. This review will summarize recent data regarding the impact of genetic variations in inflammatory genes on de novo bladder cancer recurrence, as well as recurrence in the context of bacillus Calmette-Guerin (BCG) treatment. Genomic variation as a mechanism that may modify BCG efficacy is discussed in detail.