Pro-inflammatory Genetic Profile Research Articles

Schwann cell-secreted frizzled-related protein 1 dictates neuroinflammation and peripheral nerve degeneration after neurotrauma.

Neurotrauma in limbs can induce sustained neuroinflammation, resulting in persistent disruption of nerve tissue architecture and retardation of axon regrowth. Despite macrophage-mediated inflammation promoting the removal of necrotic neural components and stimulating neo-vessel ingrowth, detrimental shifts in macrophage phenotype exacerbate nerve degeneration. Herein, we find that peripheral nerve injuries (PNIs) result in abundant secreted frizzled-related protein 1 (sFRP1) expression, particularly by Schwann cells (SCs). Heat shock protein 90 (HSP90) in macrophages recognizes sFRP1 and triggers a dysregulated secretion of inflammatory mediators. Single-cell atlas of human injured peripheral nerves reveals the appearance of sFRP1-expressing SCs with mesenchymal traits and macrophages with a proinflammatory genetic profile. Deletion of either SC-specific sFRP1 or macrophage-specific HSP90 alleviates neuroinflammation and prevents the progression of nerve degeneration. Together, our findings implicate the response of macrophages to SC-derived sFRP1 in exacerbating nerve damage following PNIs.

Association of a Multigenetic Pro-Inflammatory Profile with Ischaemic Stroke

Objective: A multigenetic pro-inflammatory profile may increase stroke risk. We investigated whether a higher number of pro-inflammatory genetic variants are associated with ischaemic stroke risk and whether other risk factors further elevate this risk. Methods: In a case-control study with 470 ischaemic stroke patients (cases) and 807 population controls, we investigated 23 haplotypes or alleles in 16 inflammatory genes (interleukin [IL]1A, IL1B, IL1 receptor antagonist, IL6, IL6 receptor, IL10, tumour necrosis factor-a; C-C motif chemokine ligand 2, C-C motif chemokine receptor 5, C-reactive protein (CRP), intercellular adhesion molecule 1, transforming growth factor β1, E-Selectin, selenoprotein S, cluster determinant 14, histone deacetylase 9 [HDAC9]). We constructed an extended gene score (EGS) as the sum of all individual risk alleles and analysed its effect on stroke, just as its association and interaction with cardiovascular risk factors and infectious scores (IgG antibodies against 5 respectively IgA antibodies against 4 microbial antigens). Results: Cases were less likely to carry the minor allele of IL10 rs1800872 and more likely to carry the HDAC9 allele rs11984041 and the pro-inflammatory haplotype of CRP, although the latter was not statistically significant in our study. Overall, cases tended to have more pro-inflammatory alleles and haplotypes than controls (mean ± SD 13.25 ± 2.25 and 13.04 ± 2.41, respectively). However, the EGS only slightly and not significantly increased the risk of stroke (OR 1.04, 95% CI 0.99–1.09). Its effect was neither associated with included risk factors nor with IgA and IgG infectious scores, and we found no significant interaction effects. Conclusion: A more pro-inflammatory genetic profile might increase stroke risk to some extent. This potential effect is most likely independent of established cardiovascular risk factors and the infectious burden of an individual.

Identification of a potential proinflammatory genetic profile influencing carotid plaque vulnerability

Atherosclerosis and vascular remodeling after injury are driven by inflammation and mononuclear cell infiltration. Unstable atherosclerotic plaques are characterized by a large necrotic core. In this study we investigated the distribution and interaction between gene polymorphisms encoding proinflammatory molecules in an Italian population with internal carotid artery stenosis (ICAS). We also evaluated whether reciprocal interaction between these gene polymorphisms increased the risk of plaque vulnerability. In this genetic association study, 11 proinflammatory gene polymorphisms were analyzed in 933 individuals comprising 344 patients with ICAS who underwent carotid endarterectomy and 589 controls without ultrasound evidence of atherosclerosis or intimal thickening. We found that interleukin (IL) 6 (IL-6), IL-1β, monocyte chemoattractant protein-1 (CCL2) macrophage inflammatory protein-1α (CCL3), E-selectin (SELE), intercellular adhesion molecule 1 (ICAM1), and matrix metalloproteinase-3 (MMP-3), and 9 (MMP-9) gene variants were independently and significantly associated with ICAS. The association remained significant even after the Bonferroni correction. We also found a genetic profile associated with different risks for ICAS, depending on the number of high-risk genotypes simultaneously present in an individual. Furthermore, proinflammatory genetic profiles are significantly more common in individuals with unstable carotid plaque. Our study shows, for the first time, a reciprocal interaction between proinflammatory genotypes for the development and progression of ICAS.

Pro-inflammatory genetic profile and familiarity of acute myocardial infarction

BackgroundAcute myocardial infarction (AMI) is a multifactorial disease with a complex pathogenesis where lifestyle, individual genetic background and environmental risk factors are involved. Altered inflammatory responses are implicated in the pathogenesis of atherosclerosis and a premature AMI of parents is associated with an increased risk of the disease in their offspring (Offs). However, the genetic background of familiarity for AMI is still largely unknown. To understand which genes may predispose to increased risk of cardiovascular disease gene polymorphism of immune regulatory genes, and clinical events from the Offs of parents with an early AMI were investigated. Genetics data from Offs were compared with those obtained from healthy subjects and an independent cohort of patients with clinical sporadic AMI. Rates of clinical events during a 24 years follow up from Offs and from an independent Italian population survey were also evaluated.ResultsThis study showed that a genetic signature consisting of the concomitant presence of the CC genotype of VEGF, the A allele of IL-10 and the A allele of IFN-γ was indeed present in the Offs population. In fact, the above genetic markers were more frequent in unaffected Offs (46.4%) and patients with sporadic AMI (31.8%) than in the CTR (17.3%) and the differences were highly statistically significant (Offs vs CTR: p = 0.0001, OR = 4.129; AMI vs CTR: p = 0.0001, OR = 2.224). During the 24-year follow-up, Offs with a positive familiarity in spite of a relatively young age showed an increased prevalence of diabetes, ischemic heart disease and stroke. These findings reinforce the notion that subjects with a familial history of AMI are at risk of an accelerated aging of cardiovascular system resulting in cardiovascular events.ConclusionOur data suggest that selected genes with immune regulatory functions are part of the complex genetic background contributing to familiarity for cardiovascular diseases. This inflammatory genetic profile, along with classical cardiovascular risk factors, may be used for better defining individual risk of AMI in unaffected subjects.

Asymptomatic carotid plaque and pro-inflammatory genetic profile in the elderly

Several indices of subclinical atherosclerosis (ATS), including ultrasound (US) scan of carotid vessels, have received attention in clinical studies of the general population. Since inflammation takes part in the development of ATS, we studied the relationship between US imaging of carotid vessels and genetic predisposition to inflammation, in both elderly subjects without acknowledged CV risk factors and elderly subjects with acknowledged CV risk factors undergoing primary prevention. Seventy-two elderly subjects (aged between 65-84) were divided into three groups on the basis of cardiovascular (CV) risk (G0: 0-9%, G1: 10-20% and G2: >20%) according to the NCEP Adult Panel III Report. They underwent US evaluation of carotid arteries and were analyzed for single nucleotide polymorphisms in the genes of a number of cytokines: TNF-alpha, TGF-beta1, IL-10, IL-6 and IFN-gamma. Asymptomatic carotid plaque (ACP) was detected in 19 subjects, not only in those belonging to the major risk group (36.8%) but also in those at lower risk (63.2%). In these subjects, we found a different genotype distribution in the polymorphisms of IFN-gamma (+874), IL-6 (-174) and IL- 10 (-1082). The TT +874 IFN-gamma and GG -174 IL-6 high producer-genotypes and the AA IL-10 low producergenotype were indeed more frequent in the ACP group (IFN-gamma: p=0.000 and IL-6: p=0.004). We found no correlation between genotype and carotid intima-media thickening. Our data suggest that, in the elderly, inflammation-associated polymorphisms are related to atherogenesis and that the finding of ACP on US scan can be valuable in identifying subjects at risk for CV events, even if they lack traditional cardiovascular risk factors such as an increase in IMT.

Inverse association between a pro-inflammatory genetic profile and Helicobacter pylori seropositivity among patients with chronic atrophic gastritis: Enhanced elimination of the infection during disease progression?

Background Helicobacter pylori infection is a key risk factor for chronic atrophic gastritis (CAG), an established precursor of gastric cancer. There is increasing evidence of frequent clearance of the infection during progression of CAG. We aimed to assess the association between host inflammatory polymorphisms and H. pylori seropositivity among CAG patients from Germany. Methods In the baseline examination of ESTHER, a population-based study conducted in Saarland, serum pepsinogens I and II and H. pylori serostatus were measured by ELISA, and selected genetic polymorphisms (IL1A C-889T, IL1B C-511T, IL1RN A9589T, IL8 T-251A, IL10 T-819C, IL10 A-1082G, LTA C+80A and TNFA G-308A) were assessed by Pyrosequencing™ for 534 serologically defined CAG cases. Results H. pylori seropositivity strongly decreased with disease severity, which is defined by quintiles of serum pepsinogen I, from higher than 90% in the least severe cases to hardly over 50% in the most severe cases. The pro-inflammatory genotypes IL10 -819CC and IL1RN 9589TT were significantly associated with decreased H. pylori seroprevalences with odds ratios of 0.45 (95% confidence interval (CI): 0.23–0.88) and 0.41 (95% CI: 0.18–0.92), respectively, after controlling for age, sex and disease severity. H. pylori seropositivity decreased with the number of pro-inflammatory genotypes ( p < 0.01). Conclusions Our results disclose a clear inverse association between a pro-inflammatory genetic profile and H. pylori seropositivity among cases with CAG, supporting suggestions of enhanced elimination of H. pylori during the development of the disease.

Association between a pro-inflammatory genetic profile and the risk of chronic atrophic gastritis among older adults from Germany

BackgroundPro-inflammatory polymorphisms have been suggested to explain part of the individual diversity in susceptibility to gastric carcinogenesis. We aimed to assess their impact on the risk of chronic atrophic gastritis (CAG) in a population-based study. MethodsAmong 9953 older adults from Saarland/Germany, eight single nucleotide polymorphisms (SNPs) were assessed for 534 cases with serologically defined CAG and 534 age- and sex-matched controls at baseline examination. ResultsOf the 8 SNPs, only IL10 T-819C showed a borderline significant association with CAG risk (odds ratio for CC versus TT: 1.67 (95% confidence interval: 1.01–2.76)). No significant differences were observed for the distribution of inferred haplotypes between cases and controls. However, joint evaluation of several cytokine variants suggested an increased risk of CAG among individuals carrying several pro-inflammatory genotypes. ConclusionsOur findings suggest that a pro-inflammatory genetic profile may contribute to inter-individual variation in gastric cancer risk by increasing the susceptibility to the development of CAG.

A Functional Polymorphism of Toll-Like Receptor 4 Gene Increases Risk of Gastric Carcinoma and Its Precursors

TLR4 is a cell-surface signaling receptor involved in the recognition and host response to Helicobacter pylori. The TLR4+896A>G polymorphism linked with impaired reactivity to bacterial lipopolysaccharide may play a role in gastric carcinogenesis. We assessed associations with premalignant gastric changes in 149 relatives of gastric cancer patients, including 45 with hypochlorhydria and gastric atrophy. We also genotyped 2 independent Caucasian population-based case-control studies of upper gastrointestinal tract cancer, initially in 312 noncardia gastric carcinoma cases and 419 controls and then in 184 noncardia gastric carcinomas, 123 cardia carcinomas, 159 esophageal cancers, and 211 frequency-matched controls. Odds ratios were computed from logistic models and adjusted for potential confounding factors. TLR4+896G carriers had an 11-fold (95% confidence interval [CI], 2.5-48) increased odds ratio (OR) for hypochlorhydria; the polymorphism was unassociated with gastric acid output in the absence of H pylori infection. Carriers also had significantly more severe gastric atrophy and inflammation. Seventeen percent of gastric carcinoma patients in the initial study and 15% of the noncardia gastric carcinoma patients in the replication study had 1 or 2 TLR4 variant alleles vs 8% of both control populations (combined OR = 2.3; 95% CI = 1.6-3.4). In contrast, prevalence of TLR4+896G was not significantly increased in esophageal squamous cell (2%, OR = 0.2) or adenocarcinoma (9%, OR = 1.4) or gastric cardia carcinoma (11%, OR = 1.4). Our data suggest that the TLR4+896A>G polymorphism is a risk factor for noncardia gastric carcinoma and its precursors. The findings underscore the role of the host innate immune response in outcome of H pylori infection.

A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma

Background & Aims: Pro-inflammatory polymorphisms within the genes interleukin (IL)-1B and IL-1RN are associated with risk for gastric carcinoma (GC) in Helicobacter pylori—infected individuals. We aimed to determine the association between variation of the tumor necrosis factor ( TNF)-α gene and the risk for chronic atrophic gastritis (CAG) and GC. We also investigated the extent to which the combined effect of proinflammatory genetic polymorphisms ( IL-1B, IL-1RN, and TNF-α), and the combined effect of TNF-α and bacterial genotypes each influence such a risk. Methods: In a case-control study including 306 controls, 221 individuals with chronic gastritis, and 287 GC patients, the TNF-α-308 and IL-1B-511 bi-allelic polymorphisms, the IL-1RN variable number of tandem repeats (VNTR), and the H. pylori genes vacA (s and m regions) and cagA were genotyped. Results: We found that carriers of the TNF-α-308∗A allele are at increased risk for GC development with an odds ratio (OR) of 1.9 (95% confidence interval [CI], 1.3–2.7). For both CAG and GC, the odds of developing disease increased with the number of high-risk genotypes. Individuals carrying high-risk genotypes at the 3 loci are at increased risk for CAG and GC with an OR of 5.8 (95% CI, 1.1–31.0) and 9.7 (95% CI, 2.6–36.0), respectively. The risk for GC was not affected significantly by the combination of bacterial and TNF-α-308 genotypes. Conclusions: These findings show that a proinflammatory polymorphism in the TNF-α gene is associated with increased risk for GC, and that it is possible to define a specific genetic profile associated with highest risk for CAG and GC.

A pro-inflammatory genetic profile increases the risk of chronic atrophic gastritis and gastric carcinoma

A pro-inflammatory genetic profile increases the risk of chronic atrophic gastritis and gastric carcinoma