Circulating C-reactive Protein Research Articles

Evaluating the effects of dietary patterns on circulating C-reactive protein levels in the general adult population: an umbrella review of meta-analyses of interventional and observational studies.

Adopting a healthy dietary pattern may be an initial step in combating inflammation-related chronic diseases; however, a comprehensive synthesis evaluating current evidence is lacking. This umbrella review aimed to summarise the current evidence on the effects of dietary patterns on circulating C-reactive protein (CRP) levels in adults. We conducted an exhaustive search of the Pubmed, Scopus and Epistemonikos databases, spanning from their inception to November 2023, to identify systematic reviews and meta-analyses across all study designs. Subsequently, we employed a random-effects model to recompute the pooled mean difference. Methodological quality was assessed using the A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) checklist, and evidence certainty was categorised as non-significant, weak, suggestive, highly suggestive or convincing (PROSPERO: CRD42023484917). We included twenty-seven articles with thirty meta-analyses of seven dietary patterns, fifteen of which (50 %) exhibited high methodological quality. The summary effects of randomised controlled trials (RCT) found that the Mediterranean diet was the most effective in reducing circulating CRP levels, followed by Vegetarian/Vegan and Energy-restricted diets, though the evidence was of weak quality. In contrast, Intermittent Fasting, Ketogenic, Nordic and Paleolithic diets did not show an inverse correlation with circulating CRP levels. Some results from combined interventional and observational studies, as well as solely observational studies, also agreed with these findings. These dietary patterns show the potential in reducing CRP levels in adults, yet the lack of high-quality evidence suggests future studies may alter the summary estimates. Therefore, further well-conducted studies are warranted.

A link between systemic low-grade inflammation and frailty in older adults: clinical evidence from a nationwide population-based study.

Despite the possible role of systemic low-grade inflammation on frailty, the majority of previous studies have focused solely on the phenotypic frailty with limited participant numbers, thereby weakening the evidence supporting the notion that circulating C-reactive protein (CRP) could be a potential frailty biomarker. This study is a nationally representative, population-based, cross-sectional analysis from the Korea National Health and Nutrition Examination Survey, involving 5,359 participants aged 65 and older. We generated a deficit accumulation frailty index (FI) based on 38 items, encompassing physical, cognitive, psychological, and social status. Frailty was classified as non-frail (FI ≤ 0.15), pre-frail (0.15 < FI ≤ 0.25), or frail (FI > 0.25). Serum high-sensitivity CRP (hsCRP) levels were measured by immunoturbidometric method. After adjusting for confounders including age, sex, income, education, smoking, hypertension, diabetes, dyslipidemia, stroke, cardiovascular diseases, and body mass index, serum hsCRP levels were 29.4% higher in frail participants compared to their non-frail counterparts (p = 0.001). Additionally, circulating hsCRP concentrations positively correlated with the FI (p = 0.003), and the odds ratio for frailty per standard deviation increase in serum hsCRP was 1.18 (p = 0.001). Moreover, older adults in the highest hsCRP quartile exhibited a significant higher FI with a 1.59-fold increased odds ratio for frailty than those in the lowest quartile (p = 0.002 and 0.001, respectively). These findings validate the impact of age-related systemic low-grade inflammation on frailty and support the utility of serum hsCRP as a potential biomarker for detecting frailty in older adults.

The association of circulating systemic inflammation with premature death and the protective role of the Mediterranean diet: a large prospective cohort study of UK biobank

BackgroundAlthough previous studies have identified specific circulating inflammatory markers associated with the risk of mortality, they have often overlooked the broader impact of a comprehensive inflammatory response on health outcomes. This study aims to assess the association between circulating systemic inflammation and age-related hospitalization and premature death, as well as explore the potential mediating effects of various dietary patterns on these associations.MethodsA total of 448,574 participants enrolled in the UK Biobank study were included. Circulating C-reactive protein(CRP), white blood cell count(WBC), platelet count(Plt), and neutrophil/lymphocyte ratio(NLR) were measured, which were used to establish a weighted systemic inflammatory index of inflammation index(INFLA-Score). Dietary intake information was documented through 24-hour dietary recalls, and dietary pattern scores including Dietary Approaches to Stop Hypertension(DASH), Mediterranean(MED), and Healthy Eating Index-2020(HEI-2020) were calculated. Cox proportional hazards regression models were performed to assess the associations between INFLA-Score and age-related disease hospitalization, cause-specific and all-cause premature death.ResultsDuring a median follow-up of 12.65 years, 23,784 premature deaths were documented. After adjusting for multiple covariates, higher levels of CRP, WBC, NLR, and INFLA-Score were significantly associated with increased risks of age-related disease hospitalization(HRCRP=1.19; 95%:1.17–1.21; HRWBC=1.17; 95%:1.15–1.19; HRNLR=1.18; 95%:1.16–1.20; HRINFLA−Score=1.19; 95%:1.17–1.21) and premature death(HRCRP=1.68; 95%:1.61–1.75; HRWBC=1.23; 95%:1.18–1.27; HRNLR=1.45; 95%:1.40–1.50; HRINFLA−Score=1.58; 95%:1.52–1.64). Compared to the lowest INFLA-Score group, the highest INFLA-Score group was associated with increased values of whole-body and organ-specific biological age, and had a shortened life expectancy of 2.96 (95% CI 2.53–3.41) and 4.14 (95% CI 3.75–4.56) years at the age of 60 years in women and men, respectively. Additionally, we observed no significant association of the INFLA-Score with aging-related hospitalization and premature death among participants who were more adhering to the Mediterranean (MED) dietary pattern(HRAging−related hospitalization=1.07; 95%:0.99–1.16;HRPremature death=1.19; 95%:0.96–1.47).ConclusionA higher INFLA-Score was correlated with an increased risk of age-related hospitalization and premature death. Nevertheless, adherence to a Mediterranean (MED) diet may mitigate these associations.

The causality between C-reactive protein and asthma: a two-sample Mendelian randomization analysis.

This study sought to investigate the causal effects of circulating C-reactive protein (CRP) level on risk of asthma and its subtypes by two-sample Mendelian randomization (MR) analysis. We utilized single nucleotide polymorphisms (SNPs) associated with both CRP and outcomes of asthma, allergic asthma, and obesity-related asthma as genetic variables via a genome-wide summary association study (GWAS). MR analysis mainly based on the inverse variance weighted (IVW) method was performed to infer the causal relationship between exposure and outcomes. Cochran's Q test and MR-Egger regression analysis were performed to determine respectively the heterogeneity and pleiotropy among instrumental variables (IVs), and leave-one-out analysis was conducted to determine the stability of the MR results. In our study, 42 SNPs were identified as IVs for MR analyses. According to the primary inference results by IVW methods, circulating CRP was demonstrated to be significantly associated with risk of asthma [odds ratio (OR):1.046; 95% confidence interval (95% CI): 1.004-1.090; P = .030] and obesity-related asthma (OR:1.072; 95% CI: 1.009-1.138; P = 0.025), whereas no distinct causality with allergic asthma was found (OR:1.051; 95% CI: 0.994-1.112; P = .081). Sensitivity analyses indicated that there was no horizontal pleiotropy among IVs, and the MR results were proved to be robust by leave-one-out sensitivity analysis, despite the presence of heterogeneity. The present study suggested that higher CRP might genetically predict an increased risk of developing asthma and obesity-related asthma, without causality with allergic asthma.

Genetic correlation and causal associations between circulating C-reactive protein levels and lung cancer risk.

We aimed to characterize genetic correlations and causal associations between circulating C-reactive protein (CRP) levels and the risk of lung cancer (LC). Leveraging summary statistics from genome-wide association studies of circulating CRP levels among 575,531 individuals of European ancestry, and LC risk among 29,266 cases and 56,450 controls, we investigated genetic associations of circulating CRP levels with the risk of overall lung cancer and its histological subtypes, by using linkage disequilibrium score (LDSC) regression and Mendelian randomization (MR) analyses. Significant positive genetic correlations between circulating CRP levels and the risk of LC and its histological subtypes were identified from LDSC regression, with correlation coefficients ranging from 0.12 to 0.26, and all false discovery adjusted p < 0.05. Univariable MR demonstrated a nominal association between CRP levels and an increased risk of lung squamous cell carcinoma (SCC) (inverse variance-weighted OR = 1.15, 95% CI 1.01-1.30). However, this association disappeared when multivariable MR included cigarettes per day and/or body mass index. By using our recently developed constrained maximum likelihood-based MR method, we identified significant associations of CRP levels with the risk of overall LC (OR 1.06, 95% CI 1.03-1.09), SCC (OR 1.06, 95% CI 1.02-1.09), and small cell lung cancer (SCLC, OR 1.09, 95% CI 1.03-1.15). Moreover, most univariable and multivariable MR analyses also revealed consistent CRP-SCLC associations. There may be a genetic and causal association between circulating CRP levels and the risk of SCLC, which is in line with previous population-based observational studies.

Exploration of the causal relationship between inflammatory cytokines and prostate carcinoma: a comprehensive Mendelian randomization study.

Prostate cancer (PCa) is one of the most prevalent malignancies affecting males; however, the role of inflammatory activity in the pathogenesis of this disease is not yet fully elucidated. Although inflammation is recognized as being closely associated with the onset and progression of PCa, the specific causal relationships between individual inflammatory factors and the disease require further clarification. Mendelian randomization (MR) methodologies can mitigate bias by utilizing whole-genome sequencing data, leveraging specific genetic variants to assess causal relationships between a given exposure and an outcome of interest. This research employed an MR approach to investigate the association between inflammatory cytokines and PCa. In total, 44 inflammatory cytokines were evaluated in a large GWAS dataset to enable the drawing of robust conclusions. Elevated circulating C-reactive protein (CRP) and prostaglandin E2 (PGE-2) levels were related to greater PCa risk. The reverse Mendelian randomization (MR) study indicates a causal relationship between prostate cancer and stem cell factor (SCF) (P=0.025). CRP and PGE-2 play crucial roles in the regulation of PCa development. Moreover, PCa may have an impact on SCF levels. Further research is imperative to elucidate whether these biomarkers can be effectively utilized to prevent or treat PCa.

Tumor necrosis factor mediates the impact of PM2.5 on bone mineral density: Inflammatory proteome Mendelian randomization and colocalization analyses

To assess the causal effect of particulate matter 2.5 (PM2.5) on human bone mineral density (BMD) and to explore the possible mechanism and proportion mediated by inflammation-related protein. The genetic correlation between PM2.5 and BMD was assessed using the Linkage Disequilibrium Score (LDSC), and the causal effect between PM2.5 and BMD was assessed by two-sample Mendelian randomization (TSMR). A 2-step Mendelian randomization (MR) approach was employed to evaluate the potential role of inflammation-associated protein as the mediator in the causal association between PM2.5 and BMD. The multivariate Mendelian randomization (MVMR) study was designed to perform mediation analyses, exclude possible confounders and calculate the proportion of mediation. Subsequently, we used Bayesian colocalization analysis to consolidate the MR results. Finally, using drug-target MR design, we evaluated the potential repurposing of tumor necrosis factor (TNF) inhibitors for the treatment of osteoporosis (OP). The results of the analyses show that BMD is negatively influenced by PM2.5 (Inverse variance weighted [IVW] beta [β] = −0.288, 95% confidence interval [CI]: −0.534 – −0.042, P < 0.05). PM2.5 has a positive causal association with TNF (IVW β = 1.564, 95% CI: 0.155 – 2.973, P < 0.05) and a negative causal association with protachykinin-1 (TAC-1) (IVW β = −1.654, 95% CI: −3.063 – −0.244, P < 0.05). TNF has a negative causal association with BMD (Wald ratio β = −0.082, 95% CI: −0.165 – 0.000, P < 0.05) and TAC-1 has a positive causal association with BMD (IVW β = 0.042, 95% CI: 0.007 – 0.077, P < 0.05). After adjusting TNF and TAC-1, PM2.5 has no causal association with BMD (IVW β = −0.200, 95% CI: −0.579 – 0.179, P > 0.05). After adjusting PM2.5 and TAC-1, there was still a negative causal association between TNF and BMD (IVW β = −0.089, 95% CI: −0.166 – −0.012, P < 0.05). In the final drug-target MR study, the protective effect of TNF/TNF receptor 1 (TNFR1) inhibition on BMD was observed. For every 10% decrease of circulating C-reactive protein (CRP) achieved by TNF/TNF receptor 1 (TNFR1) blockade, β was 0.540 (95% CI: 0.040–1.040) for BMD. We found a negative causal association between PM2.5 and BMD and that causal association was mediated by TNF. The results of drug-target MR do support TNFR1 as a promising target for OP prevention among the general population.

GENDER DIFFERENCES IN THE ASSOCIATION BETWEEN SLEEP AND INFLAMMATORY MARKERS: RESULTS FROM THE EINSTEIN AGING STUDY

Abstract Prior research links poor sleep and higher systemic inflammation. Gender differences in both sleep and in inflammatory responses have been observed. We investigated gender differences in the association between levels as well as variability of objective sleep health and inflammatory markers (including stimulated inflammatory markers) among a diverse sample of older adults. Participants free of dementia (N=215, Mage=77.5 years, 64% women; 46% White, 39% Black, 15% Hispanic/other) were from The Einstein Aging Study. Actigraphy (2 weeks) yielded wake after sleep onset (WASO), total night sleep time (TST), and midpoint night sleep. Inflammatory markers included circulating C-reactive protein (CRP) and circulating and lipopolysaccharide (LPS)-stimulated levels of interleukin (IL)-1β, IL-4, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-𝛼. Bayesian variability models evaluated associations of inflammatory markers with mean and variability of sleep measures, adjusted for BMI, gender, age, education, race/ethnicity. Circulating inflammatory markers were not associated with sleep measures, except higher TST variability with higher circulating IL-6 among women. For stimulated cytokines, among men, higher mean WASO, TST, and later midpoint were associated with higher stimulated IL-8 and TNF-𝛼. All stimulated cytokines except IL-1β were associated with greater variability in WASO, TST, and sleep timing among men. Among women, the only significant association with stimulated cytokines was between higher mean TST and higher stimulated IL-8. We found gender differences in the associations between sleep and inflammation in older adults, primarily in men and for stimulated (not circulating) cytokines. Interestingly, associations were also more frequently observed for sleep variability than mean levels.

Effect of influenza vaccination on resting metabolic rate and c-reactive protein concentrations in healthy young adults

Objectives Chronic immune activation and severe inflammatory states are positively associated with resting metabolic rate (RMR; kcal/day), but the impacts of mild immune stimuli on metabolism are poorly understood. This study investigates the within-individual association between the inflammatory response to influenza vaccination and RMR in young adults. Methods We evaluated RMRs through indirect calorimetry and circulating c-reactive protein (CRP) concentrations (mg/L)—a direct measure of inflammation—via high-sensitivity immunoassays of dried blood spots (n = 17) at baseline and two- and seven-days post-vaccine. Wilcoxon matched-pairs signed-rank tests were used to evaluate the magnitude of the CRP and RMR responses. Type II Wald chi-square tests of linear mixed-effect models assessed whether those responses were correlated. Results Baseline CRP was 1.39 ± 1.26 mg/L. On day two post-vaccine, CRP increased by 1.47 ± 1.37 mg/L (p &lt; 0.0001), representing a 106% increase above baseline values. CRP remained higher on day seven post-vaccine, 1.32 ± 2.47 mg/L (p = 0.05) above baseline values. There were no statistically significant changes in RMR from baseline to day two (p = 0.98) or day seven (p = 0.21). Change in CRP from baseline did not predict RMR variation across days (p = 0.46). Conclusions We find no evidence that adult influenza vaccination results in a corresponding increase in RMR. These results suggest that the energetic cost of an influenza vaccine’s mild inflammatory stimulus is either too small to detect or is largely compensated by a temporary downregulation of energy allocated to other metabolic tasks.

Association between active commuting and low-grade inflammation: a population-based cross-sectional study.

Prior studies suggest that physical activity lowers circulating C-reactive protein (CRP) levels. However, little is known about the association between regular active commuting, i.e. walking or cycling to work, and CRP concentrations. This study examines whether active commuting is associated with lower CRP. We conducted a cross-sectional study using population-based FINRISK data from 1997, 2002, 2007 and 2012. Participants were working adults living in Finland (n = 6208; mean age = 44 years; 53.6% women). We used linear and additive models adjusted for potential confounders to analyze whether daily active commuting, defined as the time spent walking or cycling to work, was associated with lower high-sensitivity (hs-) CRP serum concentrations compared with passive commuting. We observed that daily active commuting for 45 min or more (vs. none) was associated with lower hs-CRP [% mean difference in the main model: -16.8%; 95% confidence interval (CI) -25.6% to -7.0%), and results were robust to adjustment for leisure-time and occupational physical activity, as well as diet. Similarly, active commuting for 15-29 min daily was associated with lower hs-CRP in the main model (-7.4; 95% CI -14.1 to -0.2), but the association attenuated to null after further adjustments. In subgroup analyses, associations were only observed for women. Active commuting for at least 45 min a day was associated with lower levels of low-grade inflammation. Promoting active modes of transport may lead not only to reduced emissions from motorized traffic but also to population-level health benefits.

Abstract 13994: PKM2 Ablation Increases Pro-Inflammatory Signaling in Mice

Introduction: The predominant isoform of pyruvate kinase (PKM1) promotes oxidative metabolism in the healthy heart. We previously described a hypoxia and ischemia-mediated switch to the alternatively spliced isoform PKM2, known to promote glycolysis. Pkm2 has also been shown to reduce oxidative damage and promote cardiomyocyte cell proliferation after myocardial infarction (MI). PKM2 is also a metabolic regulator of immune cell differentiation. Hypothesis: We hypothesize that PKM2 has a role in limiting inflammatory stress by regulating the migration and activity of immune cells. Methods: PKM2 control and global KO mice were subjected to permanent ligation of the left anterior descending coronary artery to mimic an MI (n=3). Hearts were excised after 3 days and the transcriptomes and gene ontologies (GO) were then assessed by RNA-sequencing and pathway analysis. Circulating C-reactive protein (CRP) was assessed using an ELISA (n=12) and cytokines in plasma and heart tissue were assessed using a multiplex assay (n=3-5). Neutrophil myeloperoxidase secretion and differentiated cardiac macrophages were analyzed by immunofluorescent staining (n=3). Results: GO term enrichment analysis of RNA-seq results showed increased abundance of genes for neutrophil chemotaxis and apoptosis, regulation of cytokine production, and the inflammatory response in PKM2 KO hearts after MI compared to controls. PKM2 KO hearts showed increased neutrophil myeloperoxidase secretion and Ly6G/C staining for neutrophils and monocytes compared to controls. Similarly, M1 macrophages appeared to be more abundant in PKM2 KO hearts compared to controls. IL-6 levels were elevated in PKM2 KO plasma at baseline compared to controls, while CRP was elevated in PKM2 KO plasma across all conditions. IL-6 was also substantially elevated in PKM2 KO hearts after MI compared to controls. Conclusions: Loss of PKM2 increased pro-inflammatory signaling in the heart of KO mice. We saw increased cardiac and plasma IL-6 and CRP, likely related to the polarization of macrophages towards the M1 phenotype, and increased neutrophil activity in PKM2 KO hearts. We suggest that PKM2, induced by a hypoxia-related splicing event, protects the heart against the inflammation that accompanies infarction.

Active commuting and low-grade inflammation: a population-based cross-sectional study

Abstract Background Active commuting (i.e., walking and cycling to work) could have public health benefits while simultaneously fostering climate change mitigation. Current evidence suggests that regular physical activity decreases circulating C-reactive protein (CRP) levels. Yet, it is unclear whether active commuting is associated with lower CRP levels. Study aims: To explore the association between active commuting and CRP levels in working Finnish residents. Our hypothesis is that CRP levels are lower in active commuters than passive commuters. Methods A total of 6208 working Finnish residents were drawn from the FINRISK population surveys of years 1997, 2002, 2007 and 2012. We cross-sectionally analysed the association between active commuting, defined as the time spent walking or cycling to work daily, and high sensitivity (hs-) CRP serum levels in this sample. For the analyses, we used linear and additive models, and we adjusted for potential confounders. Results Participants who engaged in a minimum of 45 minutes of daily active commuting had 16.8% (95% confidence interval, CI: -25.6%, -7.0%) lower hs-CRP than passive commuters. The direction of the association in the main model was the same when active commuting lasted 15-29 minutes daily (% mean difference: -7.4; 95% CI: -14.1, -0.2), but the estimates lacked precision after adjusting for leisure-time physical activity and diet. In subgroup analyses, we observed associations for women. Conclusions High level of active commuting, at least 45 minutes a day, was associated with reduced low-grade inflammation; the association was driven by women. Key messages • Promoting active commuting could help reduce many chronic diseases. • Active modes of transport, such as walking and cycling, may not only be an alternative to motorized vehicles to decrease emissions, but they may also have public health benefits.

Downregulation of interleukin 6 signaling might reduce the risk of periodontitis: a drug target Mendelian randomization study.

Interleukin 6 (IL-6) is considered to play a role in the dysbiotic host response in the development of periodontitis. While the inhibition of the IL-6 receptor using monoclonal antibodies is a well-established therapy for some diseases, so far, its potential benefit in patients with periodontitis has not been examined. We tested the association of genetically proxied downregulation of IL-6 signaling with periodontitis to explore whether downregulation of IL-6 signaling could represent a viable treatment target for periodontitis. As proxies for IL-6 signaling downregulation, we selected 52 genetic variants in close vicinity of the gene encoding IL-6 receptor that were associated with lower circulating C-reactive protein (CRP) levels in a genome-wide association study (GWAS) of 575 531 participants of European ancestry from the UK Biobank and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Associations with periodontitis were tested with inverse-variance weighted Mendelian randomization in a study of 17 353 cases and 28 210 controls of European descent in the Gene-Lifestyle Interactions in Dental Endpoints (GLIDE) consortium. In addition, the effect of CRP reduction independent of the IL-6 pathway was assessed. Genetically proxied downregulation of IL-6 signaling was associated with lower odds of periodontitis (odds ratio (OR) = 0.81 per 1-unit decrement in log-CRP levels; 95% confidence interval (CI): [0.66;0.99]; P = 0.0497). Genetically proxied reduction of CRP independent of the IL-6 pathway had a similar effect (OR = 0.81; 95% CI: [0.68; 0.98]; P = 0.0296). In conclusion, genetically proxied downregulation of IL-6 signaling was associated with lower odds of periodontitis and CRP might be a causal target for the effect of IL-6 on the risk of periodontitis.

A predictive role of C-reactive protein in colorectal cancer risk: an updated meta-analysis from 780,985 participants and 11,289 cancer cases.

This meta-analysis is aimed at understanding the potential role of circulating C-reactive protein (CRP) in the prediction of colorectal cancer (CRC) risk and the potential effect of relevant variables, with specific concern to determine the incorporation of CRP into a CRC risk prediction model. Relevant articles on the association between circulating CRP and CRC risk were searched from PubMed, Embase, Web of Science, and Cochrane Database of Systematic Reviews through August 2022. Random-effects models were used to estimate the pooled relative risk (RR) for the highest versus lowest CRP categories. Linear and non-linear trend analyses were conducted to explore the dose-response associations between CRP and CRC risk. Twenty-three articles including 780,985 participants and 11,289 cancer cases met the selection criteria. The overall result demonstrated a remarkable association between elevated CRP levels and CRC risk (RR, 1.259; 95% CI, 1.060-1.457), but not in dose-response analysis (RR, 1.002 (95% CI, 0.964-1.041) per natural log unit change in CRP). Subgroup analyses indicated a significant difference when grouped by study location, the length of follow-up, and gender composition. No evidence of publication bias was observed. The predictive role of CRP in CRC incidence is limited to colon cancer and a period of 10years after the initial discovery of CRP elevation. The result did not support the etiological role of CRP in CRC and the inclusion of CRP into the CRC risk prediction model.

Abstract 6013: DNA methylation-based inflammation score is associated with hepatocellular carcinoma among people living with HIV

Abstract Background: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. In countries with high human immunodeficiency virus (HIV) prevalence, such as Nigeria, HIV-associated HCC causes a great health burden due to its early onset, late diagnosis, and poorer prognosis. HIV infection is involved in inflammation of the liver, which may determine an increased risk of hepatocyte neoplastic transformation. Inflammation-related DNA methylation signatures obtained in liquid biopsy, such as circulating cell-free DNA (ccfDNA) extracted from serum/plasma are promising minimally-invasive biomarkers that may inform HCC among people living with HIV. Methods: A total of 289 Nigerian participants with information on ccfDNA and other covariates were included. Participants were classified into three groups by their HCC/HIV status: 1) HCC+/HIV+ (n=28); 2) HCC-/HIV+ (n=185); and 3) HCC+/HIV- (n=76). We constructed ccfDNA methylation inflammation scores using 49 CpGs previously linked to circulating C-reactive protein (CRP) concentrations, and higher scores represented elevated CRP concentrations with lower methylation levels. To compare the ccfDNA methylation inflammation score across the groups, we performed multivariable logistic regression analyses adjusting for age, sex, alcohol consumption, smoking status, body mass index, study sites, and technical variables. Results: Participants with HCC+/HIV+ presented the highest ccfDNA methylation inflammation scores (mean=-0.03, standard deviation [SD] =0.01). Participants with HCC-/HIV+ presented the lowest scores (mean=-0.05, SD=0.01). In the multivariable logistic regressions, one SD increase of inflammation score was associated with 2.5 times higher odds of having HCC among HIV-infected participants (HCC+/HIV+ vs. HCC+/HIV-; OR=2.56, 95% CI=1.39-4.73, P=0.002). No evidence was found for the association between the inflammation score and HIV status among HCC patients (HCC+/HIV+ vs. HCC+/HIV-; OR=1.00, 95% CI=0.59-1.70, P=0.991). In the secondary analysis comparing HCC+ vs. HCC- adjusting for HIV status, one SD increase of inflammation score was associated with 3.2 times higher odds of having HCC (OR=3.22, 95% CI=1.39-7.46, P=0.006). Conclusions: We observed that ccfDNA methylation inflammation score is associated with HCC status among people with HIV. Our findings suggest that ccfDNA methylation-based inflammatory profiles may serve as a potential biomarker for early detection and risk stratification of HCC in resource-constrained countries with a high prevalence of HIV. Citation Format: Kyeezu Kim, Yinan Zheng, Claudia Hawkins, Edith Okeke, Olufunmilayo Lesi, Yishu Qu, Lewis R. Roberts, Demirkan Gursel, Fatimah B. Abdulkareem, Alani Akanmu, Godwin Imade, Jian-Jun Wei, Masha Kocherginsky, Kwang-Youn Kim, Wasiu L. Adeyemo, Firas Wehbe, Chad J. Achenbach, Atiene Sagay, Folasade T. Ogunsola, Robert L. Murphy, Lifang Hou. DNA methylation-based inflammation score is associated with hepatocellular carcinoma among people living with HIV. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6013.

Markers of inflammation in invasive treatment of coloractal cancer liver metastases

Background. In 25–30% of patients with colorectal cancer (CRC) who have no visible signs of metastasis at the time of surgery, metastases are detected within 5 years. Among the options for local treatment of metastatic liver lesions in patients with CRC, various resection options and minimally invasive methods, in particular radiofrequency ablation (RFA), occupy a prominent place. The inflammatory response caused by surgery is a factor that can negatively affect the course of tumor disease. The inflammatory responses of the body, as well as markers for their evaluation and prognosis in the treatment of CRC metastases, have not yet been sufficiently studied. Purpose – to study the dynamics of inflammatory markers in the invasive treatment of colorectal cancer liver metastases to select the most informative markers for assessing and predicting the degree of inflammatory response. Materials and methods. Clinical and laboratory examination was carried out in 18 patients with CRC during the treatment of metastases in the liver, adenocarcinoma was determined in all patients during histological examination. The examination was carried out in three stages: the day before RFA or resection, on days 3 and 14 after the intervention. Serum levels of insulin and IL-6 were measured using an enzyme-linked immunosorbent assay, and levels of C-reactive protein and ferritin were determined using an automatic biochemical analyser. Results and discussion. Markers of inflammation in patients with CRC with liver metastases after invasive intervention were identified. A significant increase in the levels of circulating C-reactive protein (CRP), IL-6 and ferritin was detected along with an increase in the insulin resistance index (HOMA-IR) on day 3 after RFA and resection. The increase in IL-6 was 2-fold higher and the HOMA-IR index was 1.5-fold higher after resection compared with RFA. Patients after RFA showed an approach of indicators to baseline values on day 14 of the study, while CRP, ferritin, IL-6 and insulin levels in patients after resection decreased by only 20–30% at the same time same period. This is consistent with other studies. In particular, elevated CRP levels are considered as a risk factor for the appearance and progression of CRC.There is also evidence that in patients with operable CRC, preoperative IL-6 levels affect the risk of recurrence. Strong evidence suggests that ferritin is a key mediator of immune dysregulation through direct immunosuppressive and pro-inflammatory effects. The accumulated data from the literature and our own results suggest the role of CRP, IL-6 and ferritin in postoperative inflammatory states as mediators and biomarkers of the further course of CRС, since their appearance identifies patients with a high risk of mortality, and timely or preventive correction of the inflammatory response improves their survival. Conclusions. The results of the study show that the most informative markers of the level of inflammatory response after RFA or surgical resection are the levels of C-reactive protein, IL-6 and ferritin. Moderate inflammatory reaction is shown in the early stages after RFA and pronounced and longer-lasting reaction after surgical treatment. Prediction, assessment of the degree of inflammatory reaction and the feasibility of anti-inflammatory therapy in the early stages after intervention can be determined by the complex of immunological, haematological and biochemical markers studied by us.

The &lt;i&gt;CRP&lt;/i&gt; Gene’s Role in the Relations between Childhood Adversity and History of Suicide Attempts in Schizophrenia

Research suggests that, in contrast to circulating C-reactive protein (CRP), genetic variants conferring higher CRP levels have protective effects against schizophrenia and moderate influences of season of birth on the development of the disease. This study aimed to explore whether the CRP gene also moderates the relations between childhood adversity and clinical characteristics of schizophrenia. The relations between childhood adversity, genotypes at rs2794521within the CRP locus, syndromes measured as five factors and two negative subfactors of the Positive and Negative Syndrome Scale, and history of suicide attempts were analyzed in 921 schizophrenia patients using analyses of covariances, Pearson’s chi-squared test, and logistic regression. A significant effect of genotype on suicide attempts in patients exposed to childhood adversity was found. The result suggests a moderating role of genetic determinants of inflammation in translating early life psychological stress effects into risk of suicide attempts in schizophrenia.

Genetic association of circulating C-reactive protein levels with idiopathic pulmonary fibrosis: a two-sample Mendelian randomization study

BackgroundSeveral observational studies have found that idiopathic pulmonary fibrosis (IPF) is often accompanied by elevated circulating C-reactive protein (CRP) levels. However, the causal relationship between them remains to be determined. Therefore, our study aimed to explore the causal effect of circulating CRP levels on IPF risk by the two-sample Mendelian randomization (MR) analysis.MethodsWe analyzed the data from two genome-wide association studies (GWAS) of European ancestry, including circulating CRP levels (204,402 individuals) and IPF (1028 cases and 196,986 controls). We primarily used inverse variance weighted (IVW) to assess the causal effect of circulating CRP levels on IPF risk. MR-Egger regression and MR-PRESSO global test were used to determine pleiotropy. Heterogeneity was examined with Cochran's Q test. The leave-one-out analysis tested the robustness of the results.ResultsWe obtained 54 SNPs as instrumental variables (IVs) for circulating CRP levels, and these IVs had no significant horizontal pleiotropy, heterogeneity, or bias. MR analysis revealed a causal effect between elevated circulating CRP levels and increased risk of IPF (ORIVW = 1.446, 95% CI 1.128–1.854, P = 0.004).ConclusionsThe present study indicated that elevated circulating CRP levels could increase the risk of developing IPF in people of European ancestry.

The Effects of Almond Consumption on Inflammatory Biomarkers in Adults: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Conflicting findings have been reported regarding the effects of almond consumption on inflammatory markers. This study aimed to summarize the current literature to determine whether almonds can affect inflammatory markers. A systematic search was carried out in PubMed, Scopus, and ISI Web of Science up to March 2021. Randomized clinical trials that compared almond with no almond consumption were included. The outcomes of interest were changes in circulating C-reactive protein (CRP), IL-6, TNF-α, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) concentrations. The random-effects model was used to find the mean differences. In total, 18 trials with 847 participants were eligible for the current analysis. Participants' ages ranged from 26.3 to 69.6 y. Combining 16 studies, almond consumption significantly reduced serum concentrations of CRP [weighted mean difference (WMD): -0.25mg/L; 95% CI: -0.43, -0.06 mg/L; I2=0.0%; P-heterogeneity=0.633]. However, the beneficial effect of almond intake only occurred at doses <60g/d. Pooling 11 effect sizes, almond interventions significantly decreased circulating IL-6 concentrations (WMD: -0.11 pg/mL; 95% CI: -0.21, -0.01 pg/mL; I2=19.9%; P-heterogeneity=0.254). In subgroup analyses, effects on CRP and IL-6 were nonsignificant in unhealthy participants or those with obesity. In addition, almond consumption had no significant effect on TNF-α (WMD: -0.05 pg/mL; 95% CI: -0.11, 0.01 pg/mL; I2=0.0%; P-heterogeneity=0.893; n=6), ICAM-1 (WMD: 6.39ng/mL; 95% CI: -9.44, 22.22 ng/mL; I2=66.6%; P-heterogeneity=0.006; n=7), or VCAM-1 (WMD: -8.31ng/mL; 95% CI: -35.32, 18.71 ng/mL; I2=58.8%; P-heterogeneity=0.033; n=6). In conclusion, almond consumption beneficially affects CRP and IL-6 concentrations in adults. However, it has no beneficial effect on TNF-α, ICAM-1, or VCAM-1. More trials are needed to determine the effects of almonds on inflammation.

Greater central adiposity resulting from increased market integration is associated with elevated C-reactive protein levels in older women from the Republic of Vanuatu

Objective: We characterized the relationship between circulating C-reactive protein (CRP) levels and nine anthropometric measures of body fat to identify the best anthropometric predictors of CRP in Ni-Vanuatu women.&#x0D; Sample and Methods: Anthropometric data and blood spot samples were collected from sixty-four Ni-Vanuatu female participants (age 35-78 years) on five islands with varying degrees of market integration, cultural change, and obesity. CRP concentration was determined with a high-sensitivity ELISA (hsCRP) assay and then compared to nine different anthropometric measurements.&#x0D; Results: BMI was significantly correlated with CRP (p=0.047). Among the eight additional anthropometrics, the suprailiac skinfold (p=0.003) and waist-circumference (p=0.009) were better predictors of CRP than BMI. Moreover, our stepwise selection model indicated that the suprailiac skinfold explained ~14% of CRP level variance.&#x0D; Conclusions: The BMI-CRP correlation coefficient for Ni-Vanuatu women falls within the range of previously reported values for East Asian populations with whom they share genetic ancestry. However, the best anthropometric predictors of CRP levels were waist circumference and suprailiac skinfold thickness. These measures capture central adiposity and are more closely associated with elevated CRP level and cardiovascular disease risk than fat distributed elsewhere on the body. Ni-Vanuatu in urban settings with high market integration are at greater risk for obesity, which is associated with elevated CRP levels. However, because nearly all Ni-Vanuatu still retain horticultural knowledge and land ownership, consumption of processed, imported foods is largely determined by degree of market integration and personal choice. Therefore, health interventions focusing on sustainable traditional food practices are feasible.